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nail-ps	nail-ps	[ "LMX1B-Related Nail-Patella Syndrome", "Fong Syndrome", "LMX1B-Related Nail-Patella Syndrome", "LIM homeobox transcription factor 1-beta", "LMX1B", "Nail-Patella Syndrome" ]	Nail-Patella Syndrome	Elizabeth Sweeney, Julie E Hoover-Fong, Iain McIntosh	Summary Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage kidney disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population. The diagnosis of nail-patella syndrome is established in a proband with suggestive findings and/or a heterozygous pathogenic variant in Nail-patella syndrome is inherited in an autosomal dominant manner. Eighty-eight percent of individuals with NPS have an affected parent; 12% of affected individuals have a	## Diagnosis Formal clinical diagnostic criteria for nail-patella syndrome (NPS) have not been published, although iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis) are considered pathognomonic. Nail-patella syndrome (NPS) Nail changes (see Absent, hypoplastic, or dystrophic Ridged longitudinally or horizontally Pitted Discolored Separated into two halves by a longitudinal cleft or ridge of skin Thin or (less often) thickened Limited to triangular lunules (lunulae), a characteristic feature of NPS Abnormal and unstable patella Small, irregularly shaped or absent patella as assessed by palpation or radiographs Recurrent subluxation or dislocation of the patella by history and/or physical exam Limitation of extension, pronation, and supination at the elbow; cubitus valgus; and antecubital pterygia Absent or hypoplastic patella that may be malpositioned Note: Patella ossification centers appear on radiographs between ages three and six years. Dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle Iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis), which are considered pathognomonic of NPS (See The diagnosis of NPS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of nail-patella syndrome is broad, individuals with the distinctive findings described in Note: Pathogenic variants in an enhancer upstream of For an introduction to multigene panels click When the diagnosis of nail-patella syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click If targeted genetic testing or exome sequencing are not diagnostic, but NPS is clinically suspected and a dominant inheritance pattern is observed, Molecular Genetic Testing Used in Nail-Patella Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Proportion of affected individuals with pathogenic variants identified by sequence analysis of exons 2-6 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Nail changes (see • Absent, hypoplastic, or dystrophic • Ridged longitudinally or horizontally • Pitted • Discolored • Separated into two halves by a longitudinal cleft or ridge of skin • Thin or (less often) thickened • Limited to triangular lunules (lunulae), a characteristic feature of NPS • Absent, hypoplastic, or dystrophic • Ridged longitudinally or horizontally • Pitted • Discolored • Separated into two halves by a longitudinal cleft or ridge of skin • Thin or (less often) thickened • Limited to triangular lunules (lunulae), a characteristic feature of NPS • Abnormal and unstable patella • Small, irregularly shaped or absent patella as assessed by palpation or radiographs • Recurrent subluxation or dislocation of the patella by history and/or physical exam • Small, irregularly shaped or absent patella as assessed by palpation or radiographs • Recurrent subluxation or dislocation of the patella by history and/or physical exam • Limitation of extension, pronation, and supination at the elbow; cubitus valgus; and antecubital pterygia • Absent, hypoplastic, or dystrophic • Ridged longitudinally or horizontally • Pitted • Discolored • Separated into two halves by a longitudinal cleft or ridge of skin • Thin or (less often) thickened • Limited to triangular lunules (lunulae), a characteristic feature of NPS • Small, irregularly shaped or absent patella as assessed by palpation or radiographs • Recurrent subluxation or dislocation of the patella by history and/or physical exam • Absent or hypoplastic patella that may be malpositioned • Note: Patella ossification centers appear on radiographs between ages three and six years. • Dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle • Iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis), which are considered pathognomonic of NPS (See ## Suggestive Findings Nail-patella syndrome (NPS) Nail changes (see Absent, hypoplastic, or dystrophic Ridged longitudinally or horizontally Pitted Discolored Separated into two halves by a longitudinal cleft or ridge of skin Thin or (less often) thickened Limited to triangular lunules (lunulae), a characteristic feature of NPS Abnormal and unstable patella Small, irregularly shaped or absent patella as assessed by palpation or radiographs Recurrent subluxation or dislocation of the patella by history and/or physical exam Limitation of extension, pronation, and supination at the elbow; cubitus valgus; and antecubital pterygia Absent or hypoplastic patella that may be malpositioned Note: Patella ossification centers appear on radiographs between ages three and six years. Dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle Iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis), which are considered pathognomonic of NPS (See • Nail changes (see • Absent, hypoplastic, or dystrophic • Ridged longitudinally or horizontally • Pitted • Discolored • Separated into two halves by a longitudinal cleft or ridge of skin • Thin or (less often) thickened • Limited to triangular lunules (lunulae), a characteristic feature of NPS • Absent, hypoplastic, or dystrophic • Ridged longitudinally or horizontally • Pitted • Discolored • Separated into two halves by a longitudinal cleft or ridge of skin • Thin or (less often) thickened • Limited to triangular lunules (lunulae), a characteristic feature of NPS • Abnormal and unstable patella • Small, irregularly shaped or absent patella as assessed by palpation or radiographs • Recurrent subluxation or dislocation of the patella by history and/or physical exam • Small, irregularly shaped or absent patella as assessed by palpation or radiographs • Recurrent subluxation or dislocation of the patella by history and/or physical exam • Limitation of extension, pronation, and supination at the elbow; cubitus valgus; and antecubital pterygia • Absent, hypoplastic, or dystrophic • Ridged longitudinally or horizontally • Pitted • Discolored • Separated into two halves by a longitudinal cleft or ridge of skin • Thin or (less often) thickened • Limited to triangular lunules (lunulae), a characteristic feature of NPS • Small, irregularly shaped or absent patella as assessed by palpation or radiographs • Recurrent subluxation or dislocation of the patella by history and/or physical exam • Absent or hypoplastic patella that may be malpositioned • Note: Patella ossification centers appear on radiographs between ages three and six years. • Dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle • Iliac horns (bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis), which are considered pathognomonic of NPS (See ## Establishing the Diagnosis The diagnosis of NPS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of nail-patella syndrome is broad, individuals with the distinctive findings described in Note: Pathogenic variants in an enhancer upstream of For an introduction to multigene panels click When the diagnosis of nail-patella syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click If targeted genetic testing or exome sequencing are not diagnostic, but NPS is clinically suspected and a dominant inheritance pattern is observed, Molecular Genetic Testing Used in Nail-Patella Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Proportion of affected individuals with pathogenic variants identified by sequence analysis of exons 2-6 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 Note: Pathogenic variants in an enhancer upstream of For an introduction to multigene panels click ## Option 2 When the diagnosis of nail-patella syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click ## Additional Testing Considerations for NPS If targeted genetic testing or exome sequencing are not diagnostic, but NPS is clinically suspected and a dominant inheritance pattern is observed, Molecular Genetic Testing Used in Nail-Patella Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Proportion of affected individuals with pathogenic variants identified by sequence analysis of exons 2-6 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics The classic clinical tetrad of nail-patella syndrome (NPS) involves changes in the nails, knees, and elbows and the presence of iliac horns (see To date, more than 170 pathogenic variants in Select Features of Nail-Patella Syndrome NPS = nail-patella syndrome Nail changes may be observed at birth and are most often bilateral and symmetric. The thumbnails are the most severely affected; the severity of the nail changes tends to decrease from the index finger toward the little finger. Each individual nail is usually more severely affected on its ulnar side. Dysplasia of the toenails is usually less marked and less frequent than that of the fingernails; if the toenails are involved, it is often the fifth toenail that is affected. The gradient of severity is the same as seen in the nails; therefore, the index fingers are the most affected. Hyperextension of the proximal interphalangeal (PIP) joints with flexion of the DIP joints (resulting in "swan-necking") and fifth-finger clinodactyly may also be seen. Patellae: Findings may be asymmetric. The patellae may be small, irregularly shaped, or absent. The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. Flexion contractures of the knees may occur as a result of tight hamstring muscles. Osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament may also occur. Early degenerative arthritis is common. Limitation of extension, pronation, and supination at the elbow Cubitus valgus Antecubital pterygia Affected individuals may experience dislocation of the radial head, usually posteriorly. Elbow involvement may be asymmetric. Pelvic radiograph is usually necessary for their detection ( Although large horns may be palpable, they are typically asymptomatic. Iliac horns may be seen on third-trimester ultrasound scanning [ In children, iliac horns may have an epiphysis at the apex. Talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, and hyperdorsiflexion of the foot may occur. Tight Achilles tendons are common, contributing to talipes equinovarus and to toe-walking. Pes planus is common. Because of limitations of phenotype search terms associated with established gene variants, By definition, arthrogryposis refers to multiple congenital, usually non-progressive joint contractures involving more than one joint; therefore, many people with NPS may be considered to have arthrogryposis (suggested by In particular, muscle mass in the upper arms and upper legs tends to be decreased. The tendency to be very lean is most evident in adolescents and young adults and becomes less apparent after middle age. Increased lumbar lordosis may make the buttocks appear prominent. The high forehead and hairline, particularly at the temples, resembles a receding male pattern hairline when seen in women. Renal involvement is present in 30%-50% of individuals with NPS. Variable rates of end-stage kidney disease (ESKD) have been described as high as 15% by The first sign of renal involvement is usually proteinuria, with or without hematuria. Proteinuria may present at any age from birth onwards and may be intermittent. Renal problems may present during (or be exacerbated by) pregnancy. Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ Nephritis may also occur in NPS. Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in individuals with NPS and include irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled "moth-eaten" appearance, and the presence of collagen-like fibers within the basement membrane and the mesangial matrix. Primary open-angle glaucoma and ocular hypertension occur at increased frequency in NPS and at a younger age than in the general population [ Congenital and normal-tension glaucoma have also been reported in individuals with NPS [ Iris pigmentary changes (termed Lester's sign) consisting of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris are seen frequently. Rarely, these symptoms may be secondary to local orthopedic problems or neurologic compromise from the spine or cervical ribs. In most cases, the paresthesia follows a glove and stocking pattern rather than the distribution of a particular dermatome or peripheral nerve. Epilepsy was reported in 6% of affected individuals in one large study [ The majority (~80%) of pathogenic variants in Nail-patella syndrome is the most accepted term but has the disadvantage of implying that nail and patellar dysplasia are the most important features. Hereditary onycho-osteodysplasia (HOOD) may be more accurate, but is rarely used. Perhaps hereditary onycho-osteodysplasia with nephropathy and glaucoma would be the best term. In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ The terms Fong's disease and Turner syndrome have also been used. Captain EE Fong described the presence of unusual horn-like anomalies on the posterior aspect of the iliac bones in a woman undergoing an intravenous pyelogram. Fong published the description in 1946 and although he did not associate the anomaly with nail-patella syndrome, his name was connected to this condition [ Turner* and Keiser published earlier descriptions of the iliac horns in individuals with nail-patella syndrome in 1933 and 1939, respectively. * Note: Referring to JW Turner and not HH Turner, who described the phenotype associated with a 45,X karyotype The prevalence of NPS has been roughly estimated at 1:50,000 but may be higher because of undiagnosed individuals with a mild phenotype. • Nail changes may be observed at birth and are most often bilateral and symmetric. • The thumbnails are the most severely affected; the severity of the nail changes tends to decrease from the index finger toward the little finger. • Each individual nail is usually more severely affected on its ulnar side. • Dysplasia of the toenails is usually less marked and less frequent than that of the fingernails; if the toenails are involved, it is often the fifth toenail that is affected. • The gradient of severity is the same as seen in the nails; therefore, the index fingers are the most affected. • Hyperextension of the proximal interphalangeal (PIP) joints with flexion of the DIP joints (resulting in "swan-necking") and fifth-finger clinodactyly may also be seen. • Patellae: • Findings may be asymmetric. • The patellae may be small, irregularly shaped, or absent. • The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. • There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. • These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. • Findings may be asymmetric. • The patellae may be small, irregularly shaped, or absent. • The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. • There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. • These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. • Flexion contractures of the knees may occur as a result of tight hamstring muscles. • Osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament may also occur. • Early degenerative arthritis is common. • Findings may be asymmetric. • The patellae may be small, irregularly shaped, or absent. • The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. • There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. • These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. • Limitation of extension, pronation, and supination at the elbow • Cubitus valgus • Antecubital pterygia • Pelvic radiograph is usually necessary for their detection ( • Although large horns may be palpable, they are typically asymptomatic. • Iliac horns may be seen on third-trimester ultrasound scanning [ • In children, iliac horns may have an epiphysis at the apex. • Talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, and hyperdorsiflexion of the foot may occur. • Tight Achilles tendons are common, contributing to talipes equinovarus and to toe-walking. • Pes planus is common. • Because of limitations of phenotype search terms associated with established gene variants, • By definition, arthrogryposis refers to multiple congenital, usually non-progressive joint contractures involving more than one joint; therefore, many people with NPS may be considered to have arthrogryposis (suggested by • In particular, muscle mass in the upper arms and upper legs tends to be decreased. • The tendency to be very lean is most evident in adolescents and young adults and becomes less apparent after middle age. • Increased lumbar lordosis may make the buttocks appear prominent. • The high forehead and hairline, particularly at the temples, resembles a receding male pattern hairline when seen in women. • Renal involvement is present in 30%-50% of individuals with NPS. Variable rates of end-stage kidney disease (ESKD) have been described as high as 15% by • The first sign of renal involvement is usually proteinuria, with or without hematuria. • Proteinuria may present at any age from birth onwards and may be intermittent. • Renal problems may present during (or be exacerbated by) pregnancy. • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ • Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ • Nephritis may also occur in NPS. • The first sign of renal involvement is usually proteinuria, with or without hematuria. • Proteinuria may present at any age from birth onwards and may be intermittent. • Renal problems may present during (or be exacerbated by) pregnancy. • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ • Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ • Nephritis may also occur in NPS. • Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in individuals with NPS and include irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled "moth-eaten" appearance, and the presence of collagen-like fibers within the basement membrane and the mesangial matrix. • The first sign of renal involvement is usually proteinuria, with or without hematuria. • Proteinuria may present at any age from birth onwards and may be intermittent. • Renal problems may present during (or be exacerbated by) pregnancy. • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ • Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ • Nephritis may also occur in NPS. • Primary open-angle glaucoma and ocular hypertension occur at increased frequency in NPS and at a younger age than in the general population [ • Congenital and normal-tension glaucoma have also been reported in individuals with NPS [ • Iris pigmentary changes (termed Lester's sign) consisting of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris are seen frequently. • Rarely, these symptoms may be secondary to local orthopedic problems or neurologic compromise from the spine or cervical ribs. • In most cases, the paresthesia follows a glove and stocking pattern rather than the distribution of a particular dermatome or peripheral nerve. • Captain EE Fong described the presence of unusual horn-like anomalies on the posterior aspect of the iliac bones in a woman undergoing an intravenous pyelogram. Fong published the description in 1946 and although he did not associate the anomaly with nail-patella syndrome, his name was connected to this condition [ • Turner* and Keiser published earlier descriptions of the iliac horns in individuals with nail-patella syndrome in 1933 and 1939, respectively. • * Note: Referring to JW Turner and not HH Turner, who described the phenotype associated with a 45,X karyotype ## Clinical Description The classic clinical tetrad of nail-patella syndrome (NPS) involves changes in the nails, knees, and elbows and the presence of iliac horns (see To date, more than 170 pathogenic variants in Select Features of Nail-Patella Syndrome NPS = nail-patella syndrome Nail changes may be observed at birth and are most often bilateral and symmetric. The thumbnails are the most severely affected; the severity of the nail changes tends to decrease from the index finger toward the little finger. Each individual nail is usually more severely affected on its ulnar side. Dysplasia of the toenails is usually less marked and less frequent than that of the fingernails; if the toenails are involved, it is often the fifth toenail that is affected. The gradient of severity is the same as seen in the nails; therefore, the index fingers are the most affected. Hyperextension of the proximal interphalangeal (PIP) joints with flexion of the DIP joints (resulting in "swan-necking") and fifth-finger clinodactyly may also be seen. Patellae: Findings may be asymmetric. The patellae may be small, irregularly shaped, or absent. The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. Flexion contractures of the knees may occur as a result of tight hamstring muscles. Osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament may also occur. Early degenerative arthritis is common. Limitation of extension, pronation, and supination at the elbow Cubitus valgus Antecubital pterygia Affected individuals may experience dislocation of the radial head, usually posteriorly. Elbow involvement may be asymmetric. Pelvic radiograph is usually necessary for their detection ( Although large horns may be palpable, they are typically asymptomatic. Iliac horns may be seen on third-trimester ultrasound scanning [ In children, iliac horns may have an epiphysis at the apex. Talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, and hyperdorsiflexion of the foot may occur. Tight Achilles tendons are common, contributing to talipes equinovarus and to toe-walking. Pes planus is common. Because of limitations of phenotype search terms associated with established gene variants, By definition, arthrogryposis refers to multiple congenital, usually non-progressive joint contractures involving more than one joint; therefore, many people with NPS may be considered to have arthrogryposis (suggested by In particular, muscle mass in the upper arms and upper legs tends to be decreased. The tendency to be very lean is most evident in adolescents and young adults and becomes less apparent after middle age. Increased lumbar lordosis may make the buttocks appear prominent. The high forehead and hairline, particularly at the temples, resembles a receding male pattern hairline when seen in women. Renal involvement is present in 30%-50% of individuals with NPS. Variable rates of end-stage kidney disease (ESKD) have been described as high as 15% by The first sign of renal involvement is usually proteinuria, with or without hematuria. Proteinuria may present at any age from birth onwards and may be intermittent. Renal problems may present during (or be exacerbated by) pregnancy. Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ Nephritis may also occur in NPS. Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in individuals with NPS and include irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled "moth-eaten" appearance, and the presence of collagen-like fibers within the basement membrane and the mesangial matrix. Primary open-angle glaucoma and ocular hypertension occur at increased frequency in NPS and at a younger age than in the general population [ Congenital and normal-tension glaucoma have also been reported in individuals with NPS [ Iris pigmentary changes (termed Lester's sign) consisting of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris are seen frequently. Rarely, these symptoms may be secondary to local orthopedic problems or neurologic compromise from the spine or cervical ribs. In most cases, the paresthesia follows a glove and stocking pattern rather than the distribution of a particular dermatome or peripheral nerve. Epilepsy was reported in 6% of affected individuals in one large study [ • Nail changes may be observed at birth and are most often bilateral and symmetric. • The thumbnails are the most severely affected; the severity of the nail changes tends to decrease from the index finger toward the little finger. • Each individual nail is usually more severely affected on its ulnar side. • Dysplasia of the toenails is usually less marked and less frequent than that of the fingernails; if the toenails are involved, it is often the fifth toenail that is affected. • The gradient of severity is the same as seen in the nails; therefore, the index fingers are the most affected. • Hyperextension of the proximal interphalangeal (PIP) joints with flexion of the DIP joints (resulting in "swan-necking") and fifth-finger clinodactyly may also be seen. • Patellae: • Findings may be asymmetric. • The patellae may be small, irregularly shaped, or absent. • The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. • There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. • These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. • Findings may be asymmetric. • The patellae may be small, irregularly shaped, or absent. • The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. • There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. • These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. • Flexion contractures of the knees may occur as a result of tight hamstring muscles. • Osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament may also occur. • Early degenerative arthritis is common. • Findings may be asymmetric. • The patellae may be small, irregularly shaped, or absent. • The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. • There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. • These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. • Limitation of extension, pronation, and supination at the elbow • Cubitus valgus • Antecubital pterygia • Pelvic radiograph is usually necessary for their detection ( • Although large horns may be palpable, they are typically asymptomatic. • Iliac horns may be seen on third-trimester ultrasound scanning [ • In children, iliac horns may have an epiphysis at the apex. • Talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, and hyperdorsiflexion of the foot may occur. • Tight Achilles tendons are common, contributing to talipes equinovarus and to toe-walking. • Pes planus is common. • Because of limitations of phenotype search terms associated with established gene variants, • By definition, arthrogryposis refers to multiple congenital, usually non-progressive joint contractures involving more than one joint; therefore, many people with NPS may be considered to have arthrogryposis (suggested by • In particular, muscle mass in the upper arms and upper legs tends to be decreased. • The tendency to be very lean is most evident in adolescents and young adults and becomes less apparent after middle age. • Increased lumbar lordosis may make the buttocks appear prominent. • The high forehead and hairline, particularly at the temples, resembles a receding male pattern hairline when seen in women. • Renal involvement is present in 30%-50% of individuals with NPS. Variable rates of end-stage kidney disease (ESKD) have been described as high as 15% by • The first sign of renal involvement is usually proteinuria, with or without hematuria. • Proteinuria may present at any age from birth onwards and may be intermittent. • Renal problems may present during (or be exacerbated by) pregnancy. • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ • Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ • Nephritis may also occur in NPS. • The first sign of renal involvement is usually proteinuria, with or without hematuria. • Proteinuria may present at any age from birth onwards and may be intermittent. • Renal problems may present during (or be exacerbated by) pregnancy. • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ • Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ • Nephritis may also occur in NPS. • Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in individuals with NPS and include irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled "moth-eaten" appearance, and the presence of collagen-like fibers within the basement membrane and the mesangial matrix. • The first sign of renal involvement is usually proteinuria, with or without hematuria. • Proteinuria may present at any age from birth onwards and may be intermittent. • Renal problems may present during (or be exacerbated by) pregnancy. • Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESKD. • Steroids may not be effective in the treatment of proteinuria in individuals with NPS [ • Progression to kidney failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified but the presence and severity of proteinuria appears to be predictive of progression [ • Nephritis may also occur in NPS. • Primary open-angle glaucoma and ocular hypertension occur at increased frequency in NPS and at a younger age than in the general population [ • Congenital and normal-tension glaucoma have also been reported in individuals with NPS [ • Iris pigmentary changes (termed Lester's sign) consisting of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris are seen frequently. • Rarely, these symptoms may be secondary to local orthopedic problems or neurologic compromise from the spine or cervical ribs. • In most cases, the paresthesia follows a glove and stocking pattern rather than the distribution of a particular dermatome or peripheral nerve. ## Genotype-Phenotype Correlations The majority (~80%) of pathogenic variants in ## Nomenclature Nail-patella syndrome is the most accepted term but has the disadvantage of implying that nail and patellar dysplasia are the most important features. Hereditary onycho-osteodysplasia (HOOD) may be more accurate, but is rarely used. Perhaps hereditary onycho-osteodysplasia with nephropathy and glaucoma would be the best term. In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ The terms Fong's disease and Turner syndrome have also been used. Captain EE Fong described the presence of unusual horn-like anomalies on the posterior aspect of the iliac bones in a woman undergoing an intravenous pyelogram. Fong published the description in 1946 and although he did not associate the anomaly with nail-patella syndrome, his name was connected to this condition [ Turner* and Keiser published earlier descriptions of the iliac horns in individuals with nail-patella syndrome in 1933 and 1939, respectively. * Note: Referring to JW Turner and not HH Turner, who described the phenotype associated with a 45,X karyotype • Captain EE Fong described the presence of unusual horn-like anomalies on the posterior aspect of the iliac bones in a woman undergoing an intravenous pyelogram. Fong published the description in 1946 and although he did not associate the anomaly with nail-patella syndrome, his name was connected to this condition [ • Turner* and Keiser published earlier descriptions of the iliac horns in individuals with nail-patella syndrome in 1933 and 1939, respectively. • * Note: Referring to JW Turner and not HH Turner, who described the phenotype associated with a 45,X karyotype ## Prevalence The prevalence of NPS has been roughly estimated at 1:50,000 but may be higher because of undiagnosed individuals with a mild phenotype. ## Genetically Related (Allelic) Disorders Pathogenic variants involving the same codon in ## Differential Diagnosis Genes of Interest in the Differential Diagnoses of Nail-Patella Syndrome Absence or hypoplasia of nails & patellae Elbow dislocation Nail hypoplasia, usually affecting the little finger nails Facial dysmorphism Absent patellae Dislocation of radial head Microtia Markedly short stature Delayed bone age Characteristic facies Absent patellae Renal anomalies Flexion deformities of knees & hips Clubfoot Hypoplasia of the ischia & iliac bones Genital anomalies Facial dysmorphism Microcephaly Intellectual disability Structural (multicystic kidneys or hydronephrosis) (vs functional) abnormalities Renal manifestations Radial defects Absent or hypoplastic patellae Dislocated joints Cleft palate Facial dysmorphism Short stature Radial defects incl absent or hypoplastic thumbs & radii Long thumbs & big toes, often w/triphalangy Other fingers & toes short because of absent or hypoplastic distal phalanx Bilateral ptosis Short broad nose w/broad nasal tip & large nostrils Structural renal tract abnormalities Cataracts Optic atrophy Dandy-Walker malformation Seizures Small or absent patellae Recurrent patella dislocations Pelvic anomalies Defective ossification at schiopubic junction Ischial hypoplasia Infra-acetabular "axe-cut" notch No nail or elbow changes, renal involvement, or ocular involvement AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NPS = nail-patella syndrome See Chromosome Disorder and Hereditary Disorders of Unknown Genetic Cause in the Differential Diagnoses of Nail-Patella Syndrome Characteristic facial appearance Short stature Mild intellectual impairment Absent or hypoplastic patellae Limited elbow supination Abnormal nails Significant learning difficulties Variable facial dysmorphism Camptodactyly & progressive joint restriction, usually of fingers & toes NPS = nail-patella syndrome • Absence or hypoplasia of nails & patellae • Elbow dislocation • Nail hypoplasia, usually affecting the little finger nails • Facial dysmorphism • Absent patellae • Dislocation of radial head • Microtia • Markedly short stature • Delayed bone age • Characteristic facies • Absent patellae • Renal anomalies • Flexion deformities of knees & hips • Clubfoot • Hypoplasia of the ischia & iliac bones • Genital anomalies • Facial dysmorphism • Microcephaly • Intellectual disability • Structural (multicystic kidneys or hydronephrosis) (vs functional) abnormalities • Renal manifestations • Radial defects • Absent or hypoplastic patellae • Dislocated joints • Cleft palate • Facial dysmorphism • Short stature • Radial defects incl absent or hypoplastic thumbs & radii • Long thumbs & big toes, often w/triphalangy • Other fingers & toes short because of absent or hypoplastic distal phalanx • Bilateral ptosis • Short broad nose w/broad nasal tip & large nostrils • Structural renal tract abnormalities • Cataracts • Optic atrophy • Dandy-Walker malformation • Seizures • Small or absent patellae • Recurrent patella dislocations • Pelvic anomalies • Defective ossification at schiopubic junction • Ischial hypoplasia • Infra-acetabular "axe-cut" notch • No nail or elbow changes, renal involvement, or ocular involvement • Characteristic facial appearance • Short stature • Mild intellectual impairment • Absent or hypoplastic patellae • Limited elbow supination • Abnormal nails • Significant learning difficulties • Variable facial dysmorphism • Camptodactyly & progressive joint restriction, usually of fingers & toes ## Management To establish the extent of disease and needs in an individual diagnosed with nail-patella syndrome (NPS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Nail-Patella Syndrome If present, referral to orthopedist Before surgery or intensive physiotherapy for orthopedic complaints; investigation via MRI for possible bone/soft tissue anatomic abnormalities Measurement of blood pressure Urinalysis & urine albumin-to-creatinine ratio To detect glaucoma, incl normal-pressure glaucoma To be completed as soon as child can cooperate w/exam Referral to ophthalmologist Community or Social work involvement for support. BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance DXA norms are readily available in most clinical settings for adults and may be pursued in all young adults (age >18 years) at least once. Pediatric DXA norms are often less readily available, but may be obtained via local pediatric endocrinologist or machine manufacturer. No formal recommendations for DXA scanning of pediatric patients exist at this time, but DXA should be pursued if fractures or unexplained skeletal pain occurs with additional clinical evaluation. This test is a more sensitive measure of kidney disease than urinalysis because it corrects for urine concentration. Any infant or young child found to have an abnormal or absent red reflex on eye examination by a primary care physician should be referred to an ophthalmologist immediately. Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Nail-Patella Syndrome ACE inhibitors are useful in slowing progression of proteinuria, but their use should be monitored carefully in children. Steroids may not be effective in treatment of proteinuria. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; ESKD = end-stage kidney disease Including pain, instability, locking, clicking, dislocation, decreased range of motion (ROM) in the absence of anatomic abnormalities that limit ROM As a result of anatomic differences that affect joint function (e.g., contractures, pterygia) Resulting in osteoporosis and/or frequent fractures Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Surveillance for Individuals with Nail-Patella Syndrome Urinalysis Urine albumin-to-creatinine ratio on a first-morning urine DXA = dual-energy x-ray absorptiometry Referral to a nephrologist if any abnormalities are detected From the time that a child is compliant with the examination Age-adjust results for child. Frequency in adults is based on clinical symptoms, abnormalities detected on previous evaluations, and standard practice in peri- and postmenopausal females and older males. Chronic use of nonsteroidal anti-inflammatory drugs should be avoided because of their detrimental effect on kidney function. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures, particularly relating to ophthalmologic and renal manifestations. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Monitoring renal findings (i.e., blood pressure, urinalysis, and urine albumin-to-creatinine ratio on a first-morning urine) and screening for glaucoma if the pathogenic variant in the family is not known. See Renal problems may present during (or be exacerbated by) pregnancy. In one study 29% of pregnant women with NPS developed preeclampsia [ See Search • If present, referral to orthopedist • Before surgery or intensive physiotherapy for orthopedic complaints; investigation via MRI for possible bone/soft tissue anatomic abnormalities • Measurement of blood pressure • Urinalysis & urine albumin-to-creatinine ratio • To detect glaucoma, incl normal-pressure glaucoma • To be completed as soon as child can cooperate w/exam • Referral to ophthalmologist • Community or • Social work involvement for support. • ACE inhibitors are useful in slowing progression of proteinuria, but their use should be monitored carefully in children. • Steroids may not be effective in treatment of proteinuria. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Urinalysis • Urine albumin-to-creatinine ratio on a first-morning urine • Molecular genetic testing if the pathogenic variant in the family is known; • Monitoring renal findings (i.e., blood pressure, urinalysis, and urine albumin-to-creatinine ratio on a first-morning urine) and screening for glaucoma if the pathogenic variant in the family is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with nail-patella syndrome (NPS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Nail-Patella Syndrome If present, referral to orthopedist Before surgery or intensive physiotherapy for orthopedic complaints; investigation via MRI for possible bone/soft tissue anatomic abnormalities Measurement of blood pressure Urinalysis & urine albumin-to-creatinine ratio To detect glaucoma, incl normal-pressure glaucoma To be completed as soon as child can cooperate w/exam Referral to ophthalmologist Community or Social work involvement for support. BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance DXA norms are readily available in most clinical settings for adults and may be pursued in all young adults (age >18 years) at least once. Pediatric DXA norms are often less readily available, but may be obtained via local pediatric endocrinologist or machine manufacturer. No formal recommendations for DXA scanning of pediatric patients exist at this time, but DXA should be pursued if fractures or unexplained skeletal pain occurs with additional clinical evaluation. This test is a more sensitive measure of kidney disease than urinalysis because it corrects for urine concentration. Any infant or young child found to have an abnormal or absent red reflex on eye examination by a primary care physician should be referred to an ophthalmologist immediately. Medical geneticist, certified genetic counselor, certified advanced genetic nurse • If present, referral to orthopedist • Before surgery or intensive physiotherapy for orthopedic complaints; investigation via MRI for possible bone/soft tissue anatomic abnormalities • Measurement of blood pressure • Urinalysis & urine albumin-to-creatinine ratio • To detect glaucoma, incl normal-pressure glaucoma • To be completed as soon as child can cooperate w/exam • Referral to ophthalmologist • Community or • Social work involvement for support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Nail-Patella Syndrome ACE inhibitors are useful in slowing progression of proteinuria, but their use should be monitored carefully in children. Steroids may not be effective in treatment of proteinuria. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; ESKD = end-stage kidney disease Including pain, instability, locking, clicking, dislocation, decreased range of motion (ROM) in the absence of anatomic abnormalities that limit ROM As a result of anatomic differences that affect joint function (e.g., contractures, pterygia) Resulting in osteoporosis and/or frequent fractures Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • ACE inhibitors are useful in slowing progression of proteinuria, but their use should be monitored carefully in children. • Steroids may not be effective in treatment of proteinuria. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Surveillance Recommended Surveillance for Individuals with Nail-Patella Syndrome Urinalysis Urine albumin-to-creatinine ratio on a first-morning urine DXA = dual-energy x-ray absorptiometry Referral to a nephrologist if any abnormalities are detected From the time that a child is compliant with the examination Age-adjust results for child. Frequency in adults is based on clinical symptoms, abnormalities detected on previous evaluations, and standard practice in peri- and postmenopausal females and older males. • Urinalysis • Urine albumin-to-creatinine ratio on a first-morning urine ## Agents/Circumstances to Avoid Chronic use of nonsteroidal anti-inflammatory drugs should be avoided because of their detrimental effect on kidney function. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures, particularly relating to ophthalmologic and renal manifestations. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Monitoring renal findings (i.e., blood pressure, urinalysis, and urine albumin-to-creatinine ratio on a first-morning urine) and screening for glaucoma if the pathogenic variant in the family is not known. See • Molecular genetic testing if the pathogenic variant in the family is known; • Monitoring renal findings (i.e., blood pressure, urinalysis, and urine albumin-to-creatinine ratio on a first-morning urine) and screening for glaucoma if the pathogenic variant in the family is not known. ## Pregnancy Management Renal problems may present during (or be exacerbated by) pregnancy. In one study 29% of pregnant women with NPS developed preeclampsia [ See ## Therapies Under Investigation Search ## Genetic Counseling Nail-patella syndrome (NPS) is inherited in an autosomal dominant manner. Eighty-eight percent of individuals diagnosed with NPS have an affected parent [ Twelve percent of individuals diagnosed with NPS have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case) and has a known If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ The family history of some individuals diagnosed with NPS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. NPS is fully penetrant in heterozygous individuals; however, the range and severity of manifestations may be extremely variable among affected family members. If the proband has a known See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Eighty-eight percent of individuals diagnosed with NPS have an affected parent [ • Twelve percent of individuals diagnosed with NPS have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case) and has a known • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ • The family history of some individuals diagnosed with NPS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. NPS is fully penetrant in heterozygous individuals; however, the range and severity of manifestations may be extremely variable among affected family members. • If the proband has a known • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Nail-patella syndrome (NPS) is inherited in an autosomal dominant manner. ## Risk to Family Members Eighty-eight percent of individuals diagnosed with NPS have an affected parent [ Twelve percent of individuals diagnosed with NPS have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case) and has a known If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ The family history of some individuals diagnosed with NPS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. NPS is fully penetrant in heterozygous individuals; however, the range and severity of manifestations may be extremely variable among affected family members. If the proband has a known • Eighty-eight percent of individuals diagnosed with NPS have an affected parent [ • Twelve percent of individuals diagnosed with NPS have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case) and has a known • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ • The family history of some individuals diagnosed with NPS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Evidence of somatic and germline mosaicism has been reported in unaffected parents [ • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. NPS is fully penetrant in heterozygous individuals; however, the range and severity of manifestations may be extremely variable among affected family members. • If the proband has a known ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • ## Molecular Genetics Nail-Patella Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nail-Patella Syndrome ( Nail-patella syndrome is caused by pathogenic loss-of-function variants in The majority (~80%) of pathogenic variants in Pathogenic missense variants within the homeodomain reduce or eliminate DNA binding [ ## Molecular Pathogenesis Nail-patella syndrome is caused by pathogenic loss-of-function variants in The majority (~80%) of pathogenic variants in Pathogenic missense variants within the homeodomain reduce or eliminate DNA binding [ ## Chapter Notes The The authors would like to acknowledge the patients we have had the privilege to meet over the last decades through our clinical practice as well as patient support groups including 14 December 2023 (jhf) Revision: information regarding pathogenic variants in an enhancer upstream of 11 May 2023 (sw) Revision: " 15 October 2020 (ma) Comprehensive update posted live 13 November 2014 (me) Comprehensive update posted live 28 July 2009 (me) Comprehensive update posted live 26 July 2005 (me) Comprehensive update posted live 31 May 2003 (me) Review posted live 14 April 2003 (im) Original submission • 14 December 2023 (jhf) Revision: information regarding pathogenic variants in an enhancer upstream of • 11 May 2023 (sw) Revision: " • 15 October 2020 (ma) Comprehensive update posted live • 13 November 2014 (me) Comprehensive update posted live • 28 July 2009 (me) Comprehensive update posted live • 26 July 2005 (me) Comprehensive update posted live • 31 May 2003 (me) Review posted live • 14 April 2003 (im) Original submission ## Author Notes The ## Acknowledgments The authors would like to acknowledge the patients we have had the privilege to meet over the last decades through our clinical practice as well as patient support groups including ## Revision History 14 December 2023 (jhf) Revision: information regarding pathogenic variants in an enhancer upstream of 11 May 2023 (sw) Revision: " 15 October 2020 (ma) Comprehensive update posted live 13 November 2014 (me) Comprehensive update posted live 28 July 2009 (me) Comprehensive update posted live 26 July 2005 (me) Comprehensive update posted live 31 May 2003 (me) Review posted live 14 April 2003 (im) Original submission • 14 December 2023 (jhf) Revision: information regarding pathogenic variants in an enhancer upstream of • 11 May 2023 (sw) Revision: " • 15 October 2020 (ma) Comprehensive update posted live • 13 November 2014 (me) Comprehensive update posted live • 28 July 2009 (me) Comprehensive update posted live • 26 July 2005 (me) Comprehensive update posted live • 31 May 2003 (me) Review posted live • 14 April 2003 (im) Original submission ## References ## Literature Cited Typical presentation of thumb nails (a) and fingernails (b) in nail-patella syndrome. The arrow points to the index finger. Note decrease in severity of nail involvement from second to fifth finger and lack of creases over the distal interphalangeal joints. Iliac horns (yellow arrows) in an individual with nail-patella syndrome	[]	31/5/2003	15/10/2020	14/12/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
narp	narp	[ "mtDNA-Associated Leigh Syndrome Spectrum", "mtDNA-Associated Leigh Syndrome Spectrum", "ATP synthase F(0) complex subunit a", "Cytochrome c oxidase subunit 1", "Cytochrome c oxidase subunit 2", "Cytochrome c oxidase subunit 3", "NADH-ubiquinone oxidoreductase chain 1", "NADH-ubiquinone oxidoreductase chain 2", "NADH-ubiquinone oxidoreductase chain 3", "NADH-ubiquinone oxidoreductase chain 4", "NADH-ubiquinone oxidoreductase chain 5", "NADH-ubiquinone oxidoreductase chain 6", "Not applicable", "MT-ATP6", "MT-CO1", "MT-CO2", "MT-CO3", "MT-ND1", "MT-ND2", "MT-ND3", "MT-ND4", "MT-ND5", "MT-ND6", "MT-TI", "MT-TK", "MT-TL1", "MT-TV", "MT-TW", "Mitochondrial DNA-Associated Leigh Syndrome Spectrum" ]	Mitochondrial DNA-Associated Leigh Syndrome Spectrum	Megan Ball, David R Thorburn, Shamima Rahman	Summary Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation, which includes the overlapping phenotypes mtDNA-associated Leigh syndrome and mtDNA-associated Leigh-like syndrome. Mitochondrial DNA-LSS is characterized by onset of manifestations typically between ages three and 12 months, often following an intercurrent illness (usually viral) or metabolic challenge (vaccinations, surgery, prolonged fasting). Decompensation (often with elevated lactate levels in blood and/or cerebrospinal fluid) is typically associated with developmental delay and/or regression. Neurologic features include hypotonia, spasticity, seizures, movement disorders, cerebellar ataxia, and peripheral neuropathy. Brain stem dysfunction may manifest with respiratory symptoms, swallowing difficulties, ophthalmoparesis, and abnormalities in thermoregulation. Extraneurologic manifestations may include poor weight gain, cardiomyopathy, and conduction defects. Up to 50% of individuals die by age three years, most often from respiratory or cardiac failure. The diagnosis of mtDNA-LSS is established in a proband fulfilling clinical diagnostic criteria for LSS by identification of a heteroplasmic or homoplasmic pathogenic variant in one of the 15 mtDNA genes known to be involved in mtDNA-LSS. Mitochondrial DNA-LSS is transmitted by maternal inheritance. The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorder. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease), or a	## Diagnosis Diagnostic criteria for Leigh syndrome spectrum (LSS) have been published [ Progressive neurologic disease with developmental delay and neurodevelopmental regression Manifestations of brain stem and/or basal ganglia disease (e.g., respiratory abnormalities, nystagmus, ophthalmoparesis, optic atrophy, ataxia, and dystonia) Seizures Psychiatric disturbance Elevated blood lactate Elevation tends to be more marked in postprandial samples. Elevated cerebrospinal fluid (CSF) lactate Note: While elevated blood and/or CSF lactate is suggestive of a mitochondrial disorder, a normal lactate does not exclude mtDNA-LSS. Plasma amino acids may show increased alanine concentration, reflecting persistent hyperlactatemia. Decreased plasma citrulline concentration and/or elevated 3-hydroxy-isovalerylcarnitine (C5-OH) levels has been reported in individuals with Urine organic acid analysis results are often nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. Note: 3-methylglutaconic aciduria may be observed in some nuclear gene-encoded causes of LSS, notably 3- Characteristic findings include bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia on T Additional findings can include cerebral atrophy, bilateral hyperintense signal abnormality in the thalamus, cerebellum, cerebral white matter, and/or spinal cord on T Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) Note: Characteristic patterns of brain lesions have been described for specific causes of nuclear gene-encoded LSS. For example, specific brain lesions affecting the mammillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum appear to be characteristic of Since the advent of next-generation sequencing, muscle biopsy is performed less frequently (especially in the pediatric population), as obtaining a muscle biopsy is invasive and often requires general anesthesia, which carries a risk of metabolic decompensation. Muscle biopsy is now generally reserved for critically unwell individuals or (occasionally) for functional validation of genetic findings. Note: (1) Although muscle histopathology is only occasionally abnormal, when it is abnormal it can be as much of a contributor to diagnostic certainty as respiratory chain enzymes or molecular testing. (2) If muscle biopsy is obtained for respiratory chain enzyme studies, histopathology should also be performed. Note: (1) Skeletal muscle (vastus lateralis) is usually the tissue of choice for respiratory chain enzyme studies. (2) Skin fibroblasts can be used, but only about 50% of respiratory chain enzyme defects identified in skeletal muscle are also identified in skin fibroblasts. (3) Approximately 10%-20% of individuals with normal skeletal muscle respiratory chain enzyme analysis may have an enzyme defect detected in liver or cardiac muscle, particularly if those tissues are involved clinically [ The diagnosis of mtDNA-LSS Developmental regression Developmental delay Psychiatric features Elevated lactate in plasma and/or CSF MRS lactate peak (in absence of acute seizures) Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) Note: Historically, the diagnosis of LSS was achieved by demonstrating mitochondrial dysfunction through relevant tissue biopsy to inform a targeted molecular genetic approach. However, the introduction of comprehensive genomic sequencing has removed the need for tissue biopsy in most scenarios. Molecular genetic testing approaches for mtDNA-LSS can include Comprehensive genomic testing includes sequencing of mtDNA and nuclear DNA. Comprehensive genomic testing does not require a phenotype-driven hypothesis and may provide or suggest a diagnosis not previously considered (e.g., variant in a different gene[s] that results in a similar clinical presentation). Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see For an introduction to comprehensive genomic testing click Targeted analysis of common pathogenic variants may be considered if there is a high clinical suspicion based on clinical or biochemical findings or if comprehensive testing is not available (see Note: (1) Most mtDNA pathogenic variants associated with mtDNA-LSS are "heteroplasmic" (i.e., abnormal mtDNA coexists with wild type mtDNA) and for some pathogenic variants, the heteroplasmy level may vary among different tissues and may increase or decrease with age. (2) Mitochondrial DNA pathogenic variants may be lost from the leukocyte population with increasing age [ Molecular Genetics of Mitochondrial DNA-Associated Leigh Syndrome Spectrum mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum Genes are listed from most frequent to least frequent genetic cause of mtDNA-LSS and then alphabetically. See These estimates are based on several cohorts of individuals with mtDNA-LSS, which are likely affected by inclusion criteria, testing strategies, and ascertainment bias [ Data derived from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense and nonsense variants and small deletions/insertions; typically, larger deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-gene mtDNA deletions have not been reported. Deletion/duplication analysis of the entire mitochondrial genome may include a range of techniques such as quantitative PCR or long-range PCR. The most common Large-scale deletions have been reported in individuals with mtDNA-LSS [ • Progressive neurologic disease with developmental delay and neurodevelopmental regression • Manifestations of brain stem and/or basal ganglia disease (e.g., respiratory abnormalities, nystagmus, ophthalmoparesis, optic atrophy, ataxia, and dystonia) • Seizures • Psychiatric disturbance • Elevated blood lactate • Elevation tends to be more marked in postprandial samples. • Elevated cerebrospinal fluid (CSF) lactate • Note: While elevated blood and/or CSF lactate is suggestive of a mitochondrial disorder, a normal lactate does not exclude mtDNA-LSS. • Plasma amino acids may show increased alanine concentration, reflecting persistent hyperlactatemia. Decreased plasma citrulline concentration and/or elevated 3-hydroxy-isovalerylcarnitine (C5-OH) levels has been reported in individuals with • Urine organic acid analysis results are often nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. • Note: 3-methylglutaconic aciduria may be observed in some nuclear gene-encoded causes of LSS, notably 3- • Characteristic findings include bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia on T • Additional findings can include cerebral atrophy, bilateral hyperintense signal abnormality in the thalamus, cerebellum, cerebral white matter, and/or spinal cord on T • Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) • Note: Characteristic patterns of brain lesions have been described for specific causes of nuclear gene-encoded LSS. For example, specific brain lesions affecting the mammillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum appear to be characteristic of • Developmental regression • Developmental delay • Psychiatric features • Elevated lactate in plasma and/or CSF • MRS lactate peak (in absence of acute seizures) • Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. • If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see ## Suggestive Findings Progressive neurologic disease with developmental delay and neurodevelopmental regression Manifestations of brain stem and/or basal ganglia disease (e.g., respiratory abnormalities, nystagmus, ophthalmoparesis, optic atrophy, ataxia, and dystonia) Seizures Psychiatric disturbance Elevated blood lactate Elevation tends to be more marked in postprandial samples. Elevated cerebrospinal fluid (CSF) lactate Note: While elevated blood and/or CSF lactate is suggestive of a mitochondrial disorder, a normal lactate does not exclude mtDNA-LSS. Plasma amino acids may show increased alanine concentration, reflecting persistent hyperlactatemia. Decreased plasma citrulline concentration and/or elevated 3-hydroxy-isovalerylcarnitine (C5-OH) levels has been reported in individuals with Urine organic acid analysis results are often nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. Note: 3-methylglutaconic aciduria may be observed in some nuclear gene-encoded causes of LSS, notably 3- Characteristic findings include bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia on T Additional findings can include cerebral atrophy, bilateral hyperintense signal abnormality in the thalamus, cerebellum, cerebral white matter, and/or spinal cord on T Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) Note: Characteristic patterns of brain lesions have been described for specific causes of nuclear gene-encoded LSS. For example, specific brain lesions affecting the mammillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum appear to be characteristic of Since the advent of next-generation sequencing, muscle biopsy is performed less frequently (especially in the pediatric population), as obtaining a muscle biopsy is invasive and often requires general anesthesia, which carries a risk of metabolic decompensation. Muscle biopsy is now generally reserved for critically unwell individuals or (occasionally) for functional validation of genetic findings. Note: (1) Although muscle histopathology is only occasionally abnormal, when it is abnormal it can be as much of a contributor to diagnostic certainty as respiratory chain enzymes or molecular testing. (2) If muscle biopsy is obtained for respiratory chain enzyme studies, histopathology should also be performed. Note: (1) Skeletal muscle (vastus lateralis) is usually the tissue of choice for respiratory chain enzyme studies. (2) Skin fibroblasts can be used, but only about 50% of respiratory chain enzyme defects identified in skeletal muscle are also identified in skin fibroblasts. (3) Approximately 10%-20% of individuals with normal skeletal muscle respiratory chain enzyme analysis may have an enzyme defect detected in liver or cardiac muscle, particularly if those tissues are involved clinically [ • Progressive neurologic disease with developmental delay and neurodevelopmental regression • Manifestations of brain stem and/or basal ganglia disease (e.g., respiratory abnormalities, nystagmus, ophthalmoparesis, optic atrophy, ataxia, and dystonia) • Seizures • Psychiatric disturbance • Elevated blood lactate • Elevation tends to be more marked in postprandial samples. • Elevated cerebrospinal fluid (CSF) lactate • Note: While elevated blood and/or CSF lactate is suggestive of a mitochondrial disorder, a normal lactate does not exclude mtDNA-LSS. • Plasma amino acids may show increased alanine concentration, reflecting persistent hyperlactatemia. Decreased plasma citrulline concentration and/or elevated 3-hydroxy-isovalerylcarnitine (C5-OH) levels has been reported in individuals with • Urine organic acid analysis results are often nonspecific and may show lactic aciduria, increased Krebs cycle intermediates, and increased dicarboxylic acids. • Note: 3-methylglutaconic aciduria may be observed in some nuclear gene-encoded causes of LSS, notably 3- • Characteristic findings include bilateral symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia on T • Additional findings can include cerebral atrophy, bilateral hyperintense signal abnormality in the thalamus, cerebellum, cerebral white matter, and/or spinal cord on T • Magnetic resonance spectroscopy (MRS) lactate peak (in the absence of acute seizures) • Note: Characteristic patterns of brain lesions have been described for specific causes of nuclear gene-encoded LSS. For example, specific brain lesions affecting the mammillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum appear to be characteristic of ## Establishing the Diagnosis The diagnosis of mtDNA-LSS Developmental regression Developmental delay Psychiatric features Elevated lactate in plasma and/or CSF MRS lactate peak (in absence of acute seizures) Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) Note: Historically, the diagnosis of LSS was achieved by demonstrating mitochondrial dysfunction through relevant tissue biopsy to inform a targeted molecular genetic approach. However, the introduction of comprehensive genomic sequencing has removed the need for tissue biopsy in most scenarios. Molecular genetic testing approaches for mtDNA-LSS can include Comprehensive genomic testing includes sequencing of mtDNA and nuclear DNA. Comprehensive genomic testing does not require a phenotype-driven hypothesis and may provide or suggest a diagnosis not previously considered (e.g., variant in a different gene[s] that results in a similar clinical presentation). Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see For an introduction to comprehensive genomic testing click Targeted analysis of common pathogenic variants may be considered if there is a high clinical suspicion based on clinical or biochemical findings or if comprehensive testing is not available (see Note: (1) Most mtDNA pathogenic variants associated with mtDNA-LSS are "heteroplasmic" (i.e., abnormal mtDNA coexists with wild type mtDNA) and for some pathogenic variants, the heteroplasmy level may vary among different tissues and may increase or decrease with age. (2) Mitochondrial DNA pathogenic variants may be lost from the leukocyte population with increasing age [ Molecular Genetics of Mitochondrial DNA-Associated Leigh Syndrome Spectrum mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum Genes are listed from most frequent to least frequent genetic cause of mtDNA-LSS and then alphabetically. See These estimates are based on several cohorts of individuals with mtDNA-LSS, which are likely affected by inclusion criteria, testing strategies, and ascertainment bias [ Data derived from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense and nonsense variants and small deletions/insertions; typically, larger deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-gene mtDNA deletions have not been reported. Deletion/duplication analysis of the entire mitochondrial genome may include a range of techniques such as quantitative PCR or long-range PCR. The most common Large-scale deletions have been reported in individuals with mtDNA-LSS [ • Developmental regression • Developmental delay • Psychiatric features • Elevated lactate in plasma and/or CSF • MRS lactate peak (in absence of acute seizures) • Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. • If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see ## Clinical Criteria for mtDNA-LSS Developmental regression Developmental delay Psychiatric features Elevated lactate in plasma and/or CSF MRS lactate peak (in absence of acute seizures) Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) Note: Historically, the diagnosis of LSS was achieved by demonstrating mitochondrial dysfunction through relevant tissue biopsy to inform a targeted molecular genetic approach. However, the introduction of comprehensive genomic sequencing has removed the need for tissue biopsy in most scenarios. • Developmental regression • Developmental delay • Psychiatric features • Elevated lactate in plasma and/or CSF • MRS lactate peak (in absence of acute seizures) • Respiratory chain enzyme activity deficiency (<30% enzyme activity) in affected tissues (muscle, liver, fibroblasts) ## Molecular Genetic Testing Molecular genetic testing approaches for mtDNA-LSS can include Comprehensive genomic testing includes sequencing of mtDNA and nuclear DNA. Comprehensive genomic testing does not require a phenotype-driven hypothesis and may provide or suggest a diagnosis not previously considered (e.g., variant in a different gene[s] that results in a similar clinical presentation). Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see For an introduction to comprehensive genomic testing click Targeted analysis of common pathogenic variants may be considered if there is a high clinical suspicion based on clinical or biochemical findings or if comprehensive testing is not available (see Note: (1) Most mtDNA pathogenic variants associated with mtDNA-LSS are "heteroplasmic" (i.e., abnormal mtDNA coexists with wild type mtDNA) and for some pathogenic variants, the heteroplasmy level may vary among different tissues and may increase or decrease with age. (2) Mitochondrial DNA pathogenic variants may be lost from the leukocyte population with increasing age [ Molecular Genetics of Mitochondrial DNA-Associated Leigh Syndrome Spectrum mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum Genes are listed from most frequent to least frequent genetic cause of mtDNA-LSS and then alphabetically. See These estimates are based on several cohorts of individuals with mtDNA-LSS, which are likely affected by inclusion criteria, testing strategies, and ascertainment bias [ Data derived from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense and nonsense variants and small deletions/insertions; typically, larger deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-gene mtDNA deletions have not been reported. Deletion/duplication analysis of the entire mitochondrial genome may include a range of techniques such as quantitative PCR or long-range PCR. The most common Large-scale deletions have been reported in individuals with mtDNA-LSS [ • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. • If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see ## Comprehensive genomic testing includes sequencing of mtDNA and nuclear DNA. Comprehensive genomic testing does not require a phenotype-driven hypothesis and may provide or suggest a diagnosis not previously considered (e.g., variant in a different gene[s] that results in a similar clinical presentation). Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see For an introduction to comprehensive genomic testing click • Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate. • If genome sequencing is not available, mtDNA sequencing is recommended. Exome sequencing should be considered in conjunction with mtDNA sequencing, especially in the pediatric population, given that approximately 70% of individuals will have nuclear gene-encoded LSS (see ## Targeted analysis of common pathogenic variants may be considered if there is a high clinical suspicion based on clinical or biochemical findings or if comprehensive testing is not available (see Note: (1) Most mtDNA pathogenic variants associated with mtDNA-LSS are "heteroplasmic" (i.e., abnormal mtDNA coexists with wild type mtDNA) and for some pathogenic variants, the heteroplasmy level may vary among different tissues and may increase or decrease with age. (2) Mitochondrial DNA pathogenic variants may be lost from the leukocyte population with increasing age [ Molecular Genetics of Mitochondrial DNA-Associated Leigh Syndrome Spectrum mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum Genes are listed from most frequent to least frequent genetic cause of mtDNA-LSS and then alphabetically. See These estimates are based on several cohorts of individuals with mtDNA-LSS, which are likely affected by inclusion criteria, testing strategies, and ascertainment bias [ Data derived from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense and nonsense variants and small deletions/insertions; typically, larger deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Single-gene mtDNA deletions have not been reported. Deletion/duplication analysis of the entire mitochondrial genome may include a range of techniques such as quantitative PCR or long-range PCR. The most common Large-scale deletions have been reported in individuals with mtDNA-LSS [ ## Clinical Characteristics Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is a continuum of progressive neurodegenerative disorders, with typical onset in infancy or early childhood of sudden neurodevelopmental regression. Individuals with LSS may have variable extraneurologic manifestations including gastrointestinal, cardiac, hepatic, renal, and endocrine disease. The clinical features of mtDNA-LSS are similar to those observed in individuals with nuclear gene-encoded Leigh syndrome spectrum (LSS). Clinically, it is difficult to distinguish mtDNA-LSS from nuclear gene-encoded LSS, and there are relatively few publications describing the full range of clinical features in mtDNA-LSS. The following description of the phenotypic features summarizes the more robust data on features of all individuals with LSS; specific information and references for mtDNA-LSS are included if available. Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Frequency of Select Features mtDNA = mitochondrial DNA; LSS = Leigh syndrome spectrum Estimated percentages are based on several cohorts of individuals with nuclear gene-encoded LSS and mtDNA-LSS (~1,000 individuals); however, each clinical feature was not reported for every individual [ Estimated percentages are based on reports of five cohorts that included clinical features of ~150 individuals with mtDNA-LSS. Estimated percentages of several of the clinical features are based on a small number of individuals (<20) and should be interpreted with caution [ Data not available for regression, as this was often described in conjunction with developmental delay. Prenatally, intrauterine growth restriction, cardiomegaly, and oligohydramnios have been reported in LSS [ Early-onset LSS (age <2 years) may present with nonspecific features such as feeding difficulties, poor weight gain, hypotonia, developmental delay, and persistent vomiting. Late-onset LSS (age >2 years) may manifest with predominant muscle weakness and movement disorders including ataxia and dystonia. Onset in adulthood may manifest with ataxia, peripheral neuropathy, and psychiatric disturbance [ Brain stem lesions may cause respiratory difficulty (apnea, central hypo- or hyperventilation, or irregular respiration), bulbar problems (e.g., abnormal swallowing and speech), persistent vomiting, and abnormalities of thermoregulation (hypo- and hyperthermia). Sensorineural hearing loss may be present in approximately 15% of individuals, originating from the cochlea or auditory nerves. Poor prognosis has been associated with early-onset disease [ For most mtDNA pathogenic variants, it is difficult to distinguish a correlation between genotype and phenotype because clinical expression of mtDNA pathogenic variants is influenced by pathogenicity of the variant, relative amount of abnormal and wild type mtDNA (heteroplasmy level), the variation in heteroplasmy level in different tissues, and the energy requirements of brain and other tissues, which may vary with age. Intrafamilial and interfamilial clinical variability are seen in individuals with the same genotype [ Several studies have tried to describe genotype-phenotype correlations in mtDNA-LSS; however, these are generally inconsistent between cohorts, limiting their translation into clinical practice. Note: Overlap in Genotype-phenotype correlations are much weaker for other mtDNA pathogenic variants (e.g., Other genotype-phenotype correlations have been suggested for mtDNA pathogenic variants affecting respiratory chain enzyme complex I, although confirmation of these findings requires further systematic analysis of larger cohorts. Individuals with complex I deficiency are more commonly reported to have cardiac and visual involvement [ Individuals with mtDNA-LSS may exhibit overlapping phenotypes with other mitochondrial phenotypes, including MELAS. Penetrance is reduced (see Leigh syndrome was originally described in an affected infant as "subacute necrotizing encephalomyelopathy" [ The term LSS is the most frequently observed phenotype of pediatric-onset mitochondrial disorders. Mitochondrial DNA-associated LSS accounts for approximately 30% of LSS. The following prevalence data are for all genetic causes of LSS. In southeastern Australia, Leigh syndrome occurs in 1:77,000 infants, and the combined birth prevalence of LSS was estimated to be at least 1:40,000 [ Analyses of 67 individuals with LSS reported by • Prenatally, intrauterine growth restriction, cardiomegaly, and oligohydramnios have been reported in LSS [ • Early-onset LSS (age <2 years) may present with nonspecific features such as feeding difficulties, poor weight gain, hypotonia, developmental delay, and persistent vomiting. • Late-onset LSS (age >2 years) may manifest with predominant muscle weakness and movement disorders including ataxia and dystonia. • Onset in adulthood may manifest with ataxia, peripheral neuropathy, and psychiatric disturbance [ • Note: Overlap in ## Clinical Description Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is a continuum of progressive neurodegenerative disorders, with typical onset in infancy or early childhood of sudden neurodevelopmental regression. Individuals with LSS may have variable extraneurologic manifestations including gastrointestinal, cardiac, hepatic, renal, and endocrine disease. The clinical features of mtDNA-LSS are similar to those observed in individuals with nuclear gene-encoded Leigh syndrome spectrum (LSS). Clinically, it is difficult to distinguish mtDNA-LSS from nuclear gene-encoded LSS, and there are relatively few publications describing the full range of clinical features in mtDNA-LSS. The following description of the phenotypic features summarizes the more robust data on features of all individuals with LSS; specific information and references for mtDNA-LSS are included if available. Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Frequency of Select Features mtDNA = mitochondrial DNA; LSS = Leigh syndrome spectrum Estimated percentages are based on several cohorts of individuals with nuclear gene-encoded LSS and mtDNA-LSS (~1,000 individuals); however, each clinical feature was not reported for every individual [ Estimated percentages are based on reports of five cohorts that included clinical features of ~150 individuals with mtDNA-LSS. Estimated percentages of several of the clinical features are based on a small number of individuals (<20) and should be interpreted with caution [ Data not available for regression, as this was often described in conjunction with developmental delay. Prenatally, intrauterine growth restriction, cardiomegaly, and oligohydramnios have been reported in LSS [ Early-onset LSS (age <2 years) may present with nonspecific features such as feeding difficulties, poor weight gain, hypotonia, developmental delay, and persistent vomiting. Late-onset LSS (age >2 years) may manifest with predominant muscle weakness and movement disorders including ataxia and dystonia. Onset in adulthood may manifest with ataxia, peripheral neuropathy, and psychiatric disturbance [ Brain stem lesions may cause respiratory difficulty (apnea, central hypo- or hyperventilation, or irregular respiration), bulbar problems (e.g., abnormal swallowing and speech), persistent vomiting, and abnormalities of thermoregulation (hypo- and hyperthermia). Sensorineural hearing loss may be present in approximately 15% of individuals, originating from the cochlea or auditory nerves. Poor prognosis has been associated with early-onset disease [ • Prenatally, intrauterine growth restriction, cardiomegaly, and oligohydramnios have been reported in LSS [ • Early-onset LSS (age <2 years) may present with nonspecific features such as feeding difficulties, poor weight gain, hypotonia, developmental delay, and persistent vomiting. • Late-onset LSS (age >2 years) may manifest with predominant muscle weakness and movement disorders including ataxia and dystonia. • Onset in adulthood may manifest with ataxia, peripheral neuropathy, and psychiatric disturbance [ ## Genotype-Phenotype Correlations For most mtDNA pathogenic variants, it is difficult to distinguish a correlation between genotype and phenotype because clinical expression of mtDNA pathogenic variants is influenced by pathogenicity of the variant, relative amount of abnormal and wild type mtDNA (heteroplasmy level), the variation in heteroplasmy level in different tissues, and the energy requirements of brain and other tissues, which may vary with age. Intrafamilial and interfamilial clinical variability are seen in individuals with the same genotype [ Several studies have tried to describe genotype-phenotype correlations in mtDNA-LSS; however, these are generally inconsistent between cohorts, limiting their translation into clinical practice. Note: Overlap in Genotype-phenotype correlations are much weaker for other mtDNA pathogenic variants (e.g., Other genotype-phenotype correlations have been suggested for mtDNA pathogenic variants affecting respiratory chain enzyme complex I, although confirmation of these findings requires further systematic analysis of larger cohorts. Individuals with complex I deficiency are more commonly reported to have cardiac and visual involvement [ Individuals with mtDNA-LSS may exhibit overlapping phenotypes with other mitochondrial phenotypes, including MELAS. • Note: Overlap in ## Penetrance Penetrance is reduced (see ## Nomenclature Leigh syndrome was originally described in an affected infant as "subacute necrotizing encephalomyelopathy" [ The term ## Prevalence LSS is the most frequently observed phenotype of pediatric-onset mitochondrial disorders. Mitochondrial DNA-associated LSS accounts for approximately 30% of LSS. The following prevalence data are for all genetic causes of LSS. In southeastern Australia, Leigh syndrome occurs in 1:77,000 infants, and the combined birth prevalence of LSS was estimated to be at least 1:40,000 [ Analyses of 67 individuals with LSS reported by ## Genetically Related Disorders Pathogenic variants in mtDNA genes known to be associated with mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) can also be associated with a variety of other mitochondrial disorders. For example, the pathogenic variants most often identified in individuals with Selected Allelic Disorders See hyperlinked ## Differential Diagnosis Other monogenic disorders that cause or resemble LSS are listed in Other Monogenic Disorders That Cause or Resemble Leigh Syndrome Spectrum AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Acquired conditions that cause or resemble LSS with similar clinical features and/or similar neuroimaging findings include the following: Acute necrotizing encephalopathy (may be triggered by viral infections) Viral encephalopathies Hypoxic-ischemic encephalopathy Wernicke encephalopathy (thiamine deficiency) • Acute necrotizing encephalopathy (may be triggered by viral infections) • Viral encephalopathies • Hypoxic-ischemic encephalopathy • Wernicke encephalopathy (thiamine deficiency) ## Management To establish the extent of disease and needs in an individual diagnosed with mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS), the evaluations summarized in Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Recommended Evaluations Following Initial Diagnosis Neurologic eval Brain MRI & MRS Plasma & CSF lactate & pyruvate Urine organic acids Consider EEG if seizures are suspected. Consider nerve conduction studies if neuropathy is suspected (due to history or ↓/absent reflexes on clinical exam). Measurement of growth parameters Nutrition / feeding team eval Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Blood pressure EKG Echocardiogram Referral to cardiologist to screen for conduction defects, arrythmias, or cardiomyopathy. Consider Holter monitoring in high-risk individuals. Liver function tests incl transaminases, bilirubin, albumin, & coagulation studies Consider abdominal ultrasound. Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; BUN = blood urea nitrogen; CSF = cerebrospinal fluid; MOI = mode of inheritance; MRS = magnetic resonance spectroscopy; mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse As for most mitochondrial disorders, no specific curative treatment for mtDNA-LSS exists [ Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Treatment of Manifestations Sodium bicarbonate or sodium citrate for significant acidosis Consider THAM if accompanying hypernatremia. Sodium valproate should be avoided because of its inhibitory effects on mitochondrial respiratory chain. Education of parents/caregivers Referral to pulmonologist as needed Ventilatory support for persons w/respiratory compromise Caloric & nutritional supplementation as needed (incl micronutrients) Feeding therapy as needed Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. Hearing aids or cochlear implants for sensorineural hearing loss Referral to speech therapy Referral to hearing support services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; THAM = tris-hydroxymethyl aminomethane Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Recommended Surveillance Measurement of growth parameters Eval of nutritional status (incl micronutrients) & safety of oral intake Blood pressure EKG Echocardiogram Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine Fasting glucose Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. Consider early-morning cortisol & short synacthen test if clinical symptoms of adrenal insufficiency. BUN = blood urea nitrogen; OGTT = oral glucose tolerance test; OT = occupational therapy; PT = physical therapy An international Delphi-based consensus on the safety of medication use in individuals with primary mitochondrial disorders was published in 2020 to assist clinical decision making. However, it is important to tailor medication recommendations to the individual [ See A number of vitamins, cofactors, and other compounds, including riboflavin, thiamine, creatine, biotin, coenzyme Q Vatiquinone (PTC-743; previously known as EPI-743) is a structurally modified variant of coenzyme Q KH176 (sonlicromanol) is a redox-modulating agent that targets the thioredoxin/peroxiredoxin system to reduce cellular reactive oxygen species. Promising preclinical studies in a mouse model for LSS [ Search • Neurologic eval • Brain MRI & MRS • Plasma & CSF lactate & pyruvate • Urine organic acids • Consider EEG if seizures are suspected. • Consider nerve conduction studies if neuropathy is suspected (due to history or ↓/absent reflexes on clinical exam). • Measurement of growth parameters • Nutrition / feeding team eval • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Blood pressure • EKG • Echocardiogram • Referral to cardiologist to screen for conduction defects, arrythmias, or cardiomyopathy. • Consider Holter monitoring in high-risk individuals. • Liver function tests incl transaminases, bilirubin, albumin, & coagulation studies • Consider abdominal ultrasound. • Urinalysis, urine albumin-to-creatinine ratio, urine amino acids • Serum electrolytes, BUN, creatinine • Community or • Social work involvement for parental support • Home nursing referral • Sodium bicarbonate or sodium citrate for significant acidosis • Consider THAM if accompanying hypernatremia. • Sodium valproate should be avoided because of its inhibitory effects on mitochondrial respiratory chain. • Education of parents/caregivers • Referral to pulmonologist as needed • Ventilatory support for persons w/respiratory compromise • Caloric & nutritional supplementation as needed (incl micronutrients) • Feeding therapy as needed • Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. • Hearing aids or cochlear implants for sensorineural hearing loss • Referral to speech therapy • Referral to hearing support services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Measurement of growth parameters • Eval of nutritional status (incl micronutrients) & safety of oral intake • Blood pressure • EKG • Echocardiogram • Urinalysis, urine albumin-to-creatinine ratio, urine amino acids • Serum electrolytes, BUN, creatinine • Fasting glucose • Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. • Consider early-morning cortisol & short synacthen test if clinical symptoms of adrenal insufficiency. ## Evaluation Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS), the evaluations summarized in Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Recommended Evaluations Following Initial Diagnosis Neurologic eval Brain MRI & MRS Plasma & CSF lactate & pyruvate Urine organic acids Consider EEG if seizures are suspected. Consider nerve conduction studies if neuropathy is suspected (due to history or ↓/absent reflexes on clinical exam). Measurement of growth parameters Nutrition / feeding team eval Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Blood pressure EKG Echocardiogram Referral to cardiologist to screen for conduction defects, arrythmias, or cardiomyopathy. Consider Holter monitoring in high-risk individuals. Liver function tests incl transaminases, bilirubin, albumin, & coagulation studies Consider abdominal ultrasound. Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; BUN = blood urea nitrogen; CSF = cerebrospinal fluid; MOI = mode of inheritance; MRS = magnetic resonance spectroscopy; mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Neurologic eval • Brain MRI & MRS • Plasma & CSF lactate & pyruvate • Urine organic acids • Consider EEG if seizures are suspected. • Consider nerve conduction studies if neuropathy is suspected (due to history or ↓/absent reflexes on clinical exam). • Measurement of growth parameters • Nutrition / feeding team eval • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Blood pressure • EKG • Echocardiogram • Referral to cardiologist to screen for conduction defects, arrythmias, or cardiomyopathy. • Consider Holter monitoring in high-risk individuals. • Liver function tests incl transaminases, bilirubin, albumin, & coagulation studies • Consider abdominal ultrasound. • Urinalysis, urine albumin-to-creatinine ratio, urine amino acids • Serum electrolytes, BUN, creatinine • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations As for most mitochondrial disorders, no specific curative treatment for mtDNA-LSS exists [ Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Treatment of Manifestations Sodium bicarbonate or sodium citrate for significant acidosis Consider THAM if accompanying hypernatremia. Sodium valproate should be avoided because of its inhibitory effects on mitochondrial respiratory chain. Education of parents/caregivers Referral to pulmonologist as needed Ventilatory support for persons w/respiratory compromise Caloric & nutritional supplementation as needed (incl micronutrients) Feeding therapy as needed Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. Hearing aids or cochlear implants for sensorineural hearing loss Referral to speech therapy Referral to hearing support services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; THAM = tris-hydroxymethyl aminomethane Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Sodium bicarbonate or sodium citrate for significant acidosis • Consider THAM if accompanying hypernatremia. • Sodium valproate should be avoided because of its inhibitory effects on mitochondrial respiratory chain. • Education of parents/caregivers • Referral to pulmonologist as needed • Ventilatory support for persons w/respiratory compromise • Caloric & nutritional supplementation as needed (incl micronutrients) • Feeding therapy as needed • Gastrostomy tube placement may improve nutritional intake for those w/persistent feeding issues, choking, or aspiration risk due to dysphagia. • Hearing aids or cochlear implants for sensorineural hearing loss • Referral to speech therapy • Referral to hearing support services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Recommended Surveillance Measurement of growth parameters Eval of nutritional status (incl micronutrients) & safety of oral intake Blood pressure EKG Echocardiogram Urinalysis, urine albumin-to-creatinine ratio, urine amino acids Serum electrolytes, BUN, creatinine Fasting glucose Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. Consider early-morning cortisol & short synacthen test if clinical symptoms of adrenal insufficiency. BUN = blood urea nitrogen; OGTT = oral glucose tolerance test; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status (incl micronutrients) & safety of oral intake • Blood pressure • EKG • Echocardiogram • Urinalysis, urine albumin-to-creatinine ratio, urine amino acids • Serum electrolytes, BUN, creatinine • Fasting glucose • Consider hemoglobin A1c or OGTT if clinical features consistent w/diabetes mellitus. • Consider early-morning cortisol & short synacthen test if clinical symptoms of adrenal insufficiency. ## Agents/Circumstances to Avoid An international Delphi-based consensus on the safety of medication use in individuals with primary mitochondrial disorders was published in 2020 to assist clinical decision making. However, it is important to tailor medication recommendations to the individual [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation A number of vitamins, cofactors, and other compounds, including riboflavin, thiamine, creatine, biotin, coenzyme Q Vatiquinone (PTC-743; previously known as EPI-743) is a structurally modified variant of coenzyme Q KH176 (sonlicromanol) is a redox-modulating agent that targets the thioredoxin/peroxiredoxin system to reduce cellular reactive oxygen species. Promising preclinical studies in a mouse model for LSS [ Search ## Other ## Genetic Counseling Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is transmitted by mitochondrial (maternal) inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ With the exception of the Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorders. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the threshold level that causes disease, or a Molecular genetic testing of the mother for the mtDNA pathogenic variant identified in the proband is recommended. Assessment in at least two different maternal tissues (e.g., blood, urine sediment cells, buccal cells) is suggested [ If the proband represents a simplex case (i.e., the only family member known to be affected) and the mtDNA pathogenic variant identified in the proband cannot be identified in maternal tissues, possibilities to consider include a If the mother of the proband has the mtDNA pathogenic variant identified in the proband, all sibs are at risk of inheriting the pathogenic variant. Sibs may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. For the Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ The risk to a sib of developing clinical manifestations is difficult to determine and depends on heteroplasmy level, the variation in heteroplasmy levels among different tissues, and the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease) for the specific variant (see In mtDNA-LSS, the It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See Variation in clinical manifestations is seen among family members with the same genotype [ If the proband is presumed to have a Offspring of a male proband with an mtDNA pathogenic variant are not at risk. All offspring of a female proband with an mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. The risk to offspring of a female proband of developing clinical manifestations is difficult to determine and depends on the maternal heteroplasmy level, the variation in heteroplasmy levels among different tissues in the proband, and the specific mtDNA pathogenic variant. Retrospective studies for some of the most common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk for the offspring of females. See The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. It should be emphasized in genetic counseling for mtDNA-LSS that it is not possible to make specific predictions about clinical outcome in individuals or their offspring. Recurrence risk assessment and prenatal testing for disorders caused by pathogenic variants in mtDNA are challenging due to the intricacies of mtDNA transmission, such as the mtDNA bottleneck effect (resulting in variation in heteroplasmy levels between generations), pathogenic variant-specific selection, the threshold effect (the heteroplasmy level associated with clinical manifestations of mitochondrial disease), and the inherent challenge in using prenatal genetic test results to predict clinical outcome. The European Neuromuscular Disease Centre International Consensus Workshops have been instrumental in developing guidelines for the counseling of reproductive options for families with mitochondrial disease [ Reproductive options for the family members of a proband with an mtDNA pathogenic variant may include prenatal testing, preimplantation genetic testing (PGT), and oocyte donation. Prenatal testing appears to be the preferred reproductive testing option for mtDNA pathogenic variants that appear to have occurred Available evidence suggests that the proportion of abnormal mtDNA in extraembryonic and embryonic tissues is similar and does not change substantially during pregnancy. For a number of mtDNA pathogenic variants, including m.8993T>G, m.8993T>C, and m.9176T>C in There is no consensus between centers regarding the preference for CVS or amniocentesis for prenatal testing for mtDNA disease, although some studies support the use of amniocentesis given reports of intraplacental variation with CVS [ Analysis should be done on direct CVS/amniocytes, not on cultured cells, as the heteroplasmy level of mtDNA pathogenic variants can change during cell culture. The major limitation of prenatal testing is the potential difficulty in predicting clinical outcome based on fetal genetic testing results. For prediction of clinical outcome to be reliable, there must be a close correlation between the heteroplasmy level and disease severity; uniform distribution of heteroplasmy levels in all tissues; and stability of the heteroplasmy level over time [ Clinical practice varies in determining which thresholds are used to determine the likelihood a fetus will be affected or unaffected based on prenatal test results. A systematic review suggested a generic threshold of 18% after it was found that individuals with muscle heteroplasmy levels below approximately 18% had a 95% chance or higher of being unaffected, independent of the mtDNA variant [ While the A model has been developed for the For other mtDNA pathogenic variants, prenatal diagnosis may be offered to females with a low proportion of abnormal mtDNA. However, weaker genotype-phenotype correlation or lack of data would mean that accurate prediction of the phenotype may not possible. Couples would require careful counseling before embarking on these procedures. Embryos should only be regarded as suitable for implantation if they have a very low proportion of abnormal mtDNA, preferably 0%, although threshold levels of 18% may imply low recurrence risk [ In some females, particularly those with a high proportion of abnormal mtDNA in blood or urine sediment cells, a large proportion of oocytes may have a high level of abnormal mtDNA, and multiple cycles of ovarian stimulation may not result in an embryo suitable for implantation. However, PGT for mtDNA pathogenic variants may provide valuable information for future reproductive planning even if a successful unaffected conception is not achieved. If most of the embryos tested have a substantial proportion of abnormal mtDNA, oocyte donation is likely to be the only current option for ensuring an unaffected embryo. In contrast, if most of the embryos tested have undetectable abnormal mtDNA, the parents may opt for prenatal testing in subsequent unassisted (natural) pregnancies. The first child born after maternal spindle transfer was reported in 2017, born to a female with After extensive scientific, ethical, and public consultation, in 2016, the UK government gave permission for MRT to prevent the transmission of severe mitochondrial disease caused by specific mtDNA pathogenic variants [ • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. • In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. • Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ • With the exception of the • In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. • Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ • With the exception of the • Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorders. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the threshold level that causes disease, or a • Molecular genetic testing of the mother for the mtDNA pathogenic variant identified in the proband is recommended. Assessment in at least two different maternal tissues (e.g., blood, urine sediment cells, buccal cells) is suggested [ • If the proband represents a simplex case (i.e., the only family member known to be affected) and the mtDNA pathogenic variant identified in the proband cannot be identified in maternal tissues, possibilities to consider include a • In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. • Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ • With the exception of the • If the mother of the proband has the mtDNA pathogenic variant identified in the proband, all sibs are at risk of inheriting the pathogenic variant. Sibs may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. • For the • Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ • For the • Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ • The risk to a sib of developing clinical manifestations is difficult to determine and depends on heteroplasmy level, the variation in heteroplasmy levels among different tissues, and the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease) for the specific variant (see • In mtDNA-LSS, the • It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See • In mtDNA-LSS, the • It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See • Variation in clinical manifestations is seen among family members with the same genotype [ • If the proband is presumed to have a • For the • Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ • In mtDNA-LSS, the • It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See • Offspring of a male proband with an mtDNA pathogenic variant are not at risk. • All offspring of a female proband with an mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. • The risk to offspring of a female proband of developing clinical manifestations is difficult to determine and depends on the maternal heteroplasmy level, the variation in heteroplasmy levels among different tissues in the proband, and the specific mtDNA pathogenic variant. Retrospective studies for some of the most common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk for the offspring of females. See • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. It should be emphasized in genetic counseling for mtDNA-LSS that it is not possible to make specific predictions about clinical outcome in individuals or their offspring. • Available evidence suggests that the proportion of abnormal mtDNA in extraembryonic and embryonic tissues is similar and does not change substantially during pregnancy. For a number of mtDNA pathogenic variants, including m.8993T>G, m.8993T>C, and m.9176T>C in • There is no consensus between centers regarding the preference for CVS or amniocentesis for prenatal testing for mtDNA disease, although some studies support the use of amniocentesis given reports of intraplacental variation with CVS [ • Analysis should be done on direct CVS/amniocytes, not on cultured cells, as the heteroplasmy level of mtDNA pathogenic variants can change during cell culture. • While the • A model has been developed for the • For other mtDNA pathogenic variants, prenatal diagnosis may be offered to females with a low proportion of abnormal mtDNA. However, weaker genotype-phenotype correlation or lack of data would mean that accurate prediction of the phenotype may not possible. Couples would require careful counseling before embarking on these procedures. • If most of the embryos tested have a substantial proportion of abnormal mtDNA, oocyte donation is likely to be the only current option for ensuring an unaffected embryo. • In contrast, if most of the embryos tested have undetectable abnormal mtDNA, the parents may opt for prenatal testing in subsequent unassisted (natural) pregnancies. ## Mode of Inheritance Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is transmitted by mitochondrial (maternal) inheritance. ## Risk to Family Members The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ With the exception of the Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorders. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the threshold level that causes disease, or a Molecular genetic testing of the mother for the mtDNA pathogenic variant identified in the proband is recommended. Assessment in at least two different maternal tissues (e.g., blood, urine sediment cells, buccal cells) is suggested [ If the proband represents a simplex case (i.e., the only family member known to be affected) and the mtDNA pathogenic variant identified in the proband cannot be identified in maternal tissues, possibilities to consider include a If the mother of the proband has the mtDNA pathogenic variant identified in the proband, all sibs are at risk of inheriting the pathogenic variant. Sibs may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. For the Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ The risk to a sib of developing clinical manifestations is difficult to determine and depends on heteroplasmy level, the variation in heteroplasmy levels among different tissues, and the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease) for the specific variant (see In mtDNA-LSS, the It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See Variation in clinical manifestations is seen among family members with the same genotype [ If the proband is presumed to have a Offspring of a male proband with an mtDNA pathogenic variant are not at risk. All offspring of a female proband with an mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. The risk to offspring of a female proband of developing clinical manifestations is difficult to determine and depends on the maternal heteroplasmy level, the variation in heteroplasmy levels among different tissues in the proband, and the specific mtDNA pathogenic variant. Retrospective studies for some of the most common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk for the offspring of females. See • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. • In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. • Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ • With the exception of the • In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. • Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ • With the exception of the • Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorders. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the threshold level that causes disease, or a • Molecular genetic testing of the mother for the mtDNA pathogenic variant identified in the proband is recommended. Assessment in at least two different maternal tissues (e.g., blood, urine sediment cells, buccal cells) is suggested [ • If the proband represents a simplex case (i.e., the only family member known to be affected) and the mtDNA pathogenic variant identified in the proband cannot be identified in maternal tissues, possibilities to consider include a • In most instances, the mother has a much lower heteroplasmy level (i.e., proportion of abnormal mtDNA) than the proband and usually remains asymptomatic or develops only mild manifestations such as gait disturbance or retinopathy. • Occasionally the mother has a substantial heteroplasmy level and develops severe manifestations of mtDNA-LSS in adulthood [ • With the exception of the • If the mother of the proband has the mtDNA pathogenic variant identified in the proband, all sibs are at risk of inheriting the pathogenic variant. Sibs may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. • For the • Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ • For the • Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ • The risk to a sib of developing clinical manifestations is difficult to determine and depends on heteroplasmy level, the variation in heteroplasmy levels among different tissues, and the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease) for the specific variant (see • In mtDNA-LSS, the • It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See • In mtDNA-LSS, the • It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See • Variation in clinical manifestations is seen among family members with the same genotype [ • If the proband is presumed to have a • For the • Due to positive selection, the m.8993T>G pathogenic variant exhibits skewed segregation [ • In mtDNA-LSS, the • It is difficult to use heteroplasmy level to predict clinical outcome (e.g., in asymptomatic family members or in prenatal diagnosis) for other mtDNA pathogenic variants detected in individuals known to be associated with mtDNA-LSS unless the value is near 0% or near 100%. Retrospective studies for some of the more common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk. See • Offspring of a male proband with an mtDNA pathogenic variant are not at risk. • All offspring of a female proband with an mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. Offspring may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. • The risk to offspring of a female proband of developing clinical manifestations is difficult to determine and depends on the maternal heteroplasmy level, the variation in heteroplasmy levels among different tissues in the proband, and the specific mtDNA pathogenic variant. Retrospective studies for some of the most common mtDNA pathogenic variants can be used to indicate an approximate (empiric) recurrence risk for the offspring of females. See ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. It should be emphasized in genetic counseling for mtDNA-LSS that it is not possible to make specific predictions about clinical outcome in individuals or their offspring. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. It should be emphasized in genetic counseling for mtDNA-LSS that it is not possible to make specific predictions about clinical outcome in individuals or their offspring. ## Prenatal Testing and Preimplantation Genetic Testing Recurrence risk assessment and prenatal testing for disorders caused by pathogenic variants in mtDNA are challenging due to the intricacies of mtDNA transmission, such as the mtDNA bottleneck effect (resulting in variation in heteroplasmy levels between generations), pathogenic variant-specific selection, the threshold effect (the heteroplasmy level associated with clinical manifestations of mitochondrial disease), and the inherent challenge in using prenatal genetic test results to predict clinical outcome. The European Neuromuscular Disease Centre International Consensus Workshops have been instrumental in developing guidelines for the counseling of reproductive options for families with mitochondrial disease [ Reproductive options for the family members of a proband with an mtDNA pathogenic variant may include prenatal testing, preimplantation genetic testing (PGT), and oocyte donation. Prenatal testing appears to be the preferred reproductive testing option for mtDNA pathogenic variants that appear to have occurred Available evidence suggests that the proportion of abnormal mtDNA in extraembryonic and embryonic tissues is similar and does not change substantially during pregnancy. For a number of mtDNA pathogenic variants, including m.8993T>G, m.8993T>C, and m.9176T>C in There is no consensus between centers regarding the preference for CVS or amniocentesis for prenatal testing for mtDNA disease, although some studies support the use of amniocentesis given reports of intraplacental variation with CVS [ Analysis should be done on direct CVS/amniocytes, not on cultured cells, as the heteroplasmy level of mtDNA pathogenic variants can change during cell culture. The major limitation of prenatal testing is the potential difficulty in predicting clinical outcome based on fetal genetic testing results. For prediction of clinical outcome to be reliable, there must be a close correlation between the heteroplasmy level and disease severity; uniform distribution of heteroplasmy levels in all tissues; and stability of the heteroplasmy level over time [ Clinical practice varies in determining which thresholds are used to determine the likelihood a fetus will be affected or unaffected based on prenatal test results. A systematic review suggested a generic threshold of 18% after it was found that individuals with muscle heteroplasmy levels below approximately 18% had a 95% chance or higher of being unaffected, independent of the mtDNA variant [ While the A model has been developed for the For other mtDNA pathogenic variants, prenatal diagnosis may be offered to females with a low proportion of abnormal mtDNA. However, weaker genotype-phenotype correlation or lack of data would mean that accurate prediction of the phenotype may not possible. Couples would require careful counseling before embarking on these procedures. Embryos should only be regarded as suitable for implantation if they have a very low proportion of abnormal mtDNA, preferably 0%, although threshold levels of 18% may imply low recurrence risk [ In some females, particularly those with a high proportion of abnormal mtDNA in blood or urine sediment cells, a large proportion of oocytes may have a high level of abnormal mtDNA, and multiple cycles of ovarian stimulation may not result in an embryo suitable for implantation. However, PGT for mtDNA pathogenic variants may provide valuable information for future reproductive planning even if a successful unaffected conception is not achieved. If most of the embryos tested have a substantial proportion of abnormal mtDNA, oocyte donation is likely to be the only current option for ensuring an unaffected embryo. In contrast, if most of the embryos tested have undetectable abnormal mtDNA, the parents may opt for prenatal testing in subsequent unassisted (natural) pregnancies. The first child born after maternal spindle transfer was reported in 2017, born to a female with After extensive scientific, ethical, and public consultation, in 2016, the UK government gave permission for MRT to prevent the transmission of severe mitochondrial disease caused by specific mtDNA pathogenic variants [ • Available evidence suggests that the proportion of abnormal mtDNA in extraembryonic and embryonic tissues is similar and does not change substantially during pregnancy. For a number of mtDNA pathogenic variants, including m.8993T>G, m.8993T>C, and m.9176T>C in • There is no consensus between centers regarding the preference for CVS or amniocentesis for prenatal testing for mtDNA disease, although some studies support the use of amniocentesis given reports of intraplacental variation with CVS [ • Analysis should be done on direct CVS/amniocytes, not on cultured cells, as the heteroplasmy level of mtDNA pathogenic variants can change during cell culture. • While the • A model has been developed for the • For other mtDNA pathogenic variants, prenatal diagnosis may be offered to females with a low proportion of abnormal mtDNA. However, weaker genotype-phenotype correlation or lack of data would mean that accurate prediction of the phenotype may not possible. Couples would require careful counseling before embarking on these procedures. • If most of the embryos tested have a substantial proportion of abnormal mtDNA, oocyte donation is likely to be the only current option for ensuring an unaffected embryo. • In contrast, if most of the embryos tested have undetectable abnormal mtDNA, the parents may opt for prenatal testing in subsequent unassisted (natural) pregnancies. ## Other Reproductive Options The first child born after maternal spindle transfer was reported in 2017, born to a female with After extensive scientific, ethical, and public consultation, in 2016, the UK government gave permission for MRT to prevent the transmission of severe mitochondrial disease caused by specific mtDNA pathogenic variants [ ## Resources United Kingdom Australia Massachusetts General Hospital Ireland United Kingdom • • • • • • United Kingdom • • • Australia • • • Massachusetts General Hospital • • • • • • Ireland • • • United Kingdom • • • ## Molecular Genetics Mitochondrial DNA-Associated Leigh Syndrome Spectrum: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Mitochondrial DNA-Associated Leigh Syndrome Spectrum ( Human mitochondrial DNA (mtDNA) encodes 37 genes, including 13 genes encoding protein subunits of the mitochondrial respiratory chain and oxidative phosphorylation system, 22 transfer RNA (tRNA) genes, and two ribosomal RNA (rRNA) genes. All mtDNA genes lack introns and are transcribed as large polycistronic transcripts that are processed into monocistronic mRNAs. Protein-coding genes are then translated by the mitochondrial-specific translational machinery. The mitochondrial-specific translational machinery is required because translation of mtDNA-encoded genes is physically separated from the cytosolic translational machinery and because the mtDNA genetic code differs from the universal genetic code in several codons. For some mtDNA pathogenic variants associated with Leigh syndrome spectrum (LSS), a strong correlation exists between the proportion of abnormal-to-wild type mtDNA and severity of the biochemical phenotype in cultured cells. For some variants, such as Pathogenic mtDNA variants causing LSS fall into two major classes, namely, those in tRNA genes and those in protein-coding genes. Transfer RNA pathogenic variants cause decreased mitochondrial protein synthesis by abnormalities in base modification and aminoacylation of the tRNA. Pathogenic variants in protein-coding mtDNA genes typically cause decreased activity of the respiratory chain complex of which that subunit is a part. Pathogenic Variants Referenced in This mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum Variants listed in the table have been provided by the authors. See • Transfer RNA pathogenic variants cause decreased mitochondrial protein synthesis by abnormalities in base modification and aminoacylation of the tRNA. • Pathogenic variants in protein-coding mtDNA genes typically cause decreased activity of the respiratory chain complex of which that subunit is a part. ## Molecular Pathogenesis Human mitochondrial DNA (mtDNA) encodes 37 genes, including 13 genes encoding protein subunits of the mitochondrial respiratory chain and oxidative phosphorylation system, 22 transfer RNA (tRNA) genes, and two ribosomal RNA (rRNA) genes. All mtDNA genes lack introns and are transcribed as large polycistronic transcripts that are processed into monocistronic mRNAs. Protein-coding genes are then translated by the mitochondrial-specific translational machinery. The mitochondrial-specific translational machinery is required because translation of mtDNA-encoded genes is physically separated from the cytosolic translational machinery and because the mtDNA genetic code differs from the universal genetic code in several codons. For some mtDNA pathogenic variants associated with Leigh syndrome spectrum (LSS), a strong correlation exists between the proportion of abnormal-to-wild type mtDNA and severity of the biochemical phenotype in cultured cells. For some variants, such as Pathogenic mtDNA variants causing LSS fall into two major classes, namely, those in tRNA genes and those in protein-coding genes. Transfer RNA pathogenic variants cause decreased mitochondrial protein synthesis by abnormalities in base modification and aminoacylation of the tRNA. Pathogenic variants in protein-coding mtDNA genes typically cause decreased activity of the respiratory chain complex of which that subunit is a part. Pathogenic Variants Referenced in This mtDNA-LSS = mitochondrial DNA-associated Leigh syndrome spectrum Variants listed in the table have been provided by the authors. See • Transfer RNA pathogenic variants cause decreased mitochondrial protein synthesis by abnormalities in base modification and aminoacylation of the tRNA. • Pathogenic variants in protein-coding mtDNA genes typically cause decreased activity of the respiratory chain complex of which that subunit is a part. ## Chapter Notes Prof Rahman, Prof Thorburn, and Dr Ball are actively involved in clinical research regarding individuals with mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS). Prof Thorburn is a member of the The authors would be happy to communicate with persons who have any questions regarding diagnosis of mtDNA-LSS or other considerations. The authors would like to acknowledge the support of clinicians, researchers, and patient advocacy groups for mtDNA-LSS. They would also like to acknowledge all the patients and families who have generously given their time and shared their experiences to advance the understanding of mtDNA-LSS. Megan Ball, MD (2024-present)Joyeeta Rahman, BSc; UCL Great Ormond Street Institute of Child Health (2017-2024)Shamima Rahman, PhD, FRCP, FRCPCH (2003-present)David R Thorburn, PhD, FHGSA, FFSc(RCPA) (2003-present) 9 May 2024 (sw) Comprehensive update posted live 28 September 2017 (sw) Comprehensive update posted live 17 April 2014 (me) Comprehensive update posted live 8 February 2011 (me) Comprehensive update posted live 3 February 2006 (me) Comprehensive update posted live 30 October 2003 (me) Review posted live 3 July 2003 (dt) Original submission • 9 May 2024 (sw) Comprehensive update posted live • 28 September 2017 (sw) Comprehensive update posted live • 17 April 2014 (me) Comprehensive update posted live • 8 February 2011 (me) Comprehensive update posted live • 3 February 2006 (me) Comprehensive update posted live • 30 October 2003 (me) Review posted live • 3 July 2003 (dt) Original submission ## Author Notes Prof Rahman, Prof Thorburn, and Dr Ball are actively involved in clinical research regarding individuals with mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS). Prof Thorburn is a member of the The authors would be happy to communicate with persons who have any questions regarding diagnosis of mtDNA-LSS or other considerations. ## Acknowledgments The authors would like to acknowledge the support of clinicians, researchers, and patient advocacy groups for mtDNA-LSS. They would also like to acknowledge all the patients and families who have generously given their time and shared their experiences to advance the understanding of mtDNA-LSS. ## Author History Megan Ball, MD (2024-present)Joyeeta Rahman, BSc; UCL Great Ormond Street Institute of Child Health (2017-2024)Shamima Rahman, PhD, FRCP, FRCPCH (2003-present)David R Thorburn, PhD, FHGSA, FFSc(RCPA) (2003-present) ## Revision History 9 May 2024 (sw) Comprehensive update posted live 28 September 2017 (sw) Comprehensive update posted live 17 April 2014 (me) Comprehensive update posted live 8 February 2011 (me) Comprehensive update posted live 3 February 2006 (me) Comprehensive update posted live 30 October 2003 (me) Review posted live 3 July 2003 (dt) Original submission • 9 May 2024 (sw) Comprehensive update posted live • 28 September 2017 (sw) Comprehensive update posted live • 17 April 2014 (me) Comprehensive update posted live • 8 February 2011 (me) Comprehensive update posted live • 3 February 2006 (me) Comprehensive update posted live • 30 October 2003 (me) Review posted live • 3 July 2003 (dt) Original submission ## References Diodato D, Schiff M, Cohen BH, Bertini E, Rahman S; Workshop participants. 258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands. Neuromuscul Disord. 2023;33:700-9. [ McCormick EM, Keller K, Taylor JP, Coffey AJ, Shen L, Krotoski D, Harding B; NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel; Gai X, Falk MJ, Zolkipli-Cunningham Z, Rahman S. Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum. Ann Neurol. 2023;94:696-712. [ Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19:10.1038/gim.2017.107. [ Poulton J, Turnbull DM. 74th European Neuromuscular Centre International Consensus Workshop on genetic counseling and prenatal diagnosis of mitochondrial DNA disorders. 19-20 November 1999, Naarden, The Netherlands. Available • Diodato D, Schiff M, Cohen BH, Bertini E, Rahman S; Workshop participants. 258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands. Neuromuscul Disord. 2023;33:700-9. [ • McCormick EM, Keller K, Taylor JP, Coffey AJ, Shen L, Krotoski D, Harding B; NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel; Gai X, Falk MJ, Zolkipli-Cunningham Z, Rahman S. Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum. Ann Neurol. 2023;94:696-712. [ • Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19:10.1038/gim.2017.107. [ • Poulton J, Turnbull DM. 74th European Neuromuscular Centre International Consensus Workshop on genetic counseling and prenatal diagnosis of mitochondrial DNA disorders. 19-20 November 1999, Naarden, The Netherlands. Available ## Published Guidelines / Consensus Statements Diodato D, Schiff M, Cohen BH, Bertini E, Rahman S; Workshop participants. 258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands. Neuromuscul Disord. 2023;33:700-9. [ McCormick EM, Keller K, Taylor JP, Coffey AJ, Shen L, Krotoski D, Harding B; NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel; Gai X, Falk MJ, Zolkipli-Cunningham Z, Rahman S. Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum. Ann Neurol. 2023;94:696-712. [ Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19:10.1038/gim.2017.107. [ Poulton J, Turnbull DM. 74th European Neuromuscular Centre International Consensus Workshop on genetic counseling and prenatal diagnosis of mitochondrial DNA disorders. 19-20 November 1999, Naarden, The Netherlands. Available • Diodato D, Schiff M, Cohen BH, Bertini E, Rahman S; Workshop participants. 258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands. Neuromuscul Disord. 2023;33:700-9. [ • McCormick EM, Keller K, Taylor JP, Coffey AJ, Shen L, Krotoski D, Harding B; NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel; Gai X, Falk MJ, Zolkipli-Cunningham Z, Rahman S. Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum. Ann Neurol. 2023;94:696-712. [ • Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, Christodoulou J, Cohen BH, Dimmock D, Enns GM, Falk MJ, Feigenbaum A, Frye RE, Ganesh J, Griesemer D, Haas R, Horvath R, Korson M, Kruer MC, Mancuso M, McCormack S, Raboisson MJ, Reimschisel T, Salvarinova R, Saneto RP, Scaglia F, Shoffner J, Stacpoole PW, Sue CM, Tarnopolsky M, Van Karnebeek C, Wolfe LA, Cunningham ZZ, Rahman S, Chinnery PF. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19:10.1038/gim.2017.107. [ • Poulton J, Turnbull DM. 74th European Neuromuscular Centre International Consensus Workshop on genetic counseling and prenatal diagnosis of mitochondrial DNA disorders. 19-20 November 1999, Naarden, The Netherlands. Available ## Literature Cited Estimated probability of a severe outcome (95% CI) for an individual with Estimated probability of having clinical manifestations of Leigh syndrome spectrum based on the heteroplasmy level detected in blood for Predicted risk to offspring (95% CI) to develop clinical manifestations of Leigh syndrome spectrum due to	[]	30/10/2003	9/5/2024	4/5/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nars1	nars1	[ "NARS1-Related Neurodevelopmental Disorder (NARS1-NDD)", "NARS1-Related Hereditary Neuropathy", "Asparagine--tRNA ligase, cytoplasmic", "NARS1", "NARS1-Related Neurologic Disorders" ]		Stephanie Efthymiou, Sara Nagy, Busra Aynekin, Henry Houlden	Summary To date, 54 individuals from 30 families with The diagnosis of a Once the	## Diagnosis No consensus clinical diagnostic criteria for A Gross motor delay (mild/moderate to severe) Intellectual disability (moderate to profound) Speech and language delays (most often severe delays; absence of language development in some) Fine motor delay (moderate to severe) Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes Family history may suggest autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity, unaffected parents) or autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings A Gross motor delay (mild/moderate to severe) Intellectual disability (moderate to profound) Speech and language delays (most often severe delays; absence of language development in some) Fine motor delay (moderate to severe) Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes Family history may suggest autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity, unaffected parents) or autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. • • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes Gross motor delay (mild/moderate to severe) Intellectual disability (moderate to profound) Speech and language delays (most often severe delays; absence of language development in some) Fine motor delay (moderate to severe) • • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) • Gross motor delay (mild/moderate to severe) • Intellectual disability (moderate to profound) • Speech and language delays (most often severe delays; absence of language development in some) • Fine motor delay (moderate to severe) Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes • Axonal sensorimotor neuropathy with predominantly distal lower limb weakness, pes cavus, claw toes, distal sensory impairment, and weak or absent reflexes. Atrophy is uncommon. • Distal hereditary motor neuropathy with distal weakness of mostly the lower limbs, pes cavus, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes ## Family History Family history may suggest autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity, unaffected parents) or autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, 54 individuals from 30 families (range: age younger than one year to 33 years) with − = not observed in any individual; + = observed in 50% of individuals; +++ = observed in 100% of individuals reported to date; NDD = neurodevelopmental disorder Typically associated with biallelic pathogenic variants or a Typically associated with a heterozygous pathogenic variant Microcephaly is reported in almost all individuals and can be observed at birth. It is commonly progressive. Nerve conduction studies confirmed a demyelinating type of neuropathy in all but one individual, who had primarily axonal degeneration. Two individuals had cataracts. The following were observed in single individuals: Dysarthria in an individual who also had bilateral tremor and occasional myoclonus Unilateral intentional hand tremor Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years Medullary sponge kidney Hepatic hemangioma To date, no genotype-phenotype correlations have been identified. To date, 43 individuals from 27 families have been reported with • Two individuals had cataracts. • The following were observed in single individuals: • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma ## Clinical Description To date, 54 individuals from 30 families (range: age younger than one year to 33 years) with − = not observed in any individual; + = observed in 50% of individuals; +++ = observed in 100% of individuals reported to date; NDD = neurodevelopmental disorder Typically associated with biallelic pathogenic variants or a Typically associated with a heterozygous pathogenic variant Microcephaly is reported in almost all individuals and can be observed at birth. It is commonly progressive. Nerve conduction studies confirmed a demyelinating type of neuropathy in all but one individual, who had primarily axonal degeneration. Two individuals had cataracts. The following were observed in single individuals: Dysarthria in an individual who also had bilateral tremor and occasional myoclonus Unilateral intentional hand tremor Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years Medullary sponge kidney Hepatic hemangioma • Two individuals had cataracts. • The following were observed in single individuals: • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma Microcephaly is reported in almost all individuals and can be observed at birth. It is commonly progressive. Nerve conduction studies confirmed a demyelinating type of neuropathy in all but one individual, who had primarily axonal degeneration. Two individuals had cataracts. The following were observed in single individuals: Dysarthria in an individual who also had bilateral tremor and occasional myoclonus Unilateral intentional hand tremor Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years Medullary sponge kidney Hepatic hemangioma • Two individuals had cataracts. • The following were observed in single individuals: • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma • Dysarthria in an individual who also had bilateral tremor and occasional myoclonus • Unilateral intentional hand tremor • Basilar thrombosis in an individual who had an infarction in the cerebellum, pons, and midbrain at age 2.5 years • Medullary sponge kidney • Hepatic hemangioma ## Genotype-Phenotype Correlations To date, no genotype-phenotype correlations have been identified. ## Prevalence To date, 43 individuals from 27 families have been reported with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis ## Management No clinical practice guidelines for In the absence of published guidelines for For information on the management of To establish the extent of disease and needs in an individual diagnosed with Assess for ataxia (e.g., SARA) & peripheral neuropathy (nerve conduction studies). To include brain MRI if not performed at the time of diagnostic eval Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) To date there is no cure for Many ASMs may be effective: levetirazetam, sodium valproate, & phenobarbital resulted in variable seizure control. Education of parents/caregivers Physical therapy Self-directed exercise Exercises to improve balance, gait training, & muscle strengthening to maintain mobility & function & to prevent contractures Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs). Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Assessment of feeding Monitoring of stool frequency Dietary assessment to maintain adequate nutrition & growth OT = occupational therapist; PT = physical therapist See Search • Assess for ataxia (e.g., SARA) & peripheral neuropathy (nerve conduction studies). • To include brain MRI if not performed at the time of diagnostic eval • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective: levetirazetam, sodium valproate, & phenobarbital resulted in variable seizure control. • Education of parents/caregivers • Physical therapy • Self-directed exercise • Exercises to improve balance, gait training, & muscle strengthening to maintain mobility & function & to prevent contractures • Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs). • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Assessment of feeding • Monitoring of stool frequency • Dietary assessment to maintain adequate nutrition & growth ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Assess for ataxia (e.g., SARA) & peripheral neuropathy (nerve conduction studies). To include brain MRI if not performed at the time of diagnostic eval Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Assess for ataxia (e.g., SARA) & peripheral neuropathy (nerve conduction studies). • To include brain MRI if not performed at the time of diagnostic eval • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations To date there is no cure for Many ASMs may be effective: levetirazetam, sodium valproate, & phenobarbital resulted in variable seizure control. Education of parents/caregivers Physical therapy Self-directed exercise Exercises to improve balance, gait training, & muscle strengthening to maintain mobility & function & to prevent contractures Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs). Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Many ASMs may be effective: levetirazetam, sodium valproate, & phenobarbital resulted in variable seizure control. • Education of parents/caregivers • Physical therapy • Self-directed exercise • Exercises to improve balance, gait training, & muscle strengthening to maintain mobility & function & to prevent contractures • Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs). • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Assessment of feeding Monitoring of stool frequency Dietary assessment to maintain adequate nutrition & growth OT = occupational therapist; PT = physical therapist • Assessment of feeding • Monitoring of stool frequency • Dietary assessment to maintain adequate nutrition & growth ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of a child with Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygous parents of a child with autosomal recessive If both parents are known to be heterozygous for a Heterozygous sibs of a proband with autosomal recessive The proportion of individuals with an autosomal dominant All probands reported to date with Some individuals diagnosed with Many individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is known to have the If the To date, individuals with Each child of an individual with The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. For the families of individuals with autosomal recessive It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of a child with • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygous parents of a child with autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygous sibs of a proband with autosomal recessive • The proportion of individuals with an autosomal dominant • All probands reported to date with • Some individuals diagnosed with • All probands reported to date with • Some individuals diagnosed with • Many individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • All probands reported to date with • Some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is known to have the • If the • To date, individuals with • Each child of an individual with • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • For the families of individuals with autosomal recessive • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. ## Mode of Inheritance ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygous parents of a child with autosomal recessive If both parents are known to be heterozygous for a Heterozygous sibs of a proband with autosomal recessive • The parents of a child with • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygous parents of a child with autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygous sibs of a proband with autosomal recessive ## Autosomal Dominant Inheritance – Risk to Family Members The proportion of individuals with an autosomal dominant All probands reported to date with Some individuals diagnosed with Many individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is known to have the If the To date, individuals with Each child of an individual with • The proportion of individuals with an autosomal dominant • All probands reported to date with • Some individuals diagnosed with • All probands reported to date with • Some individuals diagnosed with • Many individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • All probands reported to date with • Some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is known to have the • If the • To date, individuals with • Each child of an individual with ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. For the families of individuals with autosomal recessive It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • For the families of individuals with autosomal recessive • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes (carriers) or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada Speaking out for People with Intellectual and Developmental Disabilities • • • • • • • • Canada • • • • • • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics NARS1-Related Neurologic Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NARS1-Related Neurologic Disorders ( Biallelic Heterozygous Induced pluripotent stem cell (iPSC)-derived cortical brain organoids from individuals with biallelic Using the recurring homozygous c.1633C>T (p.Arg545Cys) variant as an example, it is clear from Western blot and yeast model studies that it results in near-normal protein levels and an increased yeast growth suggestive of a gain-of-function mechanism. However, protein modeling of this variant demonstrated loss of the helix linker, indicating reduced tRNA interaction and catalytic activity as well as reduced aminoacylation activity, suggesting a loss-of-function effect. Using the frequent • Using the recurring homozygous c.1633C>T (p.Arg545Cys) variant as an example, it is clear from Western blot and yeast model studies that it results in near-normal protein levels and an increased yeast growth suggestive of a gain-of-function mechanism. However, protein modeling of this variant demonstrated loss of the helix linker, indicating reduced tRNA interaction and catalytic activity as well as reduced aminoacylation activity, suggesting a loss-of-function effect. • Using the frequent ## Molecular Pathogenesis Biallelic Heterozygous Induced pluripotent stem cell (iPSC)-derived cortical brain organoids from individuals with biallelic Using the recurring homozygous c.1633C>T (p.Arg545Cys) variant as an example, it is clear from Western blot and yeast model studies that it results in near-normal protein levels and an increased yeast growth suggestive of a gain-of-function mechanism. However, protein modeling of this variant demonstrated loss of the helix linker, indicating reduced tRNA interaction and catalytic activity as well as reduced aminoacylation activity, suggesting a loss-of-function effect. Using the frequent • Using the recurring homozygous c.1633C>T (p.Arg545Cys) variant as an example, it is clear from Western blot and yeast model studies that it results in near-normal protein levels and an increased yeast growth suggestive of a gain-of-function mechanism. However, protein modeling of this variant demonstrated loss of the helix linker, indicating reduced tRNA interaction and catalytic activity as well as reduced aminoacylation activity, suggesting a loss-of-function effect. • Using the frequent ## Chapter Notes Stephanie Efthymiou, MSc, PhD ( Stephanie Efthymiou, MSc, PhD ( Stephanie Efthymiou, MSc, PhD ( Contact Stephanie Efthymiou, MSc, PhD ( Stephanie Efthymiou thanks the Solve-RD Consortium for a seeding grant and the Rory Belle Foundation for their support. 27 February 2025 (bp) Review posted live 14 November 2022 (se) Original submission • 27 February 2025 (bp) Review posted live • 14 November 2022 (se) Original submission ## Author Notes Stephanie Efthymiou, MSc, PhD ( Stephanie Efthymiou, MSc, PhD ( Stephanie Efthymiou, MSc, PhD ( Contact Stephanie Efthymiou, MSc, PhD ( ## Acknowledgments Stephanie Efthymiou thanks the Solve-RD Consortium for a seeding grant and the Rory Belle Foundation for their support. ## Revision History 27 February 2025 (bp) Review posted live 14 November 2022 (se) Original submission • 27 February 2025 (bp) Review posted live • 14 November 2022 (se) Original submission ## References ## Literature Cited	[]	27/2/2025			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nbia-ov	nbia-ov	[ "NBIA", "Aceruloplasminemia", "Neuroferritinopathy", "Pantothenate Kinase-Associated Neurodegeneration", "Fatty Acid Hydroxylase-Associated Neurodegeneration", "PLA2G6-Associated Neurodegeneration", "Mitochondrial Membrane Protein-Associated Neurodegeneration", "Woodhouse-Sakati Syndrome", "Kufor-Rakeb Syndrome", "Beta-Propeller Protein-Associated Neurodegeneration", "COASY protein-associated neurodegeneration", "85/88 kDa calcium-independent phospholipase A2", "Bifunctional coenzyme A synthase", "Ceruloplasmin", "DDB1- and CUL4-associated factor 17", "Fatty acid 2-hydroxylase", "Ferritin light chain", "Pantothenate kinase 2, mitochondrial", "Polyamine-transporting ATPase 13A2", "Protein C19orf12", "WD repeat domain phosphoinositide-interacting protein 4", "ATP13A2", "C19orf12", "COASY", "CP", "DCAF17", "FA2H", "FTL", "PANK2", "PLA2G6", "WDR45", "Neurodegeneration with Brain Iron Accumulation Disorders", "Overview" ]	Neurodegeneration with Brain Iron Accumulation Disorders Overview	Allison Gregory, Manju A Kurian, Jenny Wilson, Susan Hayflick	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review high-level Inform	## Clinical Characteristics of Neurodegeneration with Brain Iron Accumulation Neurodegeneration with brain iron accumulation (NBIA) disorders are a group of inherited neurologic disorders characterized by abnormal accumulation of iron in the basal ganglia (most often in the globus pallidus and/or substantia nigra). Additional brain abnormalities such as generalized cerebral atrophy and cerebellar atrophy are frequently observed. The hallmark clinical manifestations of NBIA vary by genetic subtype and generally include progressive dystonia, dysarthria, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Cognitive decline occurs in some types. Onset ranges from infancy to adulthood. Progression can be rapid or slow with long periods of stability. In general, the early-onset forms tend to progress more rapidly than late-onset, protracted forms of NBIA. The distinctive clinical and neuroimaging findings of the 11 genetically defined NBIA types are summarized in Neurodegeneration with Brain Iron Accumulation Disorders: Clinical Characteristics by Genetic Type Progressive generalized dystonia w/prominent bulbar/oromandibular involvement, dysarthria, rigidity, spasticity, hyperreflexia, & striatal toe signs Retinal degeneration is common & may be detected by ERG several yrs before onset of visual symptoms. Neuropsychiatric symptoms (more frequent in later-onset form) Progressive cognitive decline Strabismus, nystagmus, & optic atrophy Rapid disease progression Neuropsychiatric changes Dystonia & spastic tetraparesis Cognitive decline Slower progression Marked cognitive decline Subacute onset of dystonia-parkinsonism Eye movement abnormalities Pyramidal tract signs Children: gait abnormalities, limb spasticity, & optic atrophy Adults: gait abnormalities & acute neuropsychiatric changes Progressive cognitive decline in most persons Neuropsychiatric changes Spasticity (more prominent than dystonia), motor neuronopathy w/early upper motor neuron findings followed by signs of lower motor neuron dysfunction Optic atrophy Slowly progressive course w/survival well into adulthood Seizures of various types are more prominent in childhood & may resolve in later adolescence. Autistic features Stereotypies Hyperphagia Premature adrenarche Motor dysfunction incl broad-based or ataxic gait, hypotonia, mild spasticity Relatively sudden onset of progressive parkinsonism & dementia during late adolescence or adulthood Slowly progressive ataxia, dysarthria, dystonia, & tetraparesis Optic atrophy leading to progressive loss of visual acuity Seizures during later stages of disease Progressive cognitive decline in most affected persons Parkinsonism Dementia Supranuclear gaze palsy Facial-faucial-finger myoclonus Visual hallucinations Oculogyric dystonic spasms Progresses from extremity involvement to more generalized movement disorder Characteristic orofacial action-specific dystonia related to speech Limited speech, intellectual disability Progressive spasticity Dystonia, dysphagia Seizures Facial & neck dystonia, dysarthria, tremors, chorea, ataxia, & blepharospasm ↓ serum concentrations of copper & iron & ↑ serum concentrations of ferritin can distinguish aceruloplasminemia from other forms of NBIA. Alopecia may be earliest symptom. Intellectual disability & delayed puberty Progressive extrapyramidal disorder, generalized & focal dystonia, dysarthria, & cognitive decline Endocrine abnormalities (hypogonadism, alopecia, & diabetes mellitus) Oromandibular dystonia, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment, & obsessive-compulsive behavior Slow progression; nonambulatory in 3rd decade BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; ERG = electroretinography; FAHN = fatty acid hydroxylase-associated neurodegeneration; INAD = infantile neuroaxonal dystrophy; MPAN = mitochondrial membrane protein-associated neurodegeneration; NAD = neuroaxonal dystrophy; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = Juvenile PLAN is less common than the infantile form (INAD). A common Proposed to be an NBIA disorder based on findings described by A common The A founder pathogenic variant in The CoPAN phenotype will continue to evolve as additional affected individuals are recognized. Neurodegeneration with Brain Iron Accumulation Disorders: Neuroimaging Findings by Genetic Type BG = basal ganglia; BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; FAHN = fatty acid hydroxylase-associated neurodegeneration; GP = globus pallidus; MPAN = mitochondrial membrane protein-associated neurodegeneration; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = For a more comprehensive overview of the radiographic findings in NBIA disorders, see The eye of the tiger sign is a T Similar to Abnormal hypointensities in the liver are common (liver iron content > basal ganglia iron content). In one individual early in the disease course, T NBIA can be diagnosed in individuals with suggestive clinical features as well as characteristic neuroimaging findings. Neuropathologic findings may include basal ganglia iron accumulation or axonal spheroids in the central nervous system (both identified postmortem) and, in some types, in peripheral nerves that can be identified with a biopsy as part of the diagnostic workup. • Progressive generalized dystonia w/prominent bulbar/oromandibular involvement, dysarthria, rigidity, spasticity, hyperreflexia, & striatal toe signs • Retinal degeneration is common & may be detected by ERG several yrs before onset of visual symptoms. • Neuropsychiatric symptoms (more frequent in later-onset form) • Progressive cognitive decline • Strabismus, nystagmus, & optic atrophy • Rapid disease progression • Neuropsychiatric changes • Dystonia & spastic tetraparesis • Cognitive decline • Slower progression • Marked cognitive decline • Subacute onset of dystonia-parkinsonism • Eye movement abnormalities • Pyramidal tract signs • Children: gait abnormalities, limb spasticity, & optic atrophy • Adults: gait abnormalities & acute neuropsychiatric changes • Progressive cognitive decline in most persons • Neuropsychiatric changes • Spasticity (more prominent than dystonia), motor neuronopathy w/early upper motor neuron findings followed by signs of lower motor neuron dysfunction • Optic atrophy • Slowly progressive course w/survival well into adulthood • Seizures of various types are more prominent in childhood & may resolve in later adolescence. • Autistic features • Stereotypies • Hyperphagia • Premature adrenarche • Motor dysfunction incl broad-based or ataxic gait, hypotonia, mild spasticity • Relatively sudden onset of progressive parkinsonism & dementia during late adolescence or adulthood • Slowly progressive ataxia, dysarthria, dystonia, & tetraparesis • Optic atrophy leading to progressive loss of visual acuity • Seizures during later stages of disease • Progressive cognitive decline in most affected persons • Parkinsonism • Dementia • Supranuclear gaze palsy • Facial-faucial-finger myoclonus • Visual hallucinations • Oculogyric dystonic spasms • Progresses from extremity involvement to more generalized movement disorder • Characteristic orofacial action-specific dystonia related to speech • Limited speech, intellectual disability • Progressive spasticity • Dystonia, dysphagia • Seizures • Facial & neck dystonia, dysarthria, tremors, chorea, ataxia, & blepharospasm • ↓ serum concentrations of copper & iron & ↑ serum concentrations of ferritin can distinguish aceruloplasminemia from other forms of NBIA. • Alopecia may be earliest symptom. • Intellectual disability & delayed puberty • Progressive extrapyramidal disorder, generalized & focal dystonia, dysarthria, & cognitive decline • Endocrine abnormalities (hypogonadism, alopecia, & diabetes mellitus) • Oromandibular dystonia, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment, & obsessive-compulsive behavior • Slow progression; nonambulatory in 3rd decade ## Diagnosis of Neurodegeneration with Brain Iron Accumulation NBIA can be diagnosed in individuals with suggestive clinical features as well as characteristic neuroimaging findings. Neuropathologic findings may include basal ganglia iron accumulation or axonal spheroids in the central nervous system (both identified postmortem) and, in some types, in peripheral nerves that can be identified with a biopsy as part of the diagnostic workup. ## Genetic Causes of Neurodegeneration with Brain Iron Accumulation The 11 genes known to be associated with types of neurodegeneration with brain iron accumulation (NBIA) are Neurodegeneration with Brain Iron Accumulation: Genetic Types AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Genes are listed alphabetically. Pathogenic variants in Autosomal dominant inheritance and Based on prevalence in the International Registry for NBIA and Related Disorders from the Hayflick laboratory Described in a few case reports and one larger series of 12 families [ First reported as an NBIA disorder by ## Differential Diagnosis of Neurodegeneration with Brain Iron Accumulation The differential diagnosis of neurodegeneration with brain iron accumulation (NBIA) is usually based on a brain MRI that raises the suspicion of abnormal iron accumulation (see Conditions with Brain MRI Findings or Clinical Findings that Resemble Neurodegeneration with Brain Iron Accumulation BG = basal ganglia; CK = creatine kinase; GP = globus pallidus; RN = red nucleus; SN = substantia nigra ## Evaluation Strategies to Identify the Genetic Cause of Neurodegeneration with Brain Iron Accumulation in a Proband Establishing a specific genetic cause of neurodegeneration with brain iron accumulation (NBIA): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, family history, laboratory testing, and genomic/genetic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, family history, laboratory testing, and genomic/genetic testing. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management of Neurodegeneration with Brain Iron Accumulation To establish the extent of disease and needs in an individual diagnosed with a neurodegeneration with brain iron accumulation (NBIA) disorder, the evaluations summarized in Neurodegeneration with Brain Iron Accumulation Disorders: Recommended Evaluations Following Initial Diagnosis Consider EEG for clinical seizures or movements suspected to be seizures. Neuromotor eval (tone, hyper- or hypokinetic movement disorder, balance, & gait) Consider referral to PT, OT, orthopedics, &/or PM&R. Assess swallowing & nutritional status; consider referral for swallow study or feeding specialist. Assess communication (e.g., dysarthria); consider referral to SLP or AAC specialist. Assess quality of sleep; consider referral for sleep study. To incl motor, adaptive, cognitive, & communication Based on diagnosis, assess for autistic features (e.g., stereotypies), ADHD, anxiety, & other behaviors like abnormal breathing patterns. Gross motor & fine motor skills Contractures, spinal abnormalities, hip abnormalities Mobility, ADL, & need for adaptive devices Need for PT &/or OT Only for those NBIA disorders w/known endocrine abnormalities or if there are indicators of an abnormality such as signs of premature puberty &/or advanced bone age Persons w/Woodhouse-Sakati syndrome will require more frequent screening. Persons w/aceruloplasminemia should include screening for diabetes mellitus. Community or Social work involvement for parental support Home nursing referral Palliative care referral (may be appropriate at time of diagnosis for some persons) AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; MOI = mode of inheritance; OCD = obsessive-compulsive disorder; OT = occupational therapy; PM&R = physical medicine and rehabilitation; PT = physical therapy; SLP = speech-language pathologist Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatments for NBIA disorders are palliative and should be tailored to the specific NBIA disorder and to the affected individual. Consensus management guidelines for Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Neurodegeneration with Brain Iron Accumulation Disorders: Treatment of Manifestations Incl for persons w/a later-onset, more protracted course accompanied by neuropsychiatric symptoms Some children may benefit from educational programs or behavioral interventions like ABA therapy (particularly for BPAN) Consider need for positioning & mobility devices (e.g., AFOs, walkers, wheelchairs, hoist), disability parking placard. Several NBIA disorders require significant dystonia mgmt, Deep brain stimulation (DBS), used clinically for dystonia w/increasing frequency, shows some evidence of benefit for some NBIA disorders. While it may reduce dystonic crises for a limited amount of time, disease will still progress. DBS may also have a role in treating parkinsonism in some forms of NBIA. Botulinum toxin to target focal dystonia or spasticity Some NBIA disorders will involve interventions for low tone, esp truncal hypotonia, (e.g., use of Lycra Levodopa & other treatments for parkinsonism are beneficial in NBIA disorders where this is a prominent feature. Standing activities & vitamin D supplementation are beneficial for bone health. Many ASMs may be effective. Some children w/BPAN have intractable seizures & may try interventions like ketogenic diet or vagus nerve stimulation. Some persons w/BPAN will have infantile spasms &/or epileptic encephalopathy that require specialized mgmt. Once affected person can no longer maintain an adequate diet orally, or is choking or aspirating, a gastrostomy tube should be considered. Over-the-counter fiber supplements, laxatives, &/or stool softeners are indicated to treat constipation, which may be caused by a combination of immobility, diet, & medications. Speech delay or limited/absent speech is common in children & adults w/NBIA disorders & should be addressed by an SLP, ideally one w/expertise in AAC. For adults & teens, dysarthria is usually identified by neurologist w/referral to SLP or other specialists, such as ENT for vocal cord botulinum toxin injections, as needed. All affected persons w/communication deficits should have formal audiologic eval. With disease progression & loss of mobility, pulmonary hygiene may become useful. Bed sores & skin breakdown in areas exposed to friction from dystonia or spasticity require attention. Mgmt of secretions w/medication, suction, or eventual tracheostomy may be indicated. Ensure appropriate social work involvement to connect families w/local resources, respite, & support Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or AAC = augmentative and alternative communication; ABA = applied behavior analysis; AFO = ankle-foot orthoses; ASM = anti-seizure medication; BPAN = beta-propeller protein-associated neurodegeneration; NBIA = neurodegeneration with brain iron accumulation; OT = occupational therapist/therapy; PM&R = physical medicine and rehabilitation; PT = physical therapist; SLP = speech-language pathologist As some NBIA disorders progress, affected individuals may experience episodes of extreme dystonia lasting for days or weeks (status dystonicus). It is especially important during these episodes to evaluate for treatable causes of pain, which may include occult gastrointestinal bleeding, urinary tract infections, and occult bone fractures and pressure sores. Some individuals will have an initially dramatic response that may diminish over time; some will develop prominent dyskinesias. The combination of osteopenia in a nonambulatory person with marked stress on the long bones from dystonia places many individuals with an NBIA disorder at high risk for fractures without apparent trauma. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Neurodegeneration with Brain Iron Accumulation Disorders: Recommended Surveillance Assess for new manifestations such as seizures, changes in tone, movement disorders, & changes in speech. Assess for changes in sleep. Assess for pain. Assess efficacy / side effects of current treatments. Assess for signs of disease progression such as loss of function. Measurement of growth in children Eval of weight/nutritional status & safety of oral intake Monitor for constipation. Evaluate developmental progress/changes & developmental supports. Assess for abnormal behaviors. Screen for anxiety, depression, & other psychiatric disorders. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy Unproven targeted compounds are listed in Neurodegeneration with Brain Iron Accumulation: Therapies Under Investigation DHA = docosahexaenoic acid; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = Search • Consider EEG for clinical seizures or movements suspected to be seizures. • Neuromotor eval (tone, hyper- or hypokinetic movement disorder, balance, & gait) • Consider referral to PT, OT, orthopedics, &/or PM&R. • Assess swallowing & nutritional status; consider referral for swallow study or feeding specialist. • Assess communication (e.g., dysarthria); consider referral to SLP or AAC specialist. • Assess quality of sleep; consider referral for sleep study. • To incl motor, adaptive, cognitive, & communication • Based on diagnosis, assess for autistic features (e.g., stereotypies), ADHD, anxiety, & other behaviors like abnormal breathing patterns. • Gross motor & fine motor skills • Contractures, spinal abnormalities, hip abnormalities • Mobility, ADL, & need for adaptive devices • Need for PT &/or OT • Only for those NBIA disorders w/known endocrine abnormalities or if there are indicators of an abnormality such as signs of premature puberty &/or advanced bone age • Persons w/Woodhouse-Sakati syndrome will require more frequent screening. • Persons w/aceruloplasminemia should include screening for diabetes mellitus. • Community or • Social work involvement for parental support • Home nursing referral • Palliative care referral (may be appropriate at time of diagnosis for some persons) • Incl for persons w/a later-onset, more protracted course accompanied by neuropsychiatric symptoms • Some children may benefit from educational programs or behavioral interventions like ABA therapy (particularly for BPAN) • Consider need for positioning & mobility devices (e.g., AFOs, walkers, wheelchairs, hoist), disability parking placard. • Several NBIA disorders require significant dystonia mgmt, • Deep brain stimulation (DBS), used clinically for dystonia w/increasing frequency, shows some evidence of benefit for some NBIA disorders. While it may reduce dystonic crises for a limited amount of time, disease will still progress. DBS may also have a role in treating parkinsonism in some forms of NBIA. • Botulinum toxin to target focal dystonia or spasticity • Some NBIA disorders will involve interventions for low tone, esp truncal hypotonia, (e.g., use of Lycra • Levodopa & other treatments for parkinsonism are beneficial in NBIA disorders where this is a prominent feature. • Standing activities & vitamin D supplementation are beneficial for bone health. • Many ASMs may be effective. • Some children w/BPAN have intractable seizures & may try interventions like ketogenic diet or vagus nerve stimulation. • Some persons w/BPAN will have infantile spasms &/or epileptic encephalopathy that require specialized mgmt. • Once affected person can no longer maintain an adequate diet orally, or is choking or aspirating, a gastrostomy tube should be considered. • Over-the-counter fiber supplements, laxatives, &/or stool softeners are indicated to treat constipation, which may be caused by a combination of immobility, diet, & medications. • Speech delay or limited/absent speech is common in children & adults w/NBIA disorders & should be addressed by an SLP, ideally one w/expertise in AAC. • For adults & teens, dysarthria is usually identified by neurologist w/referral to SLP or other specialists, such as ENT for vocal cord botulinum toxin injections, as needed. • All affected persons w/communication deficits should have formal audiologic eval. • With disease progression & loss of mobility, pulmonary hygiene may become useful. • Bed sores & skin breakdown in areas exposed to friction from dystonia or spasticity require attention. • Mgmt of secretions w/medication, suction, or eventual tracheostomy may be indicated. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • Assess for new manifestations such as seizures, changes in tone, movement disorders, & changes in speech. • Assess for changes in sleep. • Assess for pain. • Assess efficacy / side effects of current treatments. • Assess for signs of disease progression such as loss of function. • Measurement of growth in children • Eval of weight/nutritional status & safety of oral intake • Monitor for constipation. • Evaluate developmental progress/changes & developmental supports. • Assess for abnormal behaviors. • Screen for anxiety, depression, & other psychiatric disorders. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a neurodegeneration with brain iron accumulation (NBIA) disorder, the evaluations summarized in Neurodegeneration with Brain Iron Accumulation Disorders: Recommended Evaluations Following Initial Diagnosis Consider EEG for clinical seizures or movements suspected to be seizures. Neuromotor eval (tone, hyper- or hypokinetic movement disorder, balance, & gait) Consider referral to PT, OT, orthopedics, &/or PM&R. Assess swallowing & nutritional status; consider referral for swallow study or feeding specialist. Assess communication (e.g., dysarthria); consider referral to SLP or AAC specialist. Assess quality of sleep; consider referral for sleep study. To incl motor, adaptive, cognitive, & communication Based on diagnosis, assess for autistic features (e.g., stereotypies), ADHD, anxiety, & other behaviors like abnormal breathing patterns. Gross motor & fine motor skills Contractures, spinal abnormalities, hip abnormalities Mobility, ADL, & need for adaptive devices Need for PT &/or OT Only for those NBIA disorders w/known endocrine abnormalities or if there are indicators of an abnormality such as signs of premature puberty &/or advanced bone age Persons w/Woodhouse-Sakati syndrome will require more frequent screening. Persons w/aceruloplasminemia should include screening for diabetes mellitus. Community or Social work involvement for parental support Home nursing referral Palliative care referral (may be appropriate at time of diagnosis for some persons) AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; MOI = mode of inheritance; OCD = obsessive-compulsive disorder; OT = occupational therapy; PM&R = physical medicine and rehabilitation; PT = physical therapy; SLP = speech-language pathologist Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Consider EEG for clinical seizures or movements suspected to be seizures. • Neuromotor eval (tone, hyper- or hypokinetic movement disorder, balance, & gait) • Consider referral to PT, OT, orthopedics, &/or PM&R. • Assess swallowing & nutritional status; consider referral for swallow study or feeding specialist. • Assess communication (e.g., dysarthria); consider referral to SLP or AAC specialist. • Assess quality of sleep; consider referral for sleep study. • To incl motor, adaptive, cognitive, & communication • Based on diagnosis, assess for autistic features (e.g., stereotypies), ADHD, anxiety, & other behaviors like abnormal breathing patterns. • Gross motor & fine motor skills • Contractures, spinal abnormalities, hip abnormalities • Mobility, ADL, & need for adaptive devices • Need for PT &/or OT • Only for those NBIA disorders w/known endocrine abnormalities or if there are indicators of an abnormality such as signs of premature puberty &/or advanced bone age • Persons w/Woodhouse-Sakati syndrome will require more frequent screening. • Persons w/aceruloplasminemia should include screening for diabetes mellitus. • Community or • Social work involvement for parental support • Home nursing referral • Palliative care referral (may be appropriate at time of diagnosis for some persons) ## Treatment of Manifestations Treatments for NBIA disorders are palliative and should be tailored to the specific NBIA disorder and to the affected individual. Consensus management guidelines for Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Neurodegeneration with Brain Iron Accumulation Disorders: Treatment of Manifestations Incl for persons w/a later-onset, more protracted course accompanied by neuropsychiatric symptoms Some children may benefit from educational programs or behavioral interventions like ABA therapy (particularly for BPAN) Consider need for positioning & mobility devices (e.g., AFOs, walkers, wheelchairs, hoist), disability parking placard. Several NBIA disorders require significant dystonia mgmt, Deep brain stimulation (DBS), used clinically for dystonia w/increasing frequency, shows some evidence of benefit for some NBIA disorders. While it may reduce dystonic crises for a limited amount of time, disease will still progress. DBS may also have a role in treating parkinsonism in some forms of NBIA. Botulinum toxin to target focal dystonia or spasticity Some NBIA disorders will involve interventions for low tone, esp truncal hypotonia, (e.g., use of Lycra Levodopa & other treatments for parkinsonism are beneficial in NBIA disorders where this is a prominent feature. Standing activities & vitamin D supplementation are beneficial for bone health. Many ASMs may be effective. Some children w/BPAN have intractable seizures & may try interventions like ketogenic diet or vagus nerve stimulation. Some persons w/BPAN will have infantile spasms &/or epileptic encephalopathy that require specialized mgmt. Once affected person can no longer maintain an adequate diet orally, or is choking or aspirating, a gastrostomy tube should be considered. Over-the-counter fiber supplements, laxatives, &/or stool softeners are indicated to treat constipation, which may be caused by a combination of immobility, diet, & medications. Speech delay or limited/absent speech is common in children & adults w/NBIA disorders & should be addressed by an SLP, ideally one w/expertise in AAC. For adults & teens, dysarthria is usually identified by neurologist w/referral to SLP or other specialists, such as ENT for vocal cord botulinum toxin injections, as needed. All affected persons w/communication deficits should have formal audiologic eval. With disease progression & loss of mobility, pulmonary hygiene may become useful. Bed sores & skin breakdown in areas exposed to friction from dystonia or spasticity require attention. Mgmt of secretions w/medication, suction, or eventual tracheostomy may be indicated. Ensure appropriate social work involvement to connect families w/local resources, respite, & support Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or AAC = augmentative and alternative communication; ABA = applied behavior analysis; AFO = ankle-foot orthoses; ASM = anti-seizure medication; BPAN = beta-propeller protein-associated neurodegeneration; NBIA = neurodegeneration with brain iron accumulation; OT = occupational therapist/therapy; PM&R = physical medicine and rehabilitation; PT = physical therapist; SLP = speech-language pathologist As some NBIA disorders progress, affected individuals may experience episodes of extreme dystonia lasting for days or weeks (status dystonicus). It is especially important during these episodes to evaluate for treatable causes of pain, which may include occult gastrointestinal bleeding, urinary tract infections, and occult bone fractures and pressure sores. Some individuals will have an initially dramatic response that may diminish over time; some will develop prominent dyskinesias. The combination of osteopenia in a nonambulatory person with marked stress on the long bones from dystonia places many individuals with an NBIA disorder at high risk for fractures without apparent trauma. • Incl for persons w/a later-onset, more protracted course accompanied by neuropsychiatric symptoms • Some children may benefit from educational programs or behavioral interventions like ABA therapy (particularly for BPAN) • Consider need for positioning & mobility devices (e.g., AFOs, walkers, wheelchairs, hoist), disability parking placard. • Several NBIA disorders require significant dystonia mgmt, • Deep brain stimulation (DBS), used clinically for dystonia w/increasing frequency, shows some evidence of benefit for some NBIA disorders. While it may reduce dystonic crises for a limited amount of time, disease will still progress. DBS may also have a role in treating parkinsonism in some forms of NBIA. • Botulinum toxin to target focal dystonia or spasticity • Some NBIA disorders will involve interventions for low tone, esp truncal hypotonia, (e.g., use of Lycra • Levodopa & other treatments for parkinsonism are beneficial in NBIA disorders where this is a prominent feature. • Standing activities & vitamin D supplementation are beneficial for bone health. • Many ASMs may be effective. • Some children w/BPAN have intractable seizures & may try interventions like ketogenic diet or vagus nerve stimulation. • Some persons w/BPAN will have infantile spasms &/or epileptic encephalopathy that require specialized mgmt. • Once affected person can no longer maintain an adequate diet orally, or is choking or aspirating, a gastrostomy tube should be considered. • Over-the-counter fiber supplements, laxatives, &/or stool softeners are indicated to treat constipation, which may be caused by a combination of immobility, diet, & medications. • Speech delay or limited/absent speech is common in children & adults w/NBIA disorders & should be addressed by an SLP, ideally one w/expertise in AAC. • For adults & teens, dysarthria is usually identified by neurologist w/referral to SLP or other specialists, such as ENT for vocal cord botulinum toxin injections, as needed. • All affected persons w/communication deficits should have formal audiologic eval. • With disease progression & loss of mobility, pulmonary hygiene may become useful. • Bed sores & skin breakdown in areas exposed to friction from dystonia or spasticity require attention. • Mgmt of secretions w/medication, suction, or eventual tracheostomy may be indicated. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Neurodegeneration with Brain Iron Accumulation Disorders: Recommended Surveillance Assess for new manifestations such as seizures, changes in tone, movement disorders, & changes in speech. Assess for changes in sleep. Assess for pain. Assess efficacy / side effects of current treatments. Assess for signs of disease progression such as loss of function. Measurement of growth in children Eval of weight/nutritional status & safety of oral intake Monitor for constipation. Evaluate developmental progress/changes & developmental supports. Assess for abnormal behaviors. Screen for anxiety, depression, & other psychiatric disorders. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy • Assess for new manifestations such as seizures, changes in tone, movement disorders, & changes in speech. • Assess for changes in sleep. • Assess for pain. • Assess efficacy / side effects of current treatments. • Assess for signs of disease progression such as loss of function. • Measurement of growth in children • Eval of weight/nutritional status & safety of oral intake • Monitor for constipation. • Evaluate developmental progress/changes & developmental supports. • Assess for abnormal behaviors. • Screen for anxiety, depression, & other psychiatric disorders. ## Therapies Under Investigation Unproven targeted compounds are listed in Neurodegeneration with Brain Iron Accumulation: Therapies Under Investigation DHA = docosahexaenoic acid; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = Search ## Genetic Counseling of Family Members of an Individual with Neurodegeneration with Brain Iron Accumulation Neurodegeneration with brain iron accumulation (NBIA) disorders can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner (see Genetic counseling and risk assessment depend on determination of the specific cause of NBIA in an individual. Most forms of NBIA are autosomal recessive. A basic view of genetic counseling issues related to autosomal recessive NBIA is presented in this section; issues that may be specific to a given family or genetic cause of autosomal recessive NBIA are not comprehensively addressed. For review of genetic counseling issues related to: Autosomal dominant NBIA, see X-linked NBIA, see The parents of an affected individual are presumed to be heterozygous for an autosomal recessive NBIA-causing pathogenic variant. Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of a proband to confirm that both parents are heterozygous for an NBIA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive NBIA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Individuals with autosomal recessive forms of NBIA rarely reproduce due to the severity of the condition. Those with later-onset, atypical disease may have offspring; all offspring will be obligate heterozygotes. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Once the NBIA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Autosomal dominant NBIA, see • X-linked NBIA, see • The parents of an affected individual are presumed to be heterozygous for an autosomal recessive NBIA-causing pathogenic variant. • Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of a proband to confirm that both parents are heterozygous for an NBIA-causing pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive NBIA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Individuals with autosomal recessive forms of NBIA rarely reproduce due to the severity of the condition. • Those with later-onset, atypical disease may have offspring; all offspring will be obligate heterozygotes. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Modes of Inheritance Neurodegeneration with brain iron accumulation (NBIA) disorders can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner (see Genetic counseling and risk assessment depend on determination of the specific cause of NBIA in an individual. Most forms of NBIA are autosomal recessive. A basic view of genetic counseling issues related to autosomal recessive NBIA is presented in this section; issues that may be specific to a given family or genetic cause of autosomal recessive NBIA are not comprehensively addressed. For review of genetic counseling issues related to: Autosomal dominant NBIA, see X-linked NBIA, see • Autosomal dominant NBIA, see • X-linked NBIA, see ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an autosomal recessive NBIA-causing pathogenic variant. Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of a proband to confirm that both parents are heterozygous for an NBIA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive NBIA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Individuals with autosomal recessive forms of NBIA rarely reproduce due to the severity of the condition. Those with later-onset, atypical disease may have offspring; all offspring will be obligate heterozygotes. • The parents of an affected individual are presumed to be heterozygous for an autosomal recessive NBIA-causing pathogenic variant. • Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of a proband to confirm that both parents are heterozygous for an NBIA-causing pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive NBIA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Individuals with autosomal recessive forms of NBIA rarely reproduce due to the severity of the condition. • Those with later-onset, atypical disease may have offspring; all offspring will be obligate heterozygotes. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the NBIA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • • • Germany • ## Chapter Notes The Susan Hayflick, MD, and Allison Gregory, MS, CGC, are interested in hearing from clinicians treating families affected by idiopathic NBIA or possible NBIA cases that have been difficult to diagnose and no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Allison Gregory to inquire about review of variants of uncertain significance. 6 March 2025 (gm) Comprehensive update posted live 21 October 2019 (bp) Comprehensive update posted live 28 February 2013 (me) Review posted live 23 April 2012 (ag) Original submission • 6 March 2025 (gm) Comprehensive update posted live • 21 October 2019 (bp) Comprehensive update posted live • 28 February 2013 (me) Review posted live • 23 April 2012 (ag) Original submission ## Author Notes The Susan Hayflick, MD, and Allison Gregory, MS, CGC, are interested in hearing from clinicians treating families affected by idiopathic NBIA or possible NBIA cases that have been difficult to diagnose and no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Allison Gregory to inquire about review of variants of uncertain significance. ## Revision History 6 March 2025 (gm) Comprehensive update posted live 21 October 2019 (bp) Comprehensive update posted live 28 February 2013 (me) Review posted live 23 April 2012 (ag) Original submission • 6 March 2025 (gm) Comprehensive update posted live • 21 October 2019 (bp) Comprehensive update posted live • 28 February 2013 (me) Review posted live • 23 April 2012 (ag) Original submission ## References ## Literature Cited Neurodegeneration with brain iron accumulation types BPAN = beta-propeller protein-associated neurodegeneration PKAN = pantothenate kinase-associated neurodegeneration PLAN = MPAN = mitochondrial membrane protein-associated neurodegeneration Minor forms include those associated with pathogenic variants in	[]	28/2/2013	6/3/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nbs	nbs	[ "NCBRS", "NCBRS", "SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2", "SMARCA2", "SMARCA2-Related Nicolaides-Baraitser Syndrome" ]		Omar Abdul-Rahman, Francis May	Summary The diagnosis of	## Diagnosis Consensus clinical diagnostic criteria for Developmental delay / intellectual disability (DD/ID), most commonly in the severe range but with some having either mild or moderate DD/ID Sparse scalp hair Prominence of the interphalangeal joints and distal phalanges secondary to poor subcutaneous fat distribution (See Characteristic facial features (see Microcephaly Seizures Hand radiographs may show cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays). Abnormal bone age, most often delayed but on occasion advanced for chronologic age Platyspondyly, flat intervertebral discs, small pelvis, pubic bone hypoplasia, small femoral heads, and short femoral neck The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and radiographic findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by dysmorphic features and intellectual disability, comprehensive genomic testing may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with • Developmental delay / intellectual disability (DD/ID), most commonly in the severe range but with some having either mild or moderate DD/ID • Sparse scalp hair • Prominence of the interphalangeal joints and distal phalanges secondary to poor subcutaneous fat distribution (See • Characteristic facial features (see • Microcephaly • Seizures • Hand radiographs may show cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays). • Abnormal bone age, most often delayed but on occasion advanced for chronologic age • Platyspondyly, flat intervertebral discs, small pelvis, pubic bone hypoplasia, small femoral heads, and short femoral neck • For an introduction to multigene panels click ## Suggestive Findings Developmental delay / intellectual disability (DD/ID), most commonly in the severe range but with some having either mild or moderate DD/ID Sparse scalp hair Prominence of the interphalangeal joints and distal phalanges secondary to poor subcutaneous fat distribution (See Characteristic facial features (see Microcephaly Seizures Hand radiographs may show cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays). Abnormal bone age, most often delayed but on occasion advanced for chronologic age Platyspondyly, flat intervertebral discs, small pelvis, pubic bone hypoplasia, small femoral heads, and short femoral neck • Developmental delay / intellectual disability (DD/ID), most commonly in the severe range but with some having either mild or moderate DD/ID • Sparse scalp hair • Prominence of the interphalangeal joints and distal phalanges secondary to poor subcutaneous fat distribution (See • Characteristic facial features (see • Microcephaly • Seizures • Hand radiographs may show cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays). • Abnormal bone age, most often delayed but on occasion advanced for chronologic age • Platyspondyly, flat intervertebral discs, small pelvis, pubic bone hypoplasia, small femoral heads, and short femoral neck ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and radiographic findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by dysmorphic features and intellectual disability, comprehensive genomic testing may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with • For an introduction to multigene panels click ## Option 1 When the phenotypic and radiographic findings suggest the diagnosis of For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by dysmorphic features and intellectual disability, comprehensive genomic testing may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Epigenetic Signature Analysis / Methylation Array A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with ## Clinical Characteristics To date, at least 80 individuals have been identified with a pathogenic variant in About 80% of affected individuals experience severe speech delay, and nearly one third of all affected individuals never develop speech or language skills. The mean age for sitting is approximately nine months and the mean age for walking independently is 21 months (range: 10 months-5 years). Although psychomotor regression is not typical, the high incidence of seizures that progressively worsen has been associated with loss of speech. Hypotonia is present in about one third of affected individuals. Infant feeding difficulties are present in at least half of affected individuals, although this does not typically require tube feeding. Microcephaly tends to be acquired, being noted in almost one third of infants at birth and in two thirds at follow up. Scalp hair is usually sparse at birth and becomes increasingly so with age, particularly in the second decade of life. In some, the sparseness improves with time. Skin pigmentation appears to be reduced, although affected individuals do not exhibit true cutaneous albinism. Poor subcutaneous fat distribution leads to prominent veins; interphalangeal joints are also prominent. Delayed tooth eruption is common, often requiring surgical extraction of primary dentition to allow secondary dentition to migrate into place. In one series, teeth were widely spaced in 58.2% of affected individuals, and hypodontia was reported in 18.6% [ Note: (1) One affected individual had caudal regression, although it is unclear if this is a rare finding in individuals with No clear clinically relevant genotype-phenotype correlations have been noted; however, all individuals with a pathogenic variant within the C-terminal helicase region of the ATPase domain have severe intellectual disability and epilepsy, a frequency higher than that in individuals with pathogenic variants in other parts of the gene. More than half of all individuals with The prevalence of • About 80% of affected individuals experience severe speech delay, and nearly one third of all affected individuals never develop speech or language skills. • The mean age for sitting is approximately nine months and the mean age for walking independently is 21 months (range: 10 months-5 years). • Although psychomotor regression is not typical, the high incidence of seizures that progressively worsen has been associated with loss of speech. • Hypotonia is present in about one third of affected individuals. • Infant feeding difficulties are present in at least half of affected individuals, although this does not typically require tube feeding. • Scalp hair is usually sparse at birth and becomes increasingly so with age, particularly in the second decade of life. In some, the sparseness improves with time. • Skin pigmentation appears to be reduced, although affected individuals do not exhibit true cutaneous albinism. • Poor subcutaneous fat distribution leads to prominent veins; interphalangeal joints are also prominent. • Delayed tooth eruption is common, often requiring surgical extraction of primary dentition to allow secondary dentition to migrate into place. In one series, teeth were widely spaced in 58.2% of affected individuals, and hypodontia was reported in 18.6% [ ## Clinical Description To date, at least 80 individuals have been identified with a pathogenic variant in About 80% of affected individuals experience severe speech delay, and nearly one third of all affected individuals never develop speech or language skills. The mean age for sitting is approximately nine months and the mean age for walking independently is 21 months (range: 10 months-5 years). Although psychomotor regression is not typical, the high incidence of seizures that progressively worsen has been associated with loss of speech. Hypotonia is present in about one third of affected individuals. Infant feeding difficulties are present in at least half of affected individuals, although this does not typically require tube feeding. Microcephaly tends to be acquired, being noted in almost one third of infants at birth and in two thirds at follow up. Scalp hair is usually sparse at birth and becomes increasingly so with age, particularly in the second decade of life. In some, the sparseness improves with time. Skin pigmentation appears to be reduced, although affected individuals do not exhibit true cutaneous albinism. Poor subcutaneous fat distribution leads to prominent veins; interphalangeal joints are also prominent. Delayed tooth eruption is common, often requiring surgical extraction of primary dentition to allow secondary dentition to migrate into place. In one series, teeth were widely spaced in 58.2% of affected individuals, and hypodontia was reported in 18.6% [ Note: (1) One affected individual had caudal regression, although it is unclear if this is a rare finding in individuals with • About 80% of affected individuals experience severe speech delay, and nearly one third of all affected individuals never develop speech or language skills. • The mean age for sitting is approximately nine months and the mean age for walking independently is 21 months (range: 10 months-5 years). • Although psychomotor regression is not typical, the high incidence of seizures that progressively worsen has been associated with loss of speech. • Hypotonia is present in about one third of affected individuals. • Infant feeding difficulties are present in at least half of affected individuals, although this does not typically require tube feeding. • Scalp hair is usually sparse at birth and becomes increasingly so with age, particularly in the second decade of life. In some, the sparseness improves with time. • Skin pigmentation appears to be reduced, although affected individuals do not exhibit true cutaneous albinism. • Poor subcutaneous fat distribution leads to prominent veins; interphalangeal joints are also prominent. • Delayed tooth eruption is common, often requiring surgical extraction of primary dentition to allow secondary dentition to migrate into place. In one series, teeth were widely spaced in 58.2% of affected individuals, and hypodontia was reported in 18.6% [ ## Genotype-Phenotype Correlations No clear clinically relevant genotype-phenotype correlations have been noted; however, all individuals with a pathogenic variant within the C-terminal helicase region of the ATPase domain have severe intellectual disability and epilepsy, a frequency higher than that in individuals with pathogenic variants in other parts of the gene. More than half of all individuals with ## Nomenclature ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders Of note, one individual inherited a pathogenic ## Differential Diagnosis Genetic disorders of interest in the differential diagnosis of Genes of Interest in the Differential Diagnosis of Digital findings are particularly helpful in differentiating these disorders: persons w/ Of note, persons w/CSS & digital findings more consistent w/diagnosis of Unlike persons w/ In addition, facial features & cardiac lesions in WS distinguish the disorder from Facial features are distinctive in Ataxia can be present in biotinidase deficiency but is not a feature of AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; The phenotypic overlap between Coffin-Siris syndrome and Most affected individuals reported to date have had a • Digital findings are particularly helpful in differentiating these disorders: persons w/ • Of note, persons w/CSS & digital findings more consistent w/diagnosis of • Unlike persons w/ • In addition, facial features & cardiac lesions in WS distinguish the disorder from • Facial features are distinctive in • Ataxia can be present in biotinidase deficiency but is not a feature of ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications. Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures. OT = occupational therapy; PT = physical therapy See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications. Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications. Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures. OT = occupational therapy; PT = physical therapy • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling To date, all individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. (Note: Based on data available to date, it is highly unlikely a If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If the If a parent of the proband is known to be heterozygous for the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • To date, all individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. (Note: Based on data available to date, it is highly unlikely a • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If the • If a parent of the proband is known to be heterozygous for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members To date, all individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. (Note: Based on data available to date, it is highly unlikely a If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If the If a parent of the proband is known to be heterozygous for the • To date, all individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. (Note: Based on data available to date, it is highly unlikely a • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If the • If a parent of the proband is known to be heterozygous for the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics SMARCA2-Related Nicolaides-Baraitser Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SMARCA2-Related Nicolaides-Baraitser Syndrome ( The SWI/SNF family of ATPase-dependent chromatin remodelers is essential for the regulation of gene expression, differentiation, and development. Pathogenic variants in Mutation of other genes within the SWI/SNF complex has been suggested as the cause in individuals who have findings suggestive of Both somatic and germline pathogenic variants affecting the SWI/SNF complex have been associated with tumor suppression, raising the question whether affected individuals containing these pathogenic variants might have increased risk of developing neoplasias. Most people with ## Molecular Pathogenesis The SWI/SNF family of ATPase-dependent chromatin remodelers is essential for the regulation of gene expression, differentiation, and development. Pathogenic variants in Mutation of other genes within the SWI/SNF complex has been suggested as the cause in individuals who have findings suggestive of Both somatic and germline pathogenic variants affecting the SWI/SNF complex have been associated with tumor suppression, raising the question whether affected individuals containing these pathogenic variants might have increased risk of developing neoplasias. Most people with ## Chapter Notes Omar Abdul-Rahman, MD, studies the clinical features and molecular basis of 6 March 2025 (ma) Comprehensive updated posted live 15 October 2015 (me) Review posted live 23 July 2015 (oa) Original submission • 6 March 2025 (ma) Comprehensive updated posted live • 15 October 2015 (me) Review posted live • 23 July 2015 (oa) Original submission ## Author Notes Omar Abdul-Rahman, MD, studies the clinical features and molecular basis of ## Revision History 6 March 2025 (ma) Comprehensive updated posted live 15 October 2015 (me) Review posted live 23 July 2015 (oa) Original submission • 6 March 2025 (ma) Comprehensive updated posted live • 15 October 2015 (me) Review posted live • 23 July 2015 (oa) Original submission ## References ## Literature Cited Prominent interphalangeal joints with reduced fat deposition in the digits Moderately prominent interphalangeal joints Coarse facies with sparse scalp hair, thin upper lip vermilion, and thick lower lip vermilion	[]	15/10/2015	6/3/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ncl	ncl	[ "Batten Disease", "CLN Disease", "NCL", "Batten Disease", "NCL", "CLN Disease", "Battenin", "Bis(monoacylglycero)phosphate synthase CLN5", "BTB/POZ domain-containing protein KCTD7", "Cathepsin D", "Cathepsin F", "Ceroid-lipofuscinosis neuronal protein 6", "DnaJ homolog subfamily C member 5", "Major facilitator superfamily domain-containing protein 8", "Palmitoyl-protein thioesterase 1", "Progranulin", "Protein CLN8", "Tripeptidyl-peptidase 1", "CLN3", "CLN5", "CLN6", "CLN8", "CTSD", "CTSF", "DNAJC5", "GRN", "KCTD7", "MFSD8", "PPT1", "TPP1", "Neuronal Ceroid Lipofuscinoses", "Overview" ]	Neuronal Ceroid Lipofuscinoses Overview	Kristina Malik, Kourtney Santucci, Leighann Sremba, Maija Steenari, Andrea Miele, Scott Demarest, Ineka Whiteman	Summary The purpose of this overview is to: Briefly describe the Review the Provide an Review Inform	## Clinical Characteristics of Neuronal Ceroid Lipofuscinoses Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders caused by lysosomal accumulation of cellular ceroid lipofuscin, a waste product of lipids and proteins often found in the neurons of the retina and brain. The NCLs (commonly known as Batten disease) are generally characterized by progressive brain involvement, progressive retinal dystrophy, and shortened life span. NCLs are inherited in an autosomal recessive manner except Except for Although these manifestations are typically present in all individuals with an NCL, the age of onset, range of manifestations, and rate of disease progression vary by the associated gene (see The possibility of an NCL should be considered in a child with developmental delay, especially speech-language delays, plus any of the following: Progressive vision loss Epilepsy Ataxia Developmental regression Additionally, an individual with epilepsy with developmental regression or ataxia should be evaluated for neurodegenerative conditions such as NCL. Although these findings might be considered possible adverse effects of anti-seizure medications (ASMs), they are not common medication side effects. • Progressive vision loss • Epilepsy • Ataxia • Developmental regression ## Genetic Causes of Neuronal Ceroid Lipofuscinoses To date, pathogenic variants in 12 genes are confirmed to be associated with NCLs (see Current NCL nomenclature incorporates the associated gene (e.g., CLN1 disease is associated with pathogenic variants in Neuronal Ceroid Lipofuscinoses: Genes and Phenotypes Late infantile Juvenile Adult Congenital/infantile Juvenile Late juvenile / protracted Adult Protracted Congenital Infantile Juvenile Protracted Teenage Adult Protracted Teenage Adult Kufs type A & B Turkish variant, late infantile Northern epilepsy / EPMR Late infantile Juvenile Adult CLN = ceroid lipofuscinosis, neuronal; MOI = mode of inheritance; AR = autosomal recessive; AD = autosomal dominant; EPMR = progressive epilepsy with mental retardation Age of onset for classic and atypical/variant phenotypes are based on Some individuals with biallelic Classic infantile phenotype Age of onset: six to 18 months Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. Atypical (late infantile, juvenile, or adult) phenotype Age of onset: 18 months to adulthood [ Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [ Atypical phenotypes Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ Life expectancy for adult-onset CLN1 disease is unknown. Classic late infantile phenotype Age of onset: two to four years Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ Atypical phenotype Age of onset: preschool to adulthood Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [ Classic phenotype Age of onset: four to seven years Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ Protracted phenotype Age of onset: juvenile to adult Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [ Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression Age of onset: adolescence to adulthood; mean age 30 years Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [ Note: Retinal degeneration is typically not present. Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date Psychomotor regression with clumsiness followed by progressive visual failure Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years. Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [ Late infantile to juvenile phenotype Age of onset: early childhood through early juvenile period Developmental delay progressing to regression Adult-onset phenotypes Age of onset: early adulthood Kufs Type A: progressive myoclonic epilepsy Kufs Type B: dementia and a range of movement disorders Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [ Adult-onset phenotypes (also known as Kufs disease) Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ Age of onset: two to three years In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [ CLN8 disease was classically defined as two distinct phenotypes; however, recent case reports describe a phenotypic spectrum [ Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy Age of onset: five to 10 years Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline Late infantile phenotype Age of onset: two years Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. Congenital phenotype Age of onset: neonatal period (i.e., birth to age 28 days) Seizures may occur prenatally; microcephaly and apnea may be present at birth. Other phenotypes Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported May include ataxia, spasticity, speech impairment, and visual disturbance Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth. Other phenotypes Late infantile phenotype. Movement disorders, seizures, and vision loss Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss Life span is shortened even in children with later-onset CLN10 disease. Age of onset: mid-childhood to second or third decade Visual loss, seizures, and ataxia. Age of onset: age 20-30 years Cognitive and psychomotor decline Age of onset: early to late infancy (younger than age two years) Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression. Collectively, the NCLs are now commonly referred to as Batten disease. While this name was originally used in reference to CLN3 disease, juvenile onset, use of the term has broadened in recent decades to encompass all subtypes. This single term serves as a concise, practical name for families, advocacy groups, and the scientific community to unify the NCLs. Batten disease should be considered synonymous with neuronal ceroid lipofuscinosis. Prior to discovery of the causative genes, NCLs were clinically classified by the age of onset of the first manifestations: i.e., infantile NCL (onset 6-24 months), late infantile NCL (onset 2-4 years), juvenile NCL (onset 4-15 years), and adult NCL (onset 15-50 years) [ • Late infantile • Juvenile • Adult • Congenital/infantile • Juvenile • Late juvenile / protracted • Adult • Protracted • Congenital • Infantile • Juvenile • Protracted • Teenage • Adult • Protracted • Teenage • Adult Kufs type A & B • Turkish variant, late infantile • Northern epilepsy / EPMR • Late infantile • Juvenile • Adult • Classic infantile phenotype • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Atypical (late infantile, juvenile, or adult) phenotype • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [ • Atypical phenotypes • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Classic late infantile phenotype • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Atypical phenotype • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [ • Classic phenotype • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Protracted phenotype • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [ • Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression • Age of onset: adolescence to adulthood; mean age 30 years • Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [ • Note: Retinal degeneration is typically not present. • Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date • Psychomotor regression with clumsiness followed by progressive visual failure • Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years. • Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [ • Late infantile to juvenile phenotype • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Adult-onset phenotypes • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [ • Adult-onset phenotypes (also known as Kufs disease) • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Age of onset: two to three years • In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [ • Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Late infantile phenotype • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Congenital phenotype • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Other phenotypes • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth. • Other phenotypes • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Age of onset: mid-childhood to second or third decade • Visual loss, seizures, and ataxia. • Age of onset: age 20-30 years • Cognitive and psychomotor decline • Age of onset: early to late infancy (younger than age two years) • Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression. ## Genes To date, pathogenic variants in 12 genes are confirmed to be associated with NCLs (see Current NCL nomenclature incorporates the associated gene (e.g., CLN1 disease is associated with pathogenic variants in Neuronal Ceroid Lipofuscinoses: Genes and Phenotypes Late infantile Juvenile Adult Congenital/infantile Juvenile Late juvenile / protracted Adult Protracted Congenital Infantile Juvenile Protracted Teenage Adult Protracted Teenage Adult Kufs type A & B Turkish variant, late infantile Northern epilepsy / EPMR Late infantile Juvenile Adult CLN = ceroid lipofuscinosis, neuronal; MOI = mode of inheritance; AR = autosomal recessive; AD = autosomal dominant; EPMR = progressive epilepsy with mental retardation Age of onset for classic and atypical/variant phenotypes are based on Some individuals with biallelic • Late infantile • Juvenile • Adult • Congenital/infantile • Juvenile • Late juvenile / protracted • Adult • Protracted • Congenital • Infantile • Juvenile • Protracted • Teenage • Adult • Protracted • Teenage • Adult Kufs type A & B • Turkish variant, late infantile • Northern epilepsy / EPMR • Late infantile • Juvenile • Adult ## CLN Disease Phenotypes Classic infantile phenotype Age of onset: six to 18 months Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. Atypical (late infantile, juvenile, or adult) phenotype Age of onset: 18 months to adulthood [ Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [ Atypical phenotypes Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ Life expectancy for adult-onset CLN1 disease is unknown. Classic late infantile phenotype Age of onset: two to four years Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ Atypical phenotype Age of onset: preschool to adulthood Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [ Classic phenotype Age of onset: four to seven years Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ Protracted phenotype Age of onset: juvenile to adult Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [ Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression Age of onset: adolescence to adulthood; mean age 30 years Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [ Note: Retinal degeneration is typically not present. Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date Psychomotor regression with clumsiness followed by progressive visual failure Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years. Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [ Late infantile to juvenile phenotype Age of onset: early childhood through early juvenile period Developmental delay progressing to regression Adult-onset phenotypes Age of onset: early adulthood Kufs Type A: progressive myoclonic epilepsy Kufs Type B: dementia and a range of movement disorders Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [ Adult-onset phenotypes (also known as Kufs disease) Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ Age of onset: two to three years In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [ CLN8 disease was classically defined as two distinct phenotypes; however, recent case reports describe a phenotypic spectrum [ Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy Age of onset: five to 10 years Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline Late infantile phenotype Age of onset: two years Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. Congenital phenotype Age of onset: neonatal period (i.e., birth to age 28 days) Seizures may occur prenatally; microcephaly and apnea may be present at birth. Other phenotypes Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported May include ataxia, spasticity, speech impairment, and visual disturbance Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth. Other phenotypes Late infantile phenotype. Movement disorders, seizures, and vision loss Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss Life span is shortened even in children with later-onset CLN10 disease. Age of onset: mid-childhood to second or third decade Visual loss, seizures, and ataxia. Age of onset: age 20-30 years Cognitive and psychomotor decline Age of onset: early to late infancy (younger than age two years) Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression. • Classic infantile phenotype • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Atypical (late infantile, juvenile, or adult) phenotype • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [ • Atypical phenotypes • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Classic late infantile phenotype • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Atypical phenotype • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [ • Classic phenotype • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Protracted phenotype • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [ • Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression • Age of onset: adolescence to adulthood; mean age 30 years • Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [ • Note: Retinal degeneration is typically not present. • Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date • Psychomotor regression with clumsiness followed by progressive visual failure • Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years. • Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [ • Late infantile to juvenile phenotype • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Adult-onset phenotypes • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [ • Adult-onset phenotypes (also known as Kufs disease) • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Age of onset: two to three years • In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [ • Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Late infantile phenotype • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Congenital phenotype • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Other phenotypes • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth. • Other phenotypes • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Age of onset: mid-childhood to second or third decade • Visual loss, seizures, and ataxia. • Age of onset: age 20-30 years • Cognitive and psychomotor decline • Age of onset: early to late infancy (younger than age two years) • Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression. ## CLN1 Disease Classic infantile phenotype Age of onset: six to 18 months Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. Atypical (late infantile, juvenile, or adult) phenotype Age of onset: 18 months to adulthood [ Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [ Atypical phenotypes Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ Life expectancy for adult-onset CLN1 disease is unknown. • Classic infantile phenotype • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Atypical (late infantile, juvenile, or adult) phenotype • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Age of onset: six to 18 months • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision. • Age of onset: 18 months to adulthood [ • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations. • Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [ • Atypical phenotypes • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years). • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [ • Life expectancy for adult-onset CLN1 disease is unknown. ## CLN2 Disease Classic late infantile phenotype Age of onset: two to four years Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ Atypical phenotype Age of onset: preschool to adulthood Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [ • Classic late infantile phenotype • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Atypical phenotype • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Age of onset: two to four years • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [ • Age of onset: preschool to adulthood • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [ • Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [ ## CLN3 Disease Classic phenotype Age of onset: four to seven years Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ Protracted phenotype Age of onset: juvenile to adult Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [ Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression • Classic phenotype • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Protracted phenotype • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Age of onset: four to seven years • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [ • Age of onset: juvenile to adult • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [ • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life) • Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [ • Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression ## CLN4 Disease Age of onset: adolescence to adulthood; mean age 30 years Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [ Note: Retinal degeneration is typically not present. • Age of onset: adolescence to adulthood; mean age 30 years • Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [ • Note: Retinal degeneration is typically not present. ## CLN5 Disease Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date Psychomotor regression with clumsiness followed by progressive visual failure Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years. Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [ • Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date • Psychomotor regression with clumsiness followed by progressive visual failure • Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years. • Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [ ## CLN6 Disease Late infantile to juvenile phenotype Age of onset: early childhood through early juvenile period Developmental delay progressing to regression Adult-onset phenotypes Age of onset: early adulthood Kufs Type A: progressive myoclonic epilepsy Kufs Type B: dementia and a range of movement disorders Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [ Adult-onset phenotypes (also known as Kufs disease) Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Late infantile to juvenile phenotype • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Adult-onset phenotypes • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Age of onset: early childhood through early juvenile period • Developmental delay progressing to regression • Age of onset: early adulthood • Kufs Type A: progressive myoclonic epilepsy • Kufs Type B: dementia and a range of movement disorders • Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [ • Adult-onset phenotypes (also known as Kufs disease) • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [ • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [ ## CLN7 Disease Age of onset: two to three years In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [ • Age of onset: two to three years • In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [ ## CLN8 Disease CLN8 disease was classically defined as two distinct phenotypes; however, recent case reports describe a phenotypic spectrum [ Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy Age of onset: five to 10 years Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline Late infantile phenotype Age of onset: two years Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Late infantile phenotype • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. • Age of onset: five to 10 years • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline • Age of onset: two years • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course. ## CLN10 Disease Congenital phenotype Age of onset: neonatal period (i.e., birth to age 28 days) Seizures may occur prenatally; microcephaly and apnea may be present at birth. Other phenotypes Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported May include ataxia, spasticity, speech impairment, and visual disturbance Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth. Other phenotypes Late infantile phenotype. Movement disorders, seizures, and vision loss Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss Life span is shortened even in children with later-onset CLN10 disease. • Congenital phenotype • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Other phenotypes • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Age of onset: neonatal period (i.e., birth to age 28 days) • Seizures may occur prenatally; microcephaly and apnea may be present at birth. • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported • May include ataxia, spasticity, speech impairment, and visual disturbance • Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth. • Other phenotypes • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. • Late infantile phenotype. Movement disorders, seizures, and vision loss • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss • Life span is shortened even in children with later-onset CLN10 disease. ## CLN11 Disease Age of onset: mid-childhood to second or third decade Visual loss, seizures, and ataxia. • Age of onset: mid-childhood to second or third decade • Visual loss, seizures, and ataxia. ## CLN13 Disease Age of onset: age 20-30 years Cognitive and psychomotor decline • Age of onset: age 20-30 years • Cognitive and psychomotor decline ## CLN14 Disease Age of onset: early to late infancy (younger than age two years) Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression. • Age of onset: early to late infancy (younger than age two years) • Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression. ## Nomenclature Collectively, the NCLs are now commonly referred to as Batten disease. While this name was originally used in reference to CLN3 disease, juvenile onset, use of the term has broadened in recent decades to encompass all subtypes. This single term serves as a concise, practical name for families, advocacy groups, and the scientific community to unify the NCLs. Batten disease should be considered synonymous with neuronal ceroid lipofuscinosis. Prior to discovery of the causative genes, NCLs were clinically classified by the age of onset of the first manifestations: i.e., infantile NCL (onset 6-24 months), late infantile NCL (onset 2-4 years), juvenile NCL (onset 4-15 years), and adult NCL (onset 15-50 years) [ ## Evaluation Strategies to Identify the Genetic Cause of a Neuronal Ceroid Lipofuscinosis in a Proband Establishing a specific genetic cause of a neuronal ceroid lipofuscinosis (NCL): Usually involves a medical history, physical examination, family history, and genomic/genetic testing; Can identify individuals with CLN2 disease, for which Can support the affected individual and their family through clarification of natural history and expected changes in function, medical needs, and life span; Can aid in Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing can be deployed earlier and for a less specific phenotype. For an introduction to multigene panels click For an introduction to CMA click For an introduction to comprehensive genomic testing click Although Testing for Neuronal Ceroid Lipofuscinoses: Ultrastructural Phenotype CLN = ceroid lipofuscinosis, neuronal; CL = curvilinear profiles; FP = fingerprint bodies; GROD = granular osmiophilic deposits; RL = rectilinear profiles Based on Although individuals with biallelic • Usually involves a medical history, physical examination, family history, and genomic/genetic testing; • Can identify individuals with CLN2 disease, for which • Can support the affected individual and their family through clarification of natural history and expected changes in function, medical needs, and life span; • Can aid in • For an introduction to multigene panels click • For an introduction to CMA click • For an introduction to comprehensive genomic testing click ## Genomic/Genetic Testing Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing can be deployed earlier and for a less specific phenotype. For an introduction to multigene panels click For an introduction to CMA click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to CMA click • For an introduction to comprehensive genomic testing click ## Enzyme Testing Although Testing for Neuronal Ceroid Lipofuscinoses: Ultrastructural Phenotype CLN = ceroid lipofuscinosis, neuronal; CL = curvilinear profiles; FP = fingerprint bodies; GROD = granular osmiophilic deposits; RL = rectilinear profiles Based on Although individuals with biallelic ## Management Clinical practice guidelines are available for CLN1 disease [ To establish the extent of disease and needs in an individual diagnosed with an NCL, the evaluations summarized in Neuronal Ceroid Lipofuscinoses: Recommended Evaluations Following Initial Diagnosis Brain MRI Consider EEG if seizures are a concern. For CLN3 disease: validated staging systems (CLN3SS) have been developed. To assess for retinal dystrophy, refractive errors, abnormal ocular movements, &/or strabismus Perform dilated eye exam as recommended by ophthalmologist. Advise on low vision services (e.g., teacher of the visually impaired). To incl cognitive, adaptive, motor, & speech-language assessments Evaluate need for early intervention programs / special education services Gross motor & fine motor skills Contractures, kyphoscoliosis Mobility, ADLs, & need for adaptive devices, cane, or orthoses Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) For persons age >18 mo: screen for social & behavioral concerns suggestive of ASD For persons age >5 years: screen for concerns incl ADHD, irritability, & anxiety Evaluate aspiration risk & nutritional status. Engage speech therapist to maintain & support swallow function. Consider eval for gastrostomy tube placement in persons w/dysphagia and/or aspiration risk. Assess weight & nutritional status. Assess for constipation. EKG at baseline Referral for additional studies if low heart rate compared to age norms or findings suggestive of left ventricular hypertrophy Assessment of family & social structure to determine need for: community or Home nursing or other respite / home care service referral Referral to a ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy, ST = speech therapy Clinical geneticist, biochemical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The Batten Disease Support, Research, and Advocacy (BDSRA) Foundation supports a growing network of clinical Centers of Excellence (CoE) for Batten Disease throughout the US. Based primarily at academic children’s hospitals, CoE provide standardized comprehensive clinical services and care in agreement with the Standards for Designation established and endorsed by the Targeted therapy (cerliponase alfa) is available for Neuronal Ceroid Lipofuscinoses: Targeted Therapy Significantly slows decline in motor & language function. Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. Presymptomatic treatment may delay disease onset. Investigation ongoing for intravitreal use. Cerliponase alfa is a recombinant human tripeptidyl peptidase-1 (TPP1) enzyme. Broad-spectrum anti-seizure medications (ASMs) including valproate, benzodiazepines (clobazam/clonazepam), lamotrigine, zonisamide,e and levetiracetam or brivaracetamare are typically preferred; however, no data support the use any one ASM. As the NCL progresses, complete freedom from seizures is often unrealistic, but it may be achievable in earlier stages. Sodium channel blockers (phenytoin, fosphenytoin, carbamazepine, lamotrigine, oxcarbazepine) should be used with caution as they may aggravate myoclonic and/or generalized seizures. Ketogenic diet and neuromodulation devices may be helpful, similar to responses observed in other individuals with refractory epilepsy. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Neuronal Ceroid Lipofuscinoses: Recommended Follow Up Monitor known neurologic findings. Monitor for newly developed findings such as spasticity, movement disorders, & ataxia Repeat eval when there is a clinical concern. EEG &/or brain MRI MRI if there are movement changes Routinely scheduled ophthalmology follow up Dilated eye exam as recommended by ophthalmologist In children, repeat evals every 6-12 mos (specific intervals can depend on type of assessment, e.g., full neuropsychological eval every 12 mos, caregiver report every 6 mos). In adults, necessity of eval may be case dependent. Track skills longitudinally to monitor for regression/dementia. Continued follow up w/focus on function Evaluate current level of mobility & ataxia. Monitor need for supportive ambulation (incl wheelchair) or other adaptive technology. Mental health follow up (anxiety, adjustment to diagnosis) Behavioral health follow up for aggression, agitation, ADHD, anxiety, ASD Evaluate aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or faltering weight. Monitor weight. Screen for sleep concerns by history. Screen for secretion concerns by history. Annually, starting at age 18 yrs if not earlier Referral for additional studies if low heart rate for age norms or any abnormalities on EKG Follow up for improved QOL, pain mgmt, & sleep quality Discussion of hospice if indicated Community or Social work involvement for parental support Home nursing referral Begin planning for adult medical & community support needs around age 12 yrs Plan for transition to adult medical providers around age 18-21 yrs. Connect w/state-based agencies that support persons w/intellectual & developmental disabilities to facilitate benefits access, adult waiver services, respite care, etc. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; QOL = quality of life Clinical geneticist, biochemical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Brain MRI • Consider EEG if seizures are a concern. • For CLN3 disease: validated staging systems (CLN3SS) have been developed. • To assess for retinal dystrophy, refractive errors, abnormal ocular movements, &/or strabismus • Perform dilated eye exam as recommended by ophthalmologist. • Advise on low vision services (e.g., teacher of the visually impaired). • To incl cognitive, adaptive, motor, & speech-language assessments • Evaluate need for early intervention programs / special education services • Gross motor & fine motor skills • Contractures, kyphoscoliosis • Mobility, ADLs, & need for adaptive devices, cane, or orthoses • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • For persons age >18 mo: screen for social & behavioral concerns suggestive of ASD • For persons age >5 years: screen for concerns incl ADHD, irritability, & anxiety • Evaluate aspiration risk & nutritional status. • Engage speech therapist to maintain & support swallow function. • Consider eval for gastrostomy tube placement in persons w/dysphagia and/or aspiration risk. • Assess weight & nutritional status. • Assess for constipation. • EKG at baseline • Referral for additional studies if low heart rate compared to age norms or findings suggestive of left ventricular hypertrophy • Assessment of family & social structure to determine need for: community or • Home nursing or other respite / home care service referral • Referral to a • Significantly slows decline in motor & language function. • Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. • Presymptomatic treatment may delay disease onset. • Investigation ongoing for intravitreal use. • Monitor known neurologic findings. • Monitor for newly developed findings such as spasticity, movement disorders, & ataxia • Repeat eval when there is a clinical concern. • EEG &/or brain MRI • MRI if there are movement changes • Routinely scheduled ophthalmology follow up • Dilated eye exam as recommended by ophthalmologist • In children, repeat evals every 6-12 mos (specific intervals can depend on type of assessment, e.g., full neuropsychological eval every 12 mos, caregiver report every 6 mos). • In adults, necessity of eval may be case dependent. • Track skills longitudinally to monitor for regression/dementia. • Continued follow up w/focus on function • Evaluate current level of mobility & ataxia. • Monitor need for supportive ambulation (incl wheelchair) or other adaptive technology. • Mental health follow up (anxiety, adjustment to diagnosis) • Behavioral health follow up for aggression, agitation, ADHD, anxiety, ASD • Evaluate aspiration risk & nutritional status. • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or faltering weight. • Monitor weight. • Screen for sleep concerns by history. • Screen for secretion concerns by history. • Annually, starting at age 18 yrs if not earlier • Referral for additional studies if low heart rate for age norms or any abnormalities on EKG • Follow up for improved QOL, pain mgmt, & sleep quality • Discussion of hospice if indicated • Community or • Social work involvement for parental support • Home nursing referral • Begin planning for adult medical & community support needs around age 12 yrs • Plan for transition to adult medical providers around age 18-21 yrs. • Connect w/state-based agencies that support persons w/intellectual & developmental disabilities to facilitate benefits access, adult waiver services, respite care, etc. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an NCL, the evaluations summarized in Neuronal Ceroid Lipofuscinoses: Recommended Evaluations Following Initial Diagnosis Brain MRI Consider EEG if seizures are a concern. For CLN3 disease: validated staging systems (CLN3SS) have been developed. To assess for retinal dystrophy, refractive errors, abnormal ocular movements, &/or strabismus Perform dilated eye exam as recommended by ophthalmologist. Advise on low vision services (e.g., teacher of the visually impaired). To incl cognitive, adaptive, motor, & speech-language assessments Evaluate need for early intervention programs / special education services Gross motor & fine motor skills Contractures, kyphoscoliosis Mobility, ADLs, & need for adaptive devices, cane, or orthoses Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) For persons age >18 mo: screen for social & behavioral concerns suggestive of ASD For persons age >5 years: screen for concerns incl ADHD, irritability, & anxiety Evaluate aspiration risk & nutritional status. Engage speech therapist to maintain & support swallow function. Consider eval for gastrostomy tube placement in persons w/dysphagia and/or aspiration risk. Assess weight & nutritional status. Assess for constipation. EKG at baseline Referral for additional studies if low heart rate compared to age norms or findings suggestive of left ventricular hypertrophy Assessment of family & social structure to determine need for: community or Home nursing or other respite / home care service referral Referral to a ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy, ST = speech therapy Clinical geneticist, biochemical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The Batten Disease Support, Research, and Advocacy (BDSRA) Foundation supports a growing network of clinical Centers of Excellence (CoE) for Batten Disease throughout the US. Based primarily at academic children’s hospitals, CoE provide standardized comprehensive clinical services and care in agreement with the Standards for Designation established and endorsed by the • Brain MRI • Consider EEG if seizures are a concern. • For CLN3 disease: validated staging systems (CLN3SS) have been developed. • To assess for retinal dystrophy, refractive errors, abnormal ocular movements, &/or strabismus • Perform dilated eye exam as recommended by ophthalmologist. • Advise on low vision services (e.g., teacher of the visually impaired). • To incl cognitive, adaptive, motor, & speech-language assessments • Evaluate need for early intervention programs / special education services • Gross motor & fine motor skills • Contractures, kyphoscoliosis • Mobility, ADLs, & need for adaptive devices, cane, or orthoses • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • For persons age >18 mo: screen for social & behavioral concerns suggestive of ASD • For persons age >5 years: screen for concerns incl ADHD, irritability, & anxiety • Evaluate aspiration risk & nutritional status. • Engage speech therapist to maintain & support swallow function. • Consider eval for gastrostomy tube placement in persons w/dysphagia and/or aspiration risk. • Assess weight & nutritional status. • Assess for constipation. • EKG at baseline • Referral for additional studies if low heart rate compared to age norms or findings suggestive of left ventricular hypertrophy • Assessment of family & social structure to determine need for: community or • Home nursing or other respite / home care service referral • Referral to a ## Treatment of Manifestations Targeted therapy (cerliponase alfa) is available for Neuronal Ceroid Lipofuscinoses: Targeted Therapy Significantly slows decline in motor & language function. Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. Presymptomatic treatment may delay disease onset. Investigation ongoing for intravitreal use. Cerliponase alfa is a recombinant human tripeptidyl peptidase-1 (TPP1) enzyme. Broad-spectrum anti-seizure medications (ASMs) including valproate, benzodiazepines (clobazam/clonazepam), lamotrigine, zonisamide,e and levetiracetam or brivaracetamare are typically preferred; however, no data support the use any one ASM. As the NCL progresses, complete freedom from seizures is often unrealistic, but it may be achievable in earlier stages. Sodium channel blockers (phenytoin, fosphenytoin, carbamazepine, lamotrigine, oxcarbazepine) should be used with caution as they may aggravate myoclonic and/or generalized seizures. Ketogenic diet and neuromodulation devices may be helpful, similar to responses observed in other individuals with refractory epilepsy. • Significantly slows decline in motor & language function. • Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. • Presymptomatic treatment may delay disease onset. • Investigation ongoing for intravitreal use. ## Targeted Therapy Targeted therapy (cerliponase alfa) is available for Neuronal Ceroid Lipofuscinoses: Targeted Therapy Significantly slows decline in motor & language function. Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. Presymptomatic treatment may delay disease onset. Investigation ongoing for intravitreal use. Cerliponase alfa is a recombinant human tripeptidyl peptidase-1 (TPP1) enzyme. • Significantly slows decline in motor & language function. • Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. • Presymptomatic treatment may delay disease onset. • Investigation ongoing for intravitreal use. ## Supportive Care Broad-spectrum anti-seizure medications (ASMs) including valproate, benzodiazepines (clobazam/clonazepam), lamotrigine, zonisamide,e and levetiracetam or brivaracetamare are typically preferred; however, no data support the use any one ASM. As the NCL progresses, complete freedom from seizures is often unrealistic, but it may be achievable in earlier stages. Sodium channel blockers (phenytoin, fosphenytoin, carbamazepine, lamotrigine, oxcarbazepine) should be used with caution as they may aggravate myoclonic and/or generalized seizures. Ketogenic diet and neuromodulation devices may be helpful, similar to responses observed in other individuals with refractory epilepsy. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Neuronal Ceroid Lipofuscinoses: Recommended Follow Up Monitor known neurologic findings. Monitor for newly developed findings such as spasticity, movement disorders, & ataxia Repeat eval when there is a clinical concern. EEG &/or brain MRI MRI if there are movement changes Routinely scheduled ophthalmology follow up Dilated eye exam as recommended by ophthalmologist In children, repeat evals every 6-12 mos (specific intervals can depend on type of assessment, e.g., full neuropsychological eval every 12 mos, caregiver report every 6 mos). In adults, necessity of eval may be case dependent. Track skills longitudinally to monitor for regression/dementia. Continued follow up w/focus on function Evaluate current level of mobility & ataxia. Monitor need for supportive ambulation (incl wheelchair) or other adaptive technology. Mental health follow up (anxiety, adjustment to diagnosis) Behavioral health follow up for aggression, agitation, ADHD, anxiety, ASD Evaluate aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or faltering weight. Monitor weight. Screen for sleep concerns by history. Screen for secretion concerns by history. Annually, starting at age 18 yrs if not earlier Referral for additional studies if low heart rate for age norms or any abnormalities on EKG Follow up for improved QOL, pain mgmt, & sleep quality Discussion of hospice if indicated Community or Social work involvement for parental support Home nursing referral Begin planning for adult medical & community support needs around age 12 yrs Plan for transition to adult medical providers around age 18-21 yrs. Connect w/state-based agencies that support persons w/intellectual & developmental disabilities to facilitate benefits access, adult waiver services, respite care, etc. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; QOL = quality of life Clinical geneticist, biochemical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Monitor known neurologic findings. • Monitor for newly developed findings such as spasticity, movement disorders, & ataxia • Repeat eval when there is a clinical concern. • EEG &/or brain MRI • MRI if there are movement changes • Routinely scheduled ophthalmology follow up • Dilated eye exam as recommended by ophthalmologist • In children, repeat evals every 6-12 mos (specific intervals can depend on type of assessment, e.g., full neuropsychological eval every 12 mos, caregiver report every 6 mos). • In adults, necessity of eval may be case dependent. • Track skills longitudinally to monitor for regression/dementia. • Continued follow up w/focus on function • Evaluate current level of mobility & ataxia. • Monitor need for supportive ambulation (incl wheelchair) or other adaptive technology. • Mental health follow up (anxiety, adjustment to diagnosis) • Behavioral health follow up for aggression, agitation, ADHD, anxiety, ASD • Evaluate aspiration risk & nutritional status. • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or faltering weight. • Monitor weight. • Screen for sleep concerns by history. • Screen for secretion concerns by history. • Annually, starting at age 18 yrs if not earlier • Referral for additional studies if low heart rate for age norms or any abnormalities on EKG • Follow up for improved QOL, pain mgmt, & sleep quality • Discussion of hospice if indicated • Community or • Social work involvement for parental support • Home nursing referral • Begin planning for adult medical & community support needs around age 12 yrs • Plan for transition to adult medical providers around age 18-21 yrs. • Connect w/state-based agencies that support persons w/intellectual & developmental disabilities to facilitate benefits access, adult waiver services, respite care, etc. ## Genetic Counseling Neuronal ceroid lipofuscinoses (NCLs) caused by pathogenic variants in The parents of an affected individual are presumed to be heterozygous for the autosomal recessive NCL-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for the NCL-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. If both parents are known to be heterozygous for an autosomal recessive NCL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. Most individuals diagnosed with CLN4 disease have an affected parent. Rarely, an individual diagnosed with CLN4 disease has the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance is high in CLN4 disease. Reduced penetrance has not been widely reported in the literature for If the If the parents are clinically unaffected but their genetic status is known, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CLN4 disease because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having an NCL-related pathogenic variant(s). Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an autosomal recessive NCL-related pathogenic variant, particularly if both partners are of the same ancestry. Founder variants in Once the NCL-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for the autosomal recessive NCL-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for the NCL-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive NCL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. • Most individuals diagnosed with CLN4 disease have an affected parent. • Rarely, an individual diagnosed with CLN4 disease has the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance is high in CLN4 disease. Reduced penetrance has not been widely reported in the literature for • If the • If the parents are clinically unaffected but their genetic status is known, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CLN4 disease because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having an NCL-related pathogenic variant(s). • Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an autosomal recessive NCL-related pathogenic variant, particularly if both partners are of the same ancestry. Founder variants in ## Mode of Inheritance Neuronal ceroid lipofuscinoses (NCLs) caused by pathogenic variants in ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are presumed to be heterozygous for the autosomal recessive NCL-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for the NCL-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. If both parents are known to be heterozygous for an autosomal recessive NCL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. • The parents of an affected individual are presumed to be heterozygous for the autosomal recessive NCL-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for the NCL-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive NCL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL. ## Autosomal Dominant Inheritance – Risk to Family Members Most individuals diagnosed with CLN4 disease have an affected parent. Rarely, an individual diagnosed with CLN4 disease has the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance is high in CLN4 disease. Reduced penetrance has not been widely reported in the literature for If the If the parents are clinically unaffected but their genetic status is known, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CLN4 disease because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • Most individuals diagnosed with CLN4 disease have an affected parent. • Rarely, an individual diagnosed with CLN4 disease has the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance is high in CLN4 disease. Reduced penetrance has not been widely reported in the literature for • If the • If the parents are clinically unaffected but their genetic status is known, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CLN4 disease because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having an NCL-related pathogenic variant(s). Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an autosomal recessive NCL-related pathogenic variant, particularly if both partners are of the same ancestry. Founder variants in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having an NCL-related pathogenic variant(s). • Carrier testing should be considered for the reproductive partners of individuals known to be carriers of an autosomal recessive NCL-related pathogenic variant, particularly if both partners are of the same ancestry. Founder variants in ## Prenatal Testing and Preimplantation Genetic Testing Once the NCL-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Australia Canada Natural History and Longitudinal Clinical Assessments in NCL • • United Kingdom • • • Australia • • • Canada • • • • • • • • • • • • • • Natural History and Longitudinal Clinical Assessments in NCL • ## Chapter Notes The authors' institutions are BDRSA Foundation Centers of Excellence and have financial support from the BDSRA Foundation USA. Scott Demarest, MD, MSCS (2025-present)Kristina Malik , MD (2025-present)Andrea Miele, PhD (2025-present)Sara E Mole, PhD; University College London (2001-2019)Kourtney Santucci, MD (2025-present)Leighann Sremba, MS (2025-present)Maija Steenari, MD (2025-present)Ineka Whiteman, PhD (2025-present)Ruth E Williams, MD; Guy's and St Thomas' NHS Foundation Trust (2001-2019) 29 May 2025 (bp) Comprehensive update posted live 11 April 2019 (ma) Chapter retired: chapter does not reflect current use of genetic testing 1 August 2013 (me) Comprehensive update posted live 2 March 2010 (me) Comprehensive update posted live 17 May 2006 (me) Comprehensive update posted live 27 January 2004 (me) Comprehensive update posted live 10 October 2001 (me) Review posted live 20 February 2001 (kw) Original submission • 29 May 2025 (bp) Comprehensive update posted live • 11 April 2019 (ma) Chapter retired: chapter does not reflect current use of genetic testing • 1 August 2013 (me) Comprehensive update posted live • 2 March 2010 (me) Comprehensive update posted live • 17 May 2006 (me) Comprehensive update posted live • 27 January 2004 (me) Comprehensive update posted live • 10 October 2001 (me) Review posted live • 20 February 2001 (kw) Original submission ## Acknowledgments The authors' institutions are BDRSA Foundation Centers of Excellence and have financial support from the BDSRA Foundation USA. ## Author History Scott Demarest, MD, MSCS (2025-present)Kristina Malik , MD (2025-present)Andrea Miele, PhD (2025-present)Sara E Mole, PhD; University College London (2001-2019)Kourtney Santucci, MD (2025-present)Leighann Sremba, MS (2025-present)Maija Steenari, MD (2025-present)Ineka Whiteman, PhD (2025-present)Ruth E Williams, MD; Guy's and St Thomas' NHS Foundation Trust (2001-2019) ## Revision History 29 May 2025 (bp) Comprehensive update posted live 11 April 2019 (ma) Chapter retired: chapter does not reflect current use of genetic testing 1 August 2013 (me) Comprehensive update posted live 2 March 2010 (me) Comprehensive update posted live 17 May 2006 (me) Comprehensive update posted live 27 January 2004 (me) Comprehensive update posted live 10 October 2001 (me) Review posted live 20 February 2001 (kw) Original submission • 29 May 2025 (bp) Comprehensive update posted live • 11 April 2019 (ma) Chapter retired: chapter does not reflect current use of genetic testing • 1 August 2013 (me) Comprehensive update posted live • 2 March 2010 (me) Comprehensive update posted live • 17 May 2006 (me) Comprehensive update posted live • 27 January 2004 (me) Comprehensive update posted live • 10 October 2001 (me) Review posted live • 20 February 2001 (kw) Original submission ## References ## Literature Cited	[]	10/10/2001	29/5/2025	15/8/2005	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ndi	ndi	[ "Aquaporin-2", "Vasopressin V2 receptor", "AQP2", "AVPR2", "Hereditary Nephrogenic Diabetes Insipidus" ]	Hereditary Nephrogenic Diabetes Insipidus	Nine Knoers, Henny Lemmink	Summary Hereditary nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals. The diagnosis of hereditary NDI is established in a male proband with NDI by identification of a hemizygous pathogenic variant in Hereditary NDI is most commonly inherited in an X-linked manner (~90% of individuals). Hereditary NDI can also be inherited in an autosomal recessive manner (~9% of individuals) or in an autosomal dominant manner (~1% of individuals). The risks to sibs and offspring depend on the mode of inheritance and the genetic status of the parents, which can be established in most families using molecular genetic testing. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the disease-causing pathogenic variant(s) in the family have been identified.	## Diagnosis Hereditary nephrogenic diabetes insipidus (NDI) Polyuria (excessive urine production) Polydipsia (excessive drinking) Family history of NDI Note: In the first few months after birth, polyuria and polydipsia may not be immediately noticed; infants with NDI usually present with poor feeding, failure to thrive, and irritability. Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H * Normal urinary osmolality values by age: 600 mOsm/kg H 1-2 years: 600 - 800 mOsm/kg H >2 years: >800 mOsm/kg H Cannot reduce urine volume or free water clearance [ Note: (1) The results of these laboratory tests may be difficult to interpret in individuals with "partial diabetes insipidus," which results from either subnormal amounts of AVP secretion (partial neurogenic DI) or partial response of the kidney to normal AVP concentrations (partial nephrogenic DI). These two disorders can be distinguished by comparing the ratio of urine osmolarity to plasma AVP concentration against normal standards. However, direct measurement of AVP is hampered by technical difficulties. Copeptin, the C-terminal component of the AVP-precursor and co-secreted with AVP, is much easier to measure than plasma AVP and is therefore a valuable surrogate of plasma AVP concentration. It has been shown to be a useful candidate biomarker for the differential diagnosis in polyuria-polydipsia syndromes [ A hemizygous pathogenic (or likely pathogenic; see Note) variant in Biallelic pathogenic variants in A heterozygous pathogenic variant in A heterozygous pathogenic variant in Biallelic pathogenic variants in A heterozygous pathogenic variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Sequence analysis of In For an introduction to multigene panels click Molecular Genetic Testing Used in Hereditary Nephrogenic Diabetes Insipidus (NDI) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Bichet & Bockenhauer [2016] • Polyuria (excessive urine production) • Polydipsia (excessive drinking) • Family history of NDI • Note: In the first few months after birth, polyuria and polydipsia may not be immediately noticed; infants with NDI usually present with poor feeding, failure to thrive, and irritability. • Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H • * Normal urinary osmolality values by age: • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • Cannot reduce urine volume or free water clearance [ • Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H • * Normal urinary osmolality values by age: • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • Cannot reduce urine volume or free water clearance [ • Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H • * Normal urinary osmolality values by age: • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • Cannot reduce urine volume or free water clearance [ • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • A hemizygous pathogenic (or likely pathogenic; see Note) variant in • Biallelic pathogenic variants in • A heterozygous pathogenic variant in • A heterozygous pathogenic variant in • Biallelic pathogenic variants in • A heterozygous pathogenic variant in • Sequence analysis of • In ## Suggestive Findings Hereditary nephrogenic diabetes insipidus (NDI) Polyuria (excessive urine production) Polydipsia (excessive drinking) Family history of NDI Note: In the first few months after birth, polyuria and polydipsia may not be immediately noticed; infants with NDI usually present with poor feeding, failure to thrive, and irritability. Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H * Normal urinary osmolality values by age: 600 mOsm/kg H 1-2 years: 600 - 800 mOsm/kg H >2 years: >800 mOsm/kg H Cannot reduce urine volume or free water clearance [ Note: (1) The results of these laboratory tests may be difficult to interpret in individuals with "partial diabetes insipidus," which results from either subnormal amounts of AVP secretion (partial neurogenic DI) or partial response of the kidney to normal AVP concentrations (partial nephrogenic DI). These two disorders can be distinguished by comparing the ratio of urine osmolarity to plasma AVP concentration against normal standards. However, direct measurement of AVP is hampered by technical difficulties. Copeptin, the C-terminal component of the AVP-precursor and co-secreted with AVP, is much easier to measure than plasma AVP and is therefore a valuable surrogate of plasma AVP concentration. It has been shown to be a useful candidate biomarker for the differential diagnosis in polyuria-polydipsia syndromes [ • Polyuria (excessive urine production) • Polydipsia (excessive drinking) • Family history of NDI • Note: In the first few months after birth, polyuria and polydipsia may not be immediately noticed; infants with NDI usually present with poor feeding, failure to thrive, and irritability. • Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H • * Normal urinary osmolality values by age: • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • Cannot reduce urine volume or free water clearance [ • Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H • * Normal urinary osmolality values by age: • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • Cannot reduce urine volume or free water clearance [ • Are unable to increase urinary osmolality, which remains below 200 mOsm/kg H • * Normal urinary osmolality values by age: • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H • Cannot reduce urine volume or free water clearance [ • 600 mOsm/kg H • 1-2 years: 600 - 800 mOsm/kg H • >2 years: >800 mOsm/kg H ## Establishing the Diagnosis A hemizygous pathogenic (or likely pathogenic; see Note) variant in Biallelic pathogenic variants in A heterozygous pathogenic variant in A heterozygous pathogenic variant in Biallelic pathogenic variants in A heterozygous pathogenic variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Sequence analysis of In For an introduction to multigene panels click Molecular Genetic Testing Used in Hereditary Nephrogenic Diabetes Insipidus (NDI) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Bichet & Bockenhauer [2016] • A hemizygous pathogenic (or likely pathogenic; see Note) variant in • Biallelic pathogenic variants in • A heterozygous pathogenic variant in • A heterozygous pathogenic variant in • Biallelic pathogenic variants in • A heterozygous pathogenic variant in • Sequence analysis of • In ## Clinical Characteristics The majority of affected individuals are diagnosed in the first year of life [ Sometimes infants as well as older individuals may present with rapid onset of severe dehydration associated with water deprivation, a hot environment, or intercurrent illnesses associated with decreased water intake and/or increased free water losses through vomiting, diarrhea, or fever. Seizures and/or coma may occur with rapid increases or decreases in plasma osmolality. Occasionally, the presenting sign is hydronephrosis, hydroureter, or megacystis. Dehydrated individuals in whom the diagnosis of NDI has not been made or who are unable to communicate their complaints run the risk of being improperly treated with IV administration of normal saline, especially in emergency situations. This may exacerbate hypernatremia. Prolonged, unrecognized, or repeated episodes of hypernatremic dehydration may result in seizures, permanent brain damage, developmental delay, and cognitive impairment. With early diagnosis and proper management, intelligence and life span are usually normal [ Chronic excretion of large volumes of urine can result in hydronephrosis, hydroureter, and megacystis (huge bladder). Some degree of urinary tract distention may be seen on ultrasound examination even in infants [ Failure to thrive or short stature may result from unsuccessful management or inadequate nutrition related to polydipsia [ With few exceptions, there is no difference in onset or clinical symptoms between The name "nephrogenic diabetes insipidus" was coined by Williams and Henry in 1947. In the literature it has been used synonymously with the terms "vasopressin- or ADH-resistant diabetes insipidus" or "diabetes insipidus renalis." The exact prevalence of hereditary NDI is not known but it is assumed to be rare. The prevalence of hereditary NDI in Quebec, Canada is estimated at 8.8:1,000,000 males [ ## Clinical Description The majority of affected individuals are diagnosed in the first year of life [ Sometimes infants as well as older individuals may present with rapid onset of severe dehydration associated with water deprivation, a hot environment, or intercurrent illnesses associated with decreased water intake and/or increased free water losses through vomiting, diarrhea, or fever. Seizures and/or coma may occur with rapid increases or decreases in plasma osmolality. Occasionally, the presenting sign is hydronephrosis, hydroureter, or megacystis. Dehydrated individuals in whom the diagnosis of NDI has not been made or who are unable to communicate their complaints run the risk of being improperly treated with IV administration of normal saline, especially in emergency situations. This may exacerbate hypernatremia. Prolonged, unrecognized, or repeated episodes of hypernatremic dehydration may result in seizures, permanent brain damage, developmental delay, and cognitive impairment. With early diagnosis and proper management, intelligence and life span are usually normal [ Chronic excretion of large volumes of urine can result in hydronephrosis, hydroureter, and megacystis (huge bladder). Some degree of urinary tract distention may be seen on ultrasound examination even in infants [ Failure to thrive or short stature may result from unsuccessful management or inadequate nutrition related to polydipsia [ ## Phenotype Correlations by Gene With few exceptions, there is no difference in onset or clinical symptoms between ## Genotype-Phenotype Correlations ## Nomenclature The name "nephrogenic diabetes insipidus" was coined by Williams and Henry in 1947. In the literature it has been used synonymously with the terms "vasopressin- or ADH-resistant diabetes insipidus" or "diabetes insipidus renalis." ## Prevalence The exact prevalence of hereditary NDI is not known but it is assumed to be rare. The prevalence of hereditary NDI in Quebec, Canada is estimated at 8.8:1,000,000 males [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Diabetes insipidus is the excretion of abnormally large volumes (i.e., >50 mL/kg body weight in 24 hours) of dilute urine (i.e., specific gravity <1.010 or osmolality <300 mOsm/kg). In addition to hereditary nephrogenic diabetes insipidus (NDI), causes of diabetes insipidus include the following: Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease. Autosomal dominant neurohypophyseal diabetes insipidus (OMIM • Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease. • Autosomal dominant neurohypophyseal diabetes insipidus (OMIM • Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease. • Autosomal dominant neurohypophyseal diabetes insipidus (OMIM • Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease. • Autosomal dominant neurohypophyseal diabetes insipidus (OMIM ## Management To establish the extent of disease in an individual diagnosed with hereditary nephrogenic diabetes insipidus (NDI), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Nephrogenic Diabetes Insipidus Consultation w/clinical geneticist &/or genetic counselor Developmental eval in children w/history of episode of severe dehydration or delay in diagnosis Management is usually best accomplished by a team consisting of a nutritionist, a pediatric (or adult) nephrologist or endocrinologist, and a clinical geneticist. Polyuria (and thus polydipsia) can be reduced by up to 50% without inducing hypernatremia by the use of one of the following drugs/combinations. Therapy is considered effective when urine output declines below a documented baseline in individuals with Note: When thiazide diuretic therapy is initiated, a transient increase in urine output may occur as a result of salt diuresis. Acute hypovolemic shock may be treated with isotonic fluid until the blood pressure and heart rate are stabilized, after which 5% dextrose in water is the preferred solution [ Dehydration associated with free water deficit is treated by gradually replacing the deficit water as well as ongoing urinary losses. Whenever possible, rehydration should occur with the oral intake of drinking water. If administration of IV fluids is required, 5% dextrose in water and/or quarter-normal saline should be used. If significant hypernatremia is present, serum sodium concentration should be monitored and the hydration solution modified to avoid reducing serum sodium concentration faster than 1 mEq/L per hour. Rapid increases or decreases in plasma osmolality can cause seizures, coma, brain damage, and death. Prevention of primary manifestations (see Prevention or reduction of serious renal, ureteral, or bladder dilatation may be achieved by reduction of urine production by drug therapy and voiding at two-hour intervals. There are no published guidelines available on recommended surveillance for children or adults with hereditary NDI. The frequency of follow up should take into consideration the medications being used and compliance with medications and diet recommendations. Recommended Surveillance for Individuals with Hereditary Nephrogenic Diabetes Insipidus 3 mos in infants 6 mos in older children 3 mos in infants 6 mos in older children Urine output and urine specific gravity are useless as indicators of hydration status. Water intake must not be restricted. It is appropriate to clarify the genetic status of at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilatation of the urinary tract. Evaluations can include: Molecular genetic testing if the In a newborn at risk for NDI who is not receiving breast milk: serum sodium, serum osmolality, and urinary osmolality can be performed while waiting for molecular results. Note: Infants at risk for NDI who are fed breast milk usually do not develop dehydration. Human milk has a low salt and protein content and therefore a low renal osmolar load. Note: Autosomal dominant NDI is usually less severe than X-linked or autosomal recessive NDI. Therefore, genetic testing of sibs of children with autosomal dominant NDI may be performed at a later age (e.g., at 10 years younger than earliest diagnosis in the family). See Heterozygous females with No pregnancies in women with Polyhydramnios is found in a minority of pregnancies in which the fetus is affected by NDI. In pregnant women with severe polyhydramnios and maternal discomfort, frequent amniotic fluid drainage may be necessary [ In a few individuals with a milder Because of the known gastrointestinal safety of selective cyclooxygenase (COX)-2 inhibitors compared to nonselective COX inhibitors (e.g., indomethacin), use of these drugs has been proposed for the treatment of hereditary NDI. The effectiveness of a specific COX-2 inhibitor in decreasing free water losses was demonstrated in male infants with hereditary NDI [ Because in vitro expression studies reveal that the majority of Other therapeutic approaches relying on AVP-independent trafficking of AQP2 to the apical membrane have been suggested and tested in vitro and/or in animal models. A comprehensive summary of these strategies is given in Since metformin, an oral antidiabetic drug, had been shown to increase AQP2 phosphorylation and accumulation in the apical membrane in animal models, a trial in a small number of individuals with hereditary NDI was started in 2015. However, it was also quickly terminated because of lack of efficacy ( Search • Consultation w/clinical geneticist &/or genetic counselor • Developmental eval in children w/history of episode of severe dehydration or delay in diagnosis • Note: When thiazide diuretic therapy is initiated, a transient increase in urine output may occur as a result of salt diuresis. • Acute hypovolemic shock may be treated with isotonic fluid until the blood pressure and heart rate are stabilized, after which 5% dextrose in water is the preferred solution [ • Dehydration associated with free water deficit is treated by gradually replacing the deficit water as well as ongoing urinary losses. Whenever possible, rehydration should occur with the oral intake of drinking water. If administration of IV fluids is required, 5% dextrose in water and/or quarter-normal saline should be used. • 3 mos in infants • 6 mos in older children • 3 mos in infants • 6 mos in older children • Molecular genetic testing if the • In a newborn at risk for NDI who is not receiving breast milk: serum sodium, serum osmolality, and urinary osmolality can be performed while waiting for molecular results. Note: Infants at risk for NDI who are fed breast milk usually do not develop dehydration. Human milk has a low salt and protein content and therefore a low renal osmolar load. ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with hereditary nephrogenic diabetes insipidus (NDI), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Nephrogenic Diabetes Insipidus Consultation w/clinical geneticist &/or genetic counselor Developmental eval in children w/history of episode of severe dehydration or delay in diagnosis • Consultation w/clinical geneticist &/or genetic counselor • Developmental eval in children w/history of episode of severe dehydration or delay in diagnosis ## Treatment of Manifestations Management is usually best accomplished by a team consisting of a nutritionist, a pediatric (or adult) nephrologist or endocrinologist, and a clinical geneticist. Polyuria (and thus polydipsia) can be reduced by up to 50% without inducing hypernatremia by the use of one of the following drugs/combinations. Therapy is considered effective when urine output declines below a documented baseline in individuals with Note: When thiazide diuretic therapy is initiated, a transient increase in urine output may occur as a result of salt diuresis. Acute hypovolemic shock may be treated with isotonic fluid until the blood pressure and heart rate are stabilized, after which 5% dextrose in water is the preferred solution [ Dehydration associated with free water deficit is treated by gradually replacing the deficit water as well as ongoing urinary losses. Whenever possible, rehydration should occur with the oral intake of drinking water. If administration of IV fluids is required, 5% dextrose in water and/or quarter-normal saline should be used. If significant hypernatremia is present, serum sodium concentration should be monitored and the hydration solution modified to avoid reducing serum sodium concentration faster than 1 mEq/L per hour. Rapid increases or decreases in plasma osmolality can cause seizures, coma, brain damage, and death. • Note: When thiazide diuretic therapy is initiated, a transient increase in urine output may occur as a result of salt diuresis. • Acute hypovolemic shock may be treated with isotonic fluid until the blood pressure and heart rate are stabilized, after which 5% dextrose in water is the preferred solution [ • Dehydration associated with free water deficit is treated by gradually replacing the deficit water as well as ongoing urinary losses. Whenever possible, rehydration should occur with the oral intake of drinking water. If administration of IV fluids is required, 5% dextrose in water and/or quarter-normal saline should be used. ## Prevention of Primary Manifestations Prevention of primary manifestations (see ## Prevention of Secondary Complications Prevention or reduction of serious renal, ureteral, or bladder dilatation may be achieved by reduction of urine production by drug therapy and voiding at two-hour intervals. ## Surveillance There are no published guidelines available on recommended surveillance for children or adults with hereditary NDI. The frequency of follow up should take into consideration the medications being used and compliance with medications and diet recommendations. Recommended Surveillance for Individuals with Hereditary Nephrogenic Diabetes Insipidus 3 mos in infants 6 mos in older children 3 mos in infants 6 mos in older children Urine output and urine specific gravity are useless as indicators of hydration status. • 3 mos in infants • 6 mos in older children • 3 mos in infants • 6 mos in older children ## Agents/Circumstances to Avoid Water intake must not be restricted. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilatation of the urinary tract. Evaluations can include: Molecular genetic testing if the In a newborn at risk for NDI who is not receiving breast milk: serum sodium, serum osmolality, and urinary osmolality can be performed while waiting for molecular results. Note: Infants at risk for NDI who are fed breast milk usually do not develop dehydration. Human milk has a low salt and protein content and therefore a low renal osmolar load. Note: Autosomal dominant NDI is usually less severe than X-linked or autosomal recessive NDI. Therefore, genetic testing of sibs of children with autosomal dominant NDI may be performed at a later age (e.g., at 10 years younger than earliest diagnosis in the family). See • Molecular genetic testing if the • In a newborn at risk for NDI who is not receiving breast milk: serum sodium, serum osmolality, and urinary osmolality can be performed while waiting for molecular results. Note: Infants at risk for NDI who are fed breast milk usually do not develop dehydration. Human milk has a low salt and protein content and therefore a low renal osmolar load. ## Pregnancy Management Heterozygous females with No pregnancies in women with Polyhydramnios is found in a minority of pregnancies in which the fetus is affected by NDI. In pregnant women with severe polyhydramnios and maternal discomfort, frequent amniotic fluid drainage may be necessary [ ## Therapies Under Investigation In a few individuals with a milder Because of the known gastrointestinal safety of selective cyclooxygenase (COX)-2 inhibitors compared to nonselective COX inhibitors (e.g., indomethacin), use of these drugs has been proposed for the treatment of hereditary NDI. The effectiveness of a specific COX-2 inhibitor in decreasing free water losses was demonstrated in male infants with hereditary NDI [ Because in vitro expression studies reveal that the majority of Other therapeutic approaches relying on AVP-independent trafficking of AQP2 to the apical membrane have been suggested and tested in vitro and/or in animal models. A comprehensive summary of these strategies is given in Since metformin, an oral antidiabetic drug, had been shown to increase AQP2 phosphorylation and accumulation in the apical membrane in animal models, a trial in a small number of individuals with hereditary NDI was started in 2015. However, it was also quickly terminated because of lack of efficacy ( Search ## Genetic Counseling Hereditary nephrogenic diabetes insipidus (NDI) may be transmitted in an X-linked manner (90% of families), an autosomal recessive manner (~9% of families), or an autosomal dominant manner (~1% of families). The father of an affected male will not have NDI nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother of the proband has an If the proband represents a simplex case and if the Note: Molecular genetic testing may be able to identify the family member in whom a Identification of asymptomatic female heterozygotes requires either (a) prior identification of the Females who are heterozygous for this X-linked disorder may have no symptoms or a variable degree of polyuria and polydipsia, or they may be as severely affected as males (see The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small. A proband with autosomal dominant NDI may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If a parent of a proband is affected and/or is known to have the If the proband has a known autosomal dominant See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. Once the NDI-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have NDI nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has an • If the proband represents a simplex case and if the • Identification of asymptomatic female heterozygotes requires either (a) prior identification of the • Females who are heterozygous for this X-linked disorder may have no symptoms or a variable degree of polyuria and polydipsia, or they may be as severely affected as males (see • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for an autosomal recessive • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small. • A proband with autosomal dominant NDI may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If a parent of a proband is affected and/or is known to have the • If the proband has a known autosomal dominant • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. ## Mode of Inheritance Hereditary nephrogenic diabetes insipidus (NDI) may be transmitted in an X-linked manner (90% of families), an autosomal recessive manner (~9% of families), or an autosomal dominant manner (~1% of families). ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have NDI nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother of the proband has an If the proband represents a simplex case and if the Note: Molecular genetic testing may be able to identify the family member in whom a Identification of asymptomatic female heterozygotes requires either (a) prior identification of the Females who are heterozygous for this X-linked disorder may have no symptoms or a variable degree of polyuria and polydipsia, or they may be as severely affected as males (see • The father of an affected male will not have NDI nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has an • If the proband represents a simplex case and if the • Identification of asymptomatic female heterozygotes requires either (a) prior identification of the • Females who are heterozygous for this X-linked disorder may have no symptoms or a variable degree of polyuria and polydipsia, or they may be as severely affected as males (see ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for an autosomal recessive • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Autosomal Dominant Inheritance – Risk to Family Members The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small. A proband with autosomal dominant NDI may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If a parent of a proband is affected and/or is known to have the If the proband has a known autosomal dominant • The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small. • A proband with autosomal dominant NDI may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If a parent of a proband is affected and/or is known to have the • If the proband has a known autosomal dominant ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. ## Prenatal Testing and Preimplantation Genetic Testing Once the NDI-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Main Street P.O. Box 1390 Eastsound WA 98245 • • • • Main Street • P.O. Box 1390 • Eastsound WA 98245 • • • ## Molecular Genetics Hereditary Nephrogenic Diabetes Insipidus: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Nephrogenic Diabetes Insipidus ( One sixteenth of all tetramers formed are normal-AQP2-only tetramers, explaining the relatively milder phenotype in autosomal dominant NDI compared to autosomal recessive NDI [ Hereditary Nephrogenic Diabetes Insipidus: Notable Variants listed in the table have been provided by the authors. • One sixteenth of all tetramers formed are normal-AQP2-only tetramers, explaining the relatively milder phenotype in autosomal dominant NDI compared to autosomal recessive NDI [ ## Molecular Pathogenesis One sixteenth of all tetramers formed are normal-AQP2-only tetramers, explaining the relatively milder phenotype in autosomal dominant NDI compared to autosomal recessive NDI [ Hereditary Nephrogenic Diabetes Insipidus: Notable Variants listed in the table have been provided by the authors. • One sixteenth of all tetramers formed are normal-AQP2-only tetramers, explaining the relatively milder phenotype in autosomal dominant NDI compared to autosomal recessive NDI [ ## Chapter Notes Nine Knoers, MD, PhD (2003-present) Henny Lemmink, PhD (2020-present)Robert S Wildin, MD; Oregon Health and Science University (2000-2003) 27 February 2020 (sw) Comprehensive update posted live 14 June 2012 (me) Comprehensive update posted live 4 March 2010 (me) Comprehensive update posted live 8 June 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis 8 March 2007 (me) Comprehensive update posted live 5 January 2005 (me) Comprehensive update posted live 28 February 2003 (me) Comprehensive update posted live 12 February 2000 (pb) Review posted live 13 January 1999 (rw) Original submission • 27 February 2020 (sw) Comprehensive update posted live • 14 June 2012 (me) Comprehensive update posted live • 4 March 2010 (me) Comprehensive update posted live • 8 June 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis • 8 March 2007 (me) Comprehensive update posted live • 5 January 2005 (me) Comprehensive update posted live • 28 February 2003 (me) Comprehensive update posted live • 12 February 2000 (pb) Review posted live • 13 January 1999 (rw) Original submission ## Author History Nine Knoers, MD, PhD (2003-present) Henny Lemmink, PhD (2020-present)Robert S Wildin, MD; Oregon Health and Science University (2000-2003) ## Revision History 27 February 2020 (sw) Comprehensive update posted live 14 June 2012 (me) Comprehensive update posted live 4 March 2010 (me) Comprehensive update posted live 8 June 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis 8 March 2007 (me) Comprehensive update posted live 5 January 2005 (me) Comprehensive update posted live 28 February 2003 (me) Comprehensive update posted live 12 February 2000 (pb) Review posted live 13 January 1999 (rw) Original submission • 27 February 2020 (sw) Comprehensive update posted live • 14 June 2012 (me) Comprehensive update posted live • 4 March 2010 (me) Comprehensive update posted live • 8 June 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis • 8 March 2007 (me) Comprehensive update posted live • 5 January 2005 (me) Comprehensive update posted live • 28 February 2003 (me) Comprehensive update posted live • 12 February 2000 (pb) Review posted live • 13 January 1999 (rw) Original submission ## References ## Literature Cited	[ "E Albertazzi, D Zanchetta, P Barbier, S Faranda, A Frattini, P Vezzoni, M Procaccio, A Bettinelli, F Guzzi, M Parenti, B. 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nem	nem	[ "Nemaline Rod Myopathy", "Nemaline Rod Myopathy", "Actin, alpha skeletal muscle", "Cofilin-2", "Kelch repeat and BTB domain-containing protein 13", "Kelch-like protein 40", "Kelch-like protein 41", "Leiomodin-3", "Nebulin", "Tropomyosin alpha-3 chain", "Tropomyosin beta chain", "Troponin T, slow skeletal muscle", "ACTA1", "CFL2", "KBTBD13", "KLHL40", "KLHL41", "LMOD3", "NEB", "TNNT1", "TPM2", "TPM3", "Nemaline Myopathy" ]	Nemaline Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Kathryn N North, Monique M Ryan	Summary Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. The clinical classification defines six forms of NM, which are classified by onset and severity of motor and respiratory involvement: Severe congenital (neonatal) (16% of all individuals with NM) Amish NM Intermediate congenital (20%) Typical congenital (46%) Childhood-onset (13%) Adult-onset (late-onset) (4%) Considerable overlap occurs among the forms. There are significant differences in survival between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk. Diagnosis is based on clinical findings and the observation of characteristic rod-shaped structures (nemaline bodies) on muscle biopsy stained with Gomori trichrome. Pathogenic variants have been identified in ten different genes, six of which encode protein components of the muscle thin filament, while three appear to be involved in the protein turnover in the muscle sarcomere via the ubiquitin proteosome pathway. NM is inherited in an autosomal dominant or autosomal recessive manner. In one series, approximately 20% of cases were autosomal recessive, approximately 30% autosomal dominant, and approximately 50% simplex (i.e., single occurrences in a family) representing heterozygosity for a	## Diagnosis The term "nemaline myopathy" (NM) refers to a group of genetically distinct disorders linked by common morphologic features observed on muscle histology. Nemaline myopathy Weakness that is predominantly proximal and generalized with or without facial weakness. Distal weakness may occur in a subset of individuals. Hypotonia and depressed deep tendon reflexes, with preserved sensation and normal cognition Feeding difficulties related to facial and bulbar weakness, respiratory difficulties, recurrent infections or a weak cough related to restrictive lung disease from weakness of the respiratory muscles. Cardiac function is usually normal. Onset in infancy, childhood, or adulthood. In infancy weakness is usually proximally predominant or generalized, while in later forms weakness may be proximally (or – less commonly – distally) predominant. Family history consistent with autosomal recessive or autosomal dominant inheritance, although many affected individuals represent simplex cases (i.e., a single occurrence in a family) attributable to autosomal recessive inheritance or a NM secondary to pathogenic variants of The diagnosis of nemaline myopathy A clinically affected muscle should be biopsied. Muscles with "end-stage" weakness should be avoided. Consideration should be given to biopsying more than one muscle, as findings can vary in different muscle groups/limbs [ The rods are often not visible on hematoxylin and eosin (H & E) staining, but appear as red or purple structures against the blue-green myofibrillar background with the modified Gomori trichrome stain. The distribution of rods within myofibers may be random, but they show a tendency to cluster under the sarcolemma and around nuclei. The proportion of fibers containing rods varies from one individual to another and from muscle to muscle. Although the number of rods appears to increase with age, no definitive correlation exists between number of rods and severity or age of onset of the myopathy [ Pathologic changes of NM are much the same irrespective of the severity of the clinical manifestations or the age of onset, but the finding of rod bodies within muscle nuclei (intranuclear rods) is often associated with a more severe clinical course. Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption are more common in nemaline myopathy associated with pathogenic variants in skeletal alpha-actin, while NM caused by pathogenic variants in slow alpha-tropomyosin is characterized by preferential rod formation in, and atrophy of, type 1 fibers [ Note: (1) Nemaline rods are not pathognomonic for NM. Nemaline rods observed on muscle biopsy in other neuromuscular disorders and unrelated conditions are considered a reflection of "secondary" NM (see No definitive pathologic markers exist for the various genetic forms of NM. Detailed pathologic studies may provide morphologic clues to guide molecular genetic testing; however, the number of individuals with NM studied in detail is still too small to draw conclusions about the specificity of these findings: Very numerous rods, abnormal accumulation of glycogen and actin filaments, marked sarcomeric disruption, and (rarely) zebra bodies have been observed in individuals with In the Amish form of NM, associated with complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [ Nebulin immunocytochemistry is normal in the majority of individuals with The NM associated with pathogenic variants in The severe nemaline myopathy associated with In NM associated with It is too early to determine the precise frequency of each of the genetic subgroups of NM, the proportion of Sequence analysis is performed first, followed by deletion/duplication analysis where relevant (see Note: (1) The genes included in a multigene panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Molecular Genetic Testing Used in Nemaline Myopathy See It is likely that more than half of nemaline myopathy cases are caused by Note: Pathogenic variants included in a panel may vary by laboratory. Testing that employs a method to detect the specific 2,502-nucleotide deletion spanning exon 55 (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Deletion/duplication analysis of Mutation of 3/117 individuals screened [ Dominant Identified only in a genetically isolated group of Old Order Amish individuals with NM [ Mutation of Additional individuals with NM do not link to any of the identified loci suggesting further genetic heterogeneity [ • Weakness that is predominantly proximal and generalized with or without facial weakness. Distal weakness may occur in a subset of individuals. • Hypotonia and depressed deep tendon reflexes, with preserved sensation and normal cognition • Feeding difficulties related to facial and bulbar weakness, respiratory difficulties, recurrent infections or a weak cough related to restrictive lung disease from weakness of the respiratory muscles. Cardiac function is usually normal. • Onset in infancy, childhood, or adulthood. In infancy weakness is usually proximally predominant or generalized, while in later forms weakness may be proximally (or – less commonly – distally) predominant. • Family history consistent with autosomal recessive or autosomal dominant inheritance, although many affected individuals represent simplex cases (i.e., a single occurrence in a family) attributable to autosomal recessive inheritance or a • NM secondary to pathogenic variants of • Very numerous rods, abnormal accumulation of glycogen and actin filaments, marked sarcomeric disruption, and (rarely) zebra bodies have been observed in individuals with • In the Amish form of NM, associated with complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [ • Nebulin immunocytochemistry is normal in the majority of individuals with • The NM associated with pathogenic variants in • The severe nemaline myopathy associated with • In NM associated with • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of ## Suggestive Findings Nemaline myopathy Weakness that is predominantly proximal and generalized with or without facial weakness. Distal weakness may occur in a subset of individuals. Hypotonia and depressed deep tendon reflexes, with preserved sensation and normal cognition Feeding difficulties related to facial and bulbar weakness, respiratory difficulties, recurrent infections or a weak cough related to restrictive lung disease from weakness of the respiratory muscles. Cardiac function is usually normal. Onset in infancy, childhood, or adulthood. In infancy weakness is usually proximally predominant or generalized, while in later forms weakness may be proximally (or – less commonly – distally) predominant. Family history consistent with autosomal recessive or autosomal dominant inheritance, although many affected individuals represent simplex cases (i.e., a single occurrence in a family) attributable to autosomal recessive inheritance or a NM secondary to pathogenic variants of • Weakness that is predominantly proximal and generalized with or without facial weakness. Distal weakness may occur in a subset of individuals. • Hypotonia and depressed deep tendon reflexes, with preserved sensation and normal cognition • Feeding difficulties related to facial and bulbar weakness, respiratory difficulties, recurrent infections or a weak cough related to restrictive lung disease from weakness of the respiratory muscles. Cardiac function is usually normal. • Onset in infancy, childhood, or adulthood. In infancy weakness is usually proximally predominant or generalized, while in later forms weakness may be proximally (or – less commonly – distally) predominant. • Family history consistent with autosomal recessive or autosomal dominant inheritance, although many affected individuals represent simplex cases (i.e., a single occurrence in a family) attributable to autosomal recessive inheritance or a • NM secondary to pathogenic variants of ## Preliminary Testing NM secondary to pathogenic variants of • NM secondary to pathogenic variants of ## Establishing the Diagnosis The diagnosis of nemaline myopathy A clinically affected muscle should be biopsied. Muscles with "end-stage" weakness should be avoided. Consideration should be given to biopsying more than one muscle, as findings can vary in different muscle groups/limbs [ The rods are often not visible on hematoxylin and eosin (H & E) staining, but appear as red or purple structures against the blue-green myofibrillar background with the modified Gomori trichrome stain. The distribution of rods within myofibers may be random, but they show a tendency to cluster under the sarcolemma and around nuclei. The proportion of fibers containing rods varies from one individual to another and from muscle to muscle. Although the number of rods appears to increase with age, no definitive correlation exists between number of rods and severity or age of onset of the myopathy [ Pathologic changes of NM are much the same irrespective of the severity of the clinical manifestations or the age of onset, but the finding of rod bodies within muscle nuclei (intranuclear rods) is often associated with a more severe clinical course. Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption are more common in nemaline myopathy associated with pathogenic variants in skeletal alpha-actin, while NM caused by pathogenic variants in slow alpha-tropomyosin is characterized by preferential rod formation in, and atrophy of, type 1 fibers [ Note: (1) Nemaline rods are not pathognomonic for NM. Nemaline rods observed on muscle biopsy in other neuromuscular disorders and unrelated conditions are considered a reflection of "secondary" NM (see No definitive pathologic markers exist for the various genetic forms of NM. Detailed pathologic studies may provide morphologic clues to guide molecular genetic testing; however, the number of individuals with NM studied in detail is still too small to draw conclusions about the specificity of these findings: Very numerous rods, abnormal accumulation of glycogen and actin filaments, marked sarcomeric disruption, and (rarely) zebra bodies have been observed in individuals with In the Amish form of NM, associated with complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [ Nebulin immunocytochemistry is normal in the majority of individuals with The NM associated with pathogenic variants in The severe nemaline myopathy associated with In NM associated with It is too early to determine the precise frequency of each of the genetic subgroups of NM, the proportion of Sequence analysis is performed first, followed by deletion/duplication analysis where relevant (see Note: (1) The genes included in a multigene panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Molecular Genetic Testing Used in Nemaline Myopathy See It is likely that more than half of nemaline myopathy cases are caused by Note: Pathogenic variants included in a panel may vary by laboratory. Testing that employs a method to detect the specific 2,502-nucleotide deletion spanning exon 55 (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Deletion/duplication analysis of Mutation of 3/117 individuals screened [ Dominant Identified only in a genetically isolated group of Old Order Amish individuals with NM [ Mutation of Additional individuals with NM do not link to any of the identified loci suggesting further genetic heterogeneity [ • Very numerous rods, abnormal accumulation of glycogen and actin filaments, marked sarcomeric disruption, and (rarely) zebra bodies have been observed in individuals with • In the Amish form of NM, associated with complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [ • Nebulin immunocytochemistry is normal in the majority of individuals with • The NM associated with pathogenic variants in • The severe nemaline myopathy associated with • In NM associated with • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of ## Muscle Biopsy A clinically affected muscle should be biopsied. Muscles with "end-stage" weakness should be avoided. Consideration should be given to biopsying more than one muscle, as findings can vary in different muscle groups/limbs [ The rods are often not visible on hematoxylin and eosin (H & E) staining, but appear as red or purple structures against the blue-green myofibrillar background with the modified Gomori trichrome stain. The distribution of rods within myofibers may be random, but they show a tendency to cluster under the sarcolemma and around nuclei. The proportion of fibers containing rods varies from one individual to another and from muscle to muscle. Although the number of rods appears to increase with age, no definitive correlation exists between number of rods and severity or age of onset of the myopathy [ Pathologic changes of NM are much the same irrespective of the severity of the clinical manifestations or the age of onset, but the finding of rod bodies within muscle nuclei (intranuclear rods) is often associated with a more severe clinical course. Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption are more common in nemaline myopathy associated with pathogenic variants in skeletal alpha-actin, while NM caused by pathogenic variants in slow alpha-tropomyosin is characterized by preferential rod formation in, and atrophy of, type 1 fibers [ Note: (1) Nemaline rods are not pathognomonic for NM. Nemaline rods observed on muscle biopsy in other neuromuscular disorders and unrelated conditions are considered a reflection of "secondary" NM (see No definitive pathologic markers exist for the various genetic forms of NM. Detailed pathologic studies may provide morphologic clues to guide molecular genetic testing; however, the number of individuals with NM studied in detail is still too small to draw conclusions about the specificity of these findings: Very numerous rods, abnormal accumulation of glycogen and actin filaments, marked sarcomeric disruption, and (rarely) zebra bodies have been observed in individuals with In the Amish form of NM, associated with complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [ Nebulin immunocytochemistry is normal in the majority of individuals with The NM associated with pathogenic variants in The severe nemaline myopathy associated with In NM associated with • Very numerous rods, abnormal accumulation of glycogen and actin filaments, marked sarcomeric disruption, and (rarely) zebra bodies have been observed in individuals with • In the Amish form of NM, associated with complete loss of troponin T, slow skeletal muscle causes selective atrophy of type 1 fibers [ • Nebulin immunocytochemistry is normal in the majority of individuals with • The NM associated with pathogenic variants in • The severe nemaline myopathy associated with • In NM associated with ## Molecular Genetic Testing It is too early to determine the precise frequency of each of the genetic subgroups of NM, the proportion of Sequence analysis is performed first, followed by deletion/duplication analysis where relevant (see Note: (1) The genes included in a multigene panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Mutation of Molecular Genetic Testing Used in Nemaline Myopathy See It is likely that more than half of nemaline myopathy cases are caused by Note: Pathogenic variants included in a panel may vary by laboratory. Testing that employs a method to detect the specific 2,502-nucleotide deletion spanning exon 55 (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Deletion/duplication analysis of Mutation of 3/117 individuals screened [ Dominant Identified only in a genetically isolated group of Old Order Amish individuals with NM [ Mutation of Additional individuals with NM do not link to any of the identified loci suggesting further genetic heterogeneity [ • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of • Mutation of ## Clinical Characteristics The cardinal features of nemaline myopathy (NM) are weakness, hypotonia, and depressed or absent deep tendon reflexes; intrafamilial variation in course and outcome is considerable. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. In some individuals with NM, the distal muscles are involved. In congenital forms of NM, the face is often long and expressionless, with a tented vermilion border of the upper lip, high palate, and retrognathia. Gross motor milestones are delayed, but most affected individuals are otherwise developmentally normal. Dysphagia and feeding difficulties are common; approximately 25% of children with congenital-onset NM require gavage feeding or gastrostomy during the first few years of life. Respiratory problems secondary to involvement of the diaphragm and intercostal muscles are common in congenital NM. The degree of skeletal muscle weakness does not necessarily reflect the degree of respiratory muscle involvement, particularly in older children and adults [ Many children with NM have hypermobility of joints in infancy and early childhood; contractures and deformities of the joints, including scoliosis, commonly develop with time. The extraocular muscles are usually spared. Cardiac contractility is usually normal but occasional cases of dilated cardiomyopathy are seen in NM [ The existing classification of NM into six forms is based on age of onset and severity of motor and respiratory involvement and includes the severe congenital (neonatal) form, Amish NM, intermediate congenital form, typical congenital form, childhood-onset form, and adult-onset (late-onset) form [ Overlap among these groups is significant. It is also important to note that adults are sometimes diagnosed with NM in the course of investigation of other family members. Individuals in whom muscle involvement is relatively mild, despite onset in infancy or childhood, may be misclassified as having the adult-onset form. In a review of 143 individuals with NM from Australia and North America, This form of NM is caused by mutation of Van Engelen and colleagues [ Inflammatory changes on biopsy are not uncommon in adult-onset NM. A small number of affected individuals have developed a monoclonal gammopathy and paresthesiae in association with their myopathy. Comorbid monoclonal gammopathy may be a marker of poor prognosis in individuals with late-onset NM [ In a review of 14 individuals with NM seen in London and 85 individuals with NM from the literature, In the 143 affected individuals reported by Genotype-phenotype correlation remains poorly defined in NM, largely because of the significant clinical overlap between differing forms of the disease ( Neonatal presentation of NM has been reported in those with autosomal recessive inheritance of pathogenic variants in "Childhood-onset" disease has been seen with autosomal dominant inheritance of pathogenic variants in Marked clinical variability is noted in individuals with Phenotype Correlations with Mutated Genes Typical congenital (majority) All other phenotypes (occasional) Range from severe congenital to childhood onset Causes 50% of severe lethal NM Rare cases with cardiac involvement Severe congenital (AR) Intermediate congenital Childhood onset (AD) Typical congenital Only 2 families reported to date Childhood onset, slowly progressive weakness w/characteristic slowness of movements Unstructured cores present on muscle biopsy, in addition to rods Severe congenital lethal Fetal akinesia Severe congenital Intermediate congenital Typical congenital Severe congenital Typical congenital AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Where known, in descending order by the proportion of nemaline myopathy attributed to pathogenic variants in the gene (see Data are insufficient to draw conclusions about penetrance in dominant Nemaline myopathy was first described in 1963 by investigators from the United States and Canada, and defined by a particular ultrastructural change on muscle biopsy: the finding of thread-shaped structures in muscle fibers, which are known as nemaline bodies, or rods (from the Greek NM is a rare disorder with an estimated incidence of 1:50,000 live births in one Finnish study and a more recent study in an American Ashkenazi Jewish population [ NM may be more common in some populations; Overall, NM represents about 17% of all congenital myopathies [ • Typical congenital (majority) • All other phenotypes (occasional) • Range from severe congenital to childhood onset • Causes 50% of severe lethal NM • Rare cases with cardiac involvement • Severe congenital (AR) • Intermediate congenital • Childhood onset (AD) • Typical congenital • Only 2 families reported to date • Childhood onset, slowly progressive weakness w/characteristic slowness of movements • Unstructured cores present on muscle biopsy, in addition to rods • Severe congenital lethal • Fetal akinesia • Severe congenital • Intermediate congenital • Typical congenital • Severe congenital • Typical congenital ## Clinical Description The cardinal features of nemaline myopathy (NM) are weakness, hypotonia, and depressed or absent deep tendon reflexes; intrafamilial variation in course and outcome is considerable. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. In some individuals with NM, the distal muscles are involved. In congenital forms of NM, the face is often long and expressionless, with a tented vermilion border of the upper lip, high palate, and retrognathia. Gross motor milestones are delayed, but most affected individuals are otherwise developmentally normal. Dysphagia and feeding difficulties are common; approximately 25% of children with congenital-onset NM require gavage feeding or gastrostomy during the first few years of life. Respiratory problems secondary to involvement of the diaphragm and intercostal muscles are common in congenital NM. The degree of skeletal muscle weakness does not necessarily reflect the degree of respiratory muscle involvement, particularly in older children and adults [ Many children with NM have hypermobility of joints in infancy and early childhood; contractures and deformities of the joints, including scoliosis, commonly develop with time. The extraocular muscles are usually spared. Cardiac contractility is usually normal but occasional cases of dilated cardiomyopathy are seen in NM [ The existing classification of NM into six forms is based on age of onset and severity of motor and respiratory involvement and includes the severe congenital (neonatal) form, Amish NM, intermediate congenital form, typical congenital form, childhood-onset form, and adult-onset (late-onset) form [ Overlap among these groups is significant. It is also important to note that adults are sometimes diagnosed with NM in the course of investigation of other family members. Individuals in whom muscle involvement is relatively mild, despite onset in infancy or childhood, may be misclassified as having the adult-onset form. In a review of 143 individuals with NM from Australia and North America, This form of NM is caused by mutation of Van Engelen and colleagues [ Inflammatory changes on biopsy are not uncommon in adult-onset NM. A small number of affected individuals have developed a monoclonal gammopathy and paresthesiae in association with their myopathy. Comorbid monoclonal gammopathy may be a marker of poor prognosis in individuals with late-onset NM [ In a review of 14 individuals with NM seen in London and 85 individuals with NM from the literature, In the 143 affected individuals reported by ## Classification The existing classification of NM into six forms is based on age of onset and severity of motor and respiratory involvement and includes the severe congenital (neonatal) form, Amish NM, intermediate congenital form, typical congenital form, childhood-onset form, and adult-onset (late-onset) form [ Overlap among these groups is significant. It is also important to note that adults are sometimes diagnosed with NM in the course of investigation of other family members. Individuals in whom muscle involvement is relatively mild, despite onset in infancy or childhood, may be misclassified as having the adult-onset form. In a review of 143 individuals with NM from Australia and North America, This form of NM is caused by mutation of Van Engelen and colleagues [ Inflammatory changes on biopsy are not uncommon in adult-onset NM. A small number of affected individuals have developed a monoclonal gammopathy and paresthesiae in association with their myopathy. Comorbid monoclonal gammopathy may be a marker of poor prognosis in individuals with late-onset NM [ ## Prognosis In a review of 14 individuals with NM seen in London and 85 individuals with NM from the literature, In the 143 affected individuals reported by ## Genotype-Phenotype Correlations Genotype-phenotype correlation remains poorly defined in NM, largely because of the significant clinical overlap between differing forms of the disease ( Neonatal presentation of NM has been reported in those with autosomal recessive inheritance of pathogenic variants in "Childhood-onset" disease has been seen with autosomal dominant inheritance of pathogenic variants in Marked clinical variability is noted in individuals with Phenotype Correlations with Mutated Genes Typical congenital (majority) All other phenotypes (occasional) Range from severe congenital to childhood onset Causes 50% of severe lethal NM Rare cases with cardiac involvement Severe congenital (AR) Intermediate congenital Childhood onset (AD) Typical congenital Only 2 families reported to date Childhood onset, slowly progressive weakness w/characteristic slowness of movements Unstructured cores present on muscle biopsy, in addition to rods Severe congenital lethal Fetal akinesia Severe congenital Intermediate congenital Typical congenital Severe congenital Typical congenital AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Where known, in descending order by the proportion of nemaline myopathy attributed to pathogenic variants in the gene (see • Typical congenital (majority) • All other phenotypes (occasional) • Range from severe congenital to childhood onset • Causes 50% of severe lethal NM • Rare cases with cardiac involvement • Severe congenital (AR) • Intermediate congenital • Childhood onset (AD) • Typical congenital • Only 2 families reported to date • Childhood onset, slowly progressive weakness w/characteristic slowness of movements • Unstructured cores present on muscle biopsy, in addition to rods • Severe congenital lethal • Fetal akinesia • Severe congenital • Intermediate congenital • Typical congenital • Severe congenital • Typical congenital ## Penetrance Data are insufficient to draw conclusions about penetrance in dominant ## Nomenclature Nemaline myopathy was first described in 1963 by investigators from the United States and Canada, and defined by a particular ultrastructural change on muscle biopsy: the finding of thread-shaped structures in muscle fibers, which are known as nemaline bodies, or rods (from the Greek ## Prevalence NM is a rare disorder with an estimated incidence of 1:50,000 live births in one Finnish study and a more recent study in an American Ashkenazi Jewish population [ NM may be more common in some populations; Overall, NM represents about 17% of all congenital myopathies [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Heterozygous pathogenic missense variants in A single case of cap disease caused by an ## Differential Diagnosis All congenital myopathies have a number of common clinical features: generalized weakness, hypotonia and hyporeflexia, poor muscle bulk, and dysmorphic features secondary to muscle weakness (e.g., pectus carinatum, scoliosis, foot deformities, a high palate, long face). Therefore, the diagnosis of nemaline myopathy (NM) rests on the presence of the specific ultrastructural changes on muscle biopsy. In addition, marked clinical overlap exists between congenital myopathies including In some individuals with congenital myopathy, cores and rods coexist (so-called "core-rod" myopathy). Another form of inherited myopathy with hyaline and nemaline bodies, for which no genetic locus has yet been identified, has been reported [ In sporadic late-onset NM, progressive weakness is often associated with a monoclonal gammopathy, which may be a marker of poor prognosis [ ## Management To establish the extent of disease and needs in an individual diagnosed with nemaline myopathy (NM), the following evaluations are recommended: Thorough assessment of respiratory status, including pulmonary function studies and assessment for nocturnal hypoxia For early-onset forms, assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux) and growth parameters to determine the need for feeding interventions such as gavage feeding or gastrostomy insertion Physical examination to evaluate for joint contractures Physical examination to evaluate for scoliosis, followed by spinal x-ray if scoliosis is suspected Physical and occupational therapy evaluations relevant to the degree of weakness Speech therapy evaluation if dysarthria and/or hypernasal speech is present Orthodontic evaluation if palatal anomalies are present Evaluation for the presence of Clinical genetics consultation Consensus for management of congenital myopathies have been published [ A multidisciplinary approach to the clinical management of the affected individual greatly improves quality of life and can influence survival: Aggressive treatment of lower respiratory tract infections Evaluation at an early stage of the need for intermittent or permanent use of a mechanical ventilator to prevent insidious nocturnal hypoxia Assurance of adequate caloric intake and appropriate nutritional status, including special feeding techniques and high-calorie formulas and foods, if indicated Standard treatment of gastroesophageal reflux, if present Referral to an orthopedist for management of scoliosis and joint contractures, as in the general population Physical therapy for maintenance/improvement of function and joint mobility Speech therapy if dysarthria and/or hypernasal speech is present Assessment of cardiac status because of the risk (albeit low) of cardiomyopathy or cor pulmonale Preoperative assessment of pulmonary function is essential to ensure optimal timing of surgical procedures and to minimize anesthetic risk. Anesthetics are generally well tolerated in individuals with NM. The following are appropriate: Regular formal assessment of respiratory function, including monitoring of sleep studies when significant respiratory impairment is identified Routine assessment for scoliosis and joint contractures Routine assessment of physical function and the need for mechanical assistance, such as a wheelchair Prolonged periods of immobilization should be avoided after illness or surgery, as immobility may markedly exacerbate muscle weakness [ It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from medical surveillance and preventive measures. If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variant(s) in the family are not known, a targeted clinical examination, with or without neurophysiologic testing, can clarify whether a muscle biopsy should be considered. See Pregnancy and delivery are relatively well tolerated by women with NM [ A high frequency of obstetric complications is associated with an affected fetus, including polyhydramnios, decreased fetal movements, and abnormal presentation and/or fetal distress [ L-tyrosine has been proposed as a potential therapy. A precursor of the neurotransmitters dopamine, norepinephrine, and epinephrine, L-tyrosine has been shown after oral administration in rats to increase catecholamine production and release, and to improve reaction and attention time and tolerance of physical stress. Two reports have shown subjectively improved muscle strength and clearance of oral secretions after oral tyrosine supplementation in individuals with NM. Subjective benefits from dietary supplementation with tyrosine have been reported in a small series of individuals with nemaline myopathy. L-tyrosine may be particularly effective in improving bulbar dysfunction and exercise tolerance in this condition [ L-tyrosine was shown to improve muscle strength in a mouse model of severe Search In a mouse model, endurance exercise programs may overcome the increase in muscle weakness that follows prolonged periods of immobilization [ • Thorough assessment of respiratory status, including pulmonary function studies and assessment for nocturnal hypoxia • For early-onset forms, assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux) and growth parameters to determine the need for feeding interventions such as gavage feeding or gastrostomy insertion • Physical examination to evaluate for joint contractures • Physical examination to evaluate for scoliosis, followed by spinal x-ray if scoliosis is suspected • Physical and occupational therapy evaluations relevant to the degree of weakness • Speech therapy evaluation if dysarthria and/or hypernasal speech is present • Orthodontic evaluation if palatal anomalies are present • Evaluation for the presence of • Clinical genetics consultation • Aggressive treatment of lower respiratory tract infections • Evaluation at an early stage of the need for intermittent or permanent use of a mechanical ventilator to prevent insidious nocturnal hypoxia • Assurance of adequate caloric intake and appropriate nutritional status, including special feeding techniques and high-calorie formulas and foods, if indicated • Standard treatment of gastroesophageal reflux, if present • Referral to an orthopedist for management of scoliosis and joint contractures, as in the general population • Physical therapy for maintenance/improvement of function and joint mobility • Speech therapy if dysarthria and/or hypernasal speech is present • Assessment of cardiac status because of the risk (albeit low) of cardiomyopathy or cor pulmonale • Regular formal assessment of respiratory function, including monitoring of sleep studies when significant respiratory impairment is identified • Routine assessment for scoliosis and joint contractures • Routine assessment of physical function and the need for mechanical assistance, such as a wheelchair • If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variant(s) in the family are not known, a targeted clinical examination, with or without neurophysiologic testing, can clarify whether a muscle biopsy should be considered. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with nemaline myopathy (NM), the following evaluations are recommended: Thorough assessment of respiratory status, including pulmonary function studies and assessment for nocturnal hypoxia For early-onset forms, assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux) and growth parameters to determine the need for feeding interventions such as gavage feeding or gastrostomy insertion Physical examination to evaluate for joint contractures Physical examination to evaluate for scoliosis, followed by spinal x-ray if scoliosis is suspected Physical and occupational therapy evaluations relevant to the degree of weakness Speech therapy evaluation if dysarthria and/or hypernasal speech is present Orthodontic evaluation if palatal anomalies are present Evaluation for the presence of Clinical genetics consultation • Thorough assessment of respiratory status, including pulmonary function studies and assessment for nocturnal hypoxia • For early-onset forms, assessment of feeding abilities (sucking, swallowing, gastroesophageal reflux) and growth parameters to determine the need for feeding interventions such as gavage feeding or gastrostomy insertion • Physical examination to evaluate for joint contractures • Physical examination to evaluate for scoliosis, followed by spinal x-ray if scoliosis is suspected • Physical and occupational therapy evaluations relevant to the degree of weakness • Speech therapy evaluation if dysarthria and/or hypernasal speech is present • Orthodontic evaluation if palatal anomalies are present • Evaluation for the presence of • Clinical genetics consultation ## Treatment of Manifestations Consensus for management of congenital myopathies have been published [ A multidisciplinary approach to the clinical management of the affected individual greatly improves quality of life and can influence survival: Aggressive treatment of lower respiratory tract infections Evaluation at an early stage of the need for intermittent or permanent use of a mechanical ventilator to prevent insidious nocturnal hypoxia Assurance of adequate caloric intake and appropriate nutritional status, including special feeding techniques and high-calorie formulas and foods, if indicated Standard treatment of gastroesophageal reflux, if present Referral to an orthopedist for management of scoliosis and joint contractures, as in the general population Physical therapy for maintenance/improvement of function and joint mobility Speech therapy if dysarthria and/or hypernasal speech is present Assessment of cardiac status because of the risk (albeit low) of cardiomyopathy or cor pulmonale • Aggressive treatment of lower respiratory tract infections • Evaluation at an early stage of the need for intermittent or permanent use of a mechanical ventilator to prevent insidious nocturnal hypoxia • Assurance of adequate caloric intake and appropriate nutritional status, including special feeding techniques and high-calorie formulas and foods, if indicated • Standard treatment of gastroesophageal reflux, if present • Referral to an orthopedist for management of scoliosis and joint contractures, as in the general population • Physical therapy for maintenance/improvement of function and joint mobility • Speech therapy if dysarthria and/or hypernasal speech is present • Assessment of cardiac status because of the risk (albeit low) of cardiomyopathy or cor pulmonale ## Prevention of Secondary Complications Preoperative assessment of pulmonary function is essential to ensure optimal timing of surgical procedures and to minimize anesthetic risk. Anesthetics are generally well tolerated in individuals with NM. ## Surveillance The following are appropriate: Regular formal assessment of respiratory function, including monitoring of sleep studies when significant respiratory impairment is identified Routine assessment for scoliosis and joint contractures Routine assessment of physical function and the need for mechanical assistance, such as a wheelchair • Regular formal assessment of respiratory function, including monitoring of sleep studies when significant respiratory impairment is identified • Routine assessment for scoliosis and joint contractures • Routine assessment of physical function and the need for mechanical assistance, such as a wheelchair ## Agents/Circumstances to Avoid Prolonged periods of immobilization should be avoided after illness or surgery, as immobility may markedly exacerbate muscle weakness [ ## Evaluation of Relatives at Risk It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from medical surveillance and preventive measures. If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variant(s) in the family are not known, a targeted clinical examination, with or without neurophysiologic testing, can clarify whether a muscle biopsy should be considered. See • If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variant(s) in the family are not known, a targeted clinical examination, with or without neurophysiologic testing, can clarify whether a muscle biopsy should be considered. ## Pregnancy Management Pregnancy and delivery are relatively well tolerated by women with NM [ A high frequency of obstetric complications is associated with an affected fetus, including polyhydramnios, decreased fetal movements, and abnormal presentation and/or fetal distress [ ## Therapies Under Investigation L-tyrosine has been proposed as a potential therapy. A precursor of the neurotransmitters dopamine, norepinephrine, and epinephrine, L-tyrosine has been shown after oral administration in rats to increase catecholamine production and release, and to improve reaction and attention time and tolerance of physical stress. Two reports have shown subjectively improved muscle strength and clearance of oral secretions after oral tyrosine supplementation in individuals with NM. Subjective benefits from dietary supplementation with tyrosine have been reported in a small series of individuals with nemaline myopathy. L-tyrosine may be particularly effective in improving bulbar dysfunction and exercise tolerance in this condition [ L-tyrosine was shown to improve muscle strength in a mouse model of severe Search ## Other In a mouse model, endurance exercise programs may overcome the increase in muscle weakness that follows prolonged periods of immobilization [ ## Genetic Counseling Nemaline myopathy (NM) is inherited in an autosomal dominant or autosomal recessive manner. Some individuals diagnosed with NM have an affected parent. A proband with NM may have the disorder as the result of a Most cases of The family history of some individuals diagnosed with nemaline myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband. Recommendations for the evaluation of parents of an individual with no known family history of NM include evaluation of both parents for evidence of minor muscle weakness and possible muscle biopsy. If a proband has an identified Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. The risk to the sibs of the proband depends on the genetic status of the parents: If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. To date, germline mosaicism has been reported only in association with Each parent is a carrier for one pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family. Inheritance is usually autosomal dominant as the result of either an inherited pathogenic variant or a In some families, both clinically healthy parents have shown abnormalities on muscle biopsy, suggesting a manifesting heterozygous state for a recessive allelic variant. Thus, if only one parent were to undergo muscle biopsy and show abnormalities, it cannot be determined if those changes are manifestations of a dominant allelic variant. If one parent shows overt disease clinically and typical histologic abnormalities on muscle biopsy, and the other parent is healthy and shows normal findings on muscle biopsy, the likely mode of inheritance is autosomal dominant. If both parents are clinically healthy and show no abnormality on muscle biopsy, dominant transmission from one of the parents is unlikely, leaving the possibility of a As the molecular genetics of NM are clarified, some of these genetic counseling issues may be resolved. In research studies in which pathogenic variants can be identified, correlations can be made between the gene involved and the mode of inheritance. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk. Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for nemaline myopathy are possible. • Some individuals diagnosed with NM have an affected parent. • A proband with NM may have the disorder as the result of a • Most cases of • The family history of some individuals diagnosed with nemaline myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband. • Recommendations for the evaluation of parents of an individual with no known family history of NM include evaluation of both parents for evidence of minor muscle weakness and possible muscle biopsy. If a proband has an identified • The risk to the sibs of the proband depends on the genetic status of the parents: • If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. • If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. • To date, germline mosaicism has been reported only in association with • If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. • Each parent is a carrier for one pathogenic variant. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, • Inheritance is usually autosomal dominant as the result of either an inherited pathogenic variant or a • In some families, both clinically healthy parents have shown abnormalities on muscle biopsy, suggesting a manifesting heterozygous state for a recessive allelic variant. Thus, if only one parent were to undergo muscle biopsy and show abnormalities, it cannot be determined if those changes are manifestations of a dominant allelic variant. • If one parent shows overt disease clinically and typical histologic abnormalities on muscle biopsy, and the other parent is healthy and shows normal findings on muscle biopsy, the likely mode of inheritance is autosomal dominant. • If both parents are clinically healthy and show no abnormality on muscle biopsy, dominant transmission from one of the parents is unlikely, leaving the possibility of a • As the molecular genetics of NM are clarified, some of these genetic counseling issues may be resolved. • In research studies in which pathogenic variants can be identified, correlations can be made between the gene involved and the mode of inheritance. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk. ## Mode of Inheritance Nemaline myopathy (NM) is inherited in an autosomal dominant or autosomal recessive manner. ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with NM have an affected parent. A proband with NM may have the disorder as the result of a Most cases of The family history of some individuals diagnosed with nemaline myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband. Recommendations for the evaluation of parents of an individual with no known family history of NM include evaluation of both parents for evidence of minor muscle weakness and possible muscle biopsy. If a proband has an identified Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. The risk to the sibs of the proband depends on the genetic status of the parents: If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. To date, germline mosaicism has been reported only in association with • Some individuals diagnosed with NM have an affected parent. • A proband with NM may have the disorder as the result of a • Most cases of • The family history of some individuals diagnosed with nemaline myopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband. • Recommendations for the evaluation of parents of an individual with no known family history of NM include evaluation of both parents for evidence of minor muscle weakness and possible muscle biopsy. If a proband has an identified • The risk to the sibs of the proband depends on the genetic status of the parents: • If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. • If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. • To date, germline mosaicism has been reported only in association with • If a parent is affected and has a family history suggestive of AD inheritance or has a pathogenic variant in • If the parents are clinically unaffected and show no abnormality on muscle biopsy, the risk to the sibs of a proband appears to be low unless the disorder is inherited in an autosomal recessive manner. ## Autosomal Recessive Inheritance Each parent is a carrier for one pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family. • Each parent is a carrier for one pathogenic variant. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, ## Risk to Family Members Each parent is a carrier for one pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, • Each parent is a carrier for one pathogenic variant. • Heterozygotes (carriers) are asymptomatic. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, ## Carrier (Heterozygote) Detection Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family. ## Related Genetic Counseling Issues Inheritance is usually autosomal dominant as the result of either an inherited pathogenic variant or a In some families, both clinically healthy parents have shown abnormalities on muscle biopsy, suggesting a manifesting heterozygous state for a recessive allelic variant. Thus, if only one parent were to undergo muscle biopsy and show abnormalities, it cannot be determined if those changes are manifestations of a dominant allelic variant. If one parent shows overt disease clinically and typical histologic abnormalities on muscle biopsy, and the other parent is healthy and shows normal findings on muscle biopsy, the likely mode of inheritance is autosomal dominant. If both parents are clinically healthy and show no abnormality on muscle biopsy, dominant transmission from one of the parents is unlikely, leaving the possibility of a As the molecular genetics of NM are clarified, some of these genetic counseling issues may be resolved. In research studies in which pathogenic variants can be identified, correlations can be made between the gene involved and the mode of inheritance. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk. • Inheritance is usually autosomal dominant as the result of either an inherited pathogenic variant or a • In some families, both clinically healthy parents have shown abnormalities on muscle biopsy, suggesting a manifesting heterozygous state for a recessive allelic variant. Thus, if only one parent were to undergo muscle biopsy and show abnormalities, it cannot be determined if those changes are manifestations of a dominant allelic variant. • If one parent shows overt disease clinically and typical histologic abnormalities on muscle biopsy, and the other parent is healthy and shows normal findings on muscle biopsy, the likely mode of inheritance is autosomal dominant. • If both parents are clinically healthy and show no abnormality on muscle biopsy, dominant transmission from one of the parents is unlikely, leaving the possibility of a • As the molecular genetics of NM are clarified, some of these genetic counseling issues may be resolved. • In research studies in which pathogenic variants can be identified, correlations can be made between the gene involved and the mode of inheritance. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk. ## Prenatal Testing and Preimplantation Genetic Diagnosis Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for nemaline myopathy are possible. ## Resources 222 South Riverside Plaza Suite 1500 Chicago IL 60606 61A Great Suffolk Street London SE1 0BU United Kingdom 19401 South Vermont Avenue Suite J100 Torrance CA 90502 • • 222 South Riverside Plaza • Suite 1500 • Chicago IL 60606 • • • 61A Great Suffolk Street • London SE1 0BU • United Kingdom • • • • 19401 South Vermont Avenue • Suite J100 • Torrance CA 90502 • ## Molecular Genetics Nemaline Myopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nemaline Myopathy ( Nemaline myopathy (NM) is a disorder of thin filament proteins and proteins of the ubiquitin proteosome pathway. Interruption of the normal function and interaction of these proteins is thought to underpin the abnormal muscle contraction causing muscle weakness in NM. Alpha-actinin, the major protein component of nemaline bodies, forms diagonal cross-connections between the thin filaments, which are anchored via a network of interactions between α-actinin, actin, nebulin, and other proteins. The myosin-containing thick filaments interdigitate with the thin filaments, which are made up of a double-stranded helix of globular actin monomers (e.g., F actin) associated with a single molecule of nebulin. More than 770 kd in size, nebulin ranks as one of the largest known proteins. The central portion contains up to 185 tandem repeats of 35 residues, each of which likely binds a single actin monomer. The carboxy terminus is unique and is embedded in the Z-lines. Along the length of the thin filaments, the tropomyosins and troponins together form a complex of proteins responsible for control of contraction by regulating the interactions of actin and myosin. At rest, tropomyosin dimers lie along the actin filament in a potential myosin-binding site, sterically inhibiting myosin-actin interactions. Tropomyosin position and movement are controlled by the troponin complex consisting of three subunits: TN-I (inhibitory), TN-T (tropomyosin-binding), and TN-C (calcium-binding). When muscle is stimulated, intracellular calcium levels increase to a critical level and bind to TN-C. This releases the inhibitory effect of TN-I, so that tropomyosin moves into the groove between actin helices, unmasking the myosin binding sites and triggering the contraction cycle. Pathogenic variants in the genes encoding various components of the thin filament likely disrupt the orderly assembly of sarcomeric proteins and the functional interaction between the thin and thick filament during muscle contraction. Tissue culture studies of pathogenic variants in The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function, but appears to be of functional importance, since pathogenic variants in this domain are associated with disease. Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. Three members of the Kelch-like protein family – Interaction between thin filament proteins and the kelch protein family has been demonstrated; KLHL40 is a binding partner of both LMOD3 and NEB, suggesting a common pathogenesis of different genetic forms of NM. See The majority of pathogenic variants are frameshifts caused by small deletions or insertions or single nucleotide variants causing premature stop codons or abnormal splicing. In addition, a 2,502-bp deletion in Selected Variants listed in the table have been provided by the authors. Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Selected Note on variant classification: Variants listed in the table have been provided by the authors. Note on nomenclature: A homozygous missense change (c.103C>A) was found in two sisters from a consanguineous family of Middle Eastern origin. Both children had typical clinical features of a congenital myopathy that included congenital hypotonia, delayed early milestones, frequent falls, and inability to run. Nemaline bodies were seen on muscle biopsy at age two years in one child, together with occasional minicore lesions and actin filament accumulations. A muscle biopsy of the older child at age four years showed nonspecific abnormalities [ A subsequent report described two sibs from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. Sequencing showed a novel homozygous pathogenic missense variant in exon 2 of More severe weakness was described in a third kindred with a confirmed case and two probably affected cousins, all of whom were ventilator-dependent from early infancy. Exome sequencing identified a novel homozygous null variant in Selected Variants listed in the table have been provided by the authors. Selected Variants listed in the table have been provided by the authors. • BTB domains facilitate protein binding and dimerization. • The BACK domain has no known function, but appears to be of functional importance, since pathogenic variants in this domain are associated with disease. • Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. • Three members of the Kelch-like protein family – ## Molecular Pathogenesis Nemaline myopathy (NM) is a disorder of thin filament proteins and proteins of the ubiquitin proteosome pathway. Interruption of the normal function and interaction of these proteins is thought to underpin the abnormal muscle contraction causing muscle weakness in NM. Alpha-actinin, the major protein component of nemaline bodies, forms diagonal cross-connections between the thin filaments, which are anchored via a network of interactions between α-actinin, actin, nebulin, and other proteins. The myosin-containing thick filaments interdigitate with the thin filaments, which are made up of a double-stranded helix of globular actin monomers (e.g., F actin) associated with a single molecule of nebulin. More than 770 kd in size, nebulin ranks as one of the largest known proteins. The central portion contains up to 185 tandem repeats of 35 residues, each of which likely binds a single actin monomer. The carboxy terminus is unique and is embedded in the Z-lines. Along the length of the thin filaments, the tropomyosins and troponins together form a complex of proteins responsible for control of contraction by regulating the interactions of actin and myosin. At rest, tropomyosin dimers lie along the actin filament in a potential myosin-binding site, sterically inhibiting myosin-actin interactions. Tropomyosin position and movement are controlled by the troponin complex consisting of three subunits: TN-I (inhibitory), TN-T (tropomyosin-binding), and TN-C (calcium-binding). When muscle is stimulated, intracellular calcium levels increase to a critical level and bind to TN-C. This releases the inhibitory effect of TN-I, so that tropomyosin moves into the groove between actin helices, unmasking the myosin binding sites and triggering the contraction cycle. Pathogenic variants in the genes encoding various components of the thin filament likely disrupt the orderly assembly of sarcomeric proteins and the functional interaction between the thin and thick filament during muscle contraction. Tissue culture studies of pathogenic variants in The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function, but appears to be of functional importance, since pathogenic variants in this domain are associated with disease. Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. Three members of the Kelch-like protein family – Interaction between thin filament proteins and the kelch protein family has been demonstrated; KLHL40 is a binding partner of both LMOD3 and NEB, suggesting a common pathogenesis of different genetic forms of NM. See The majority of pathogenic variants are frameshifts caused by small deletions or insertions or single nucleotide variants causing premature stop codons or abnormal splicing. In addition, a 2,502-bp deletion in Selected Variants listed in the table have been provided by the authors. Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Selected Note on variant classification: Variants listed in the table have been provided by the authors. Note on nomenclature: A homozygous missense change (c.103C>A) was found in two sisters from a consanguineous family of Middle Eastern origin. Both children had typical clinical features of a congenital myopathy that included congenital hypotonia, delayed early milestones, frequent falls, and inability to run. Nemaline bodies were seen on muscle biopsy at age two years in one child, together with occasional minicore lesions and actin filament accumulations. A muscle biopsy of the older child at age four years showed nonspecific abnormalities [ A subsequent report described two sibs from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. Sequencing showed a novel homozygous pathogenic missense variant in exon 2 of More severe weakness was described in a third kindred with a confirmed case and two probably affected cousins, all of whom were ventilator-dependent from early infancy. Exome sequencing identified a novel homozygous null variant in Selected Variants listed in the table have been provided by the authors. Selected Variants listed in the table have been provided by the authors. • BTB domains facilitate protein binding and dimerization. • The BACK domain has no known function, but appears to be of functional importance, since pathogenic variants in this domain are associated with disease. • Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins. • Three members of the Kelch-like protein family – ## The majority of pathogenic variants are frameshifts caused by small deletions or insertions or single nucleotide variants causing premature stop codons or abnormal splicing. In addition, a 2,502-bp deletion in Selected Variants listed in the table have been provided by the authors. ## ## Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## ## Selected Note on variant classification: Variants listed in the table have been provided by the authors. Note on nomenclature: ## A homozygous missense change (c.103C>A) was found in two sisters from a consanguineous family of Middle Eastern origin. Both children had typical clinical features of a congenital myopathy that included congenital hypotonia, delayed early milestones, frequent falls, and inability to run. Nemaline bodies were seen on muscle biopsy at age two years in one child, together with occasional minicore lesions and actin filament accumulations. A muscle biopsy of the older child at age four years showed nonspecific abnormalities [ A subsequent report described two sibs from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. Sequencing showed a novel homozygous pathogenic missense variant in exon 2 of More severe weakness was described in a third kindred with a confirmed case and two probably affected cousins, all of whom were ventilator-dependent from early infancy. Exome sequencing identified a novel homozygous null variant in Selected Variants listed in the table have been provided by the authors. ## Selected Variants listed in the table have been provided by the authors. ## ## ## ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Chapter Notes 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation 11 June 2015 (aa) Revision: 18 September 2014 (me) Comprehensive update posted live 15 March 2012 (me) Comprehensive update posted live 21 October 2010 (cd) Revision: deletion/duplication analysis for 17 August 2010 (me) Comprehensive update posted live 2 April 2009 (me) Comprehensive update posted live 16 October 2006 (me) Comprehensive update posted live 17 June 2004 (me) Comprehensive update posted live 25 November 2002 (kn) Revisions 19 June 2002 (me) Review posted live 24 February 2002 (kn) Original submission • 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation • 11 June 2015 (aa) Revision: • 18 September 2014 (me) Comprehensive update posted live • 15 March 2012 (me) Comprehensive update posted live • 21 October 2010 (cd) Revision: deletion/duplication analysis for • 17 August 2010 (me) Comprehensive update posted live • 2 April 2009 (me) Comprehensive update posted live • 16 October 2006 (me) Comprehensive update posted live • 17 June 2004 (me) Comprehensive update posted live • 25 November 2002 (kn) Revisions • 19 June 2002 (me) Review posted live • 24 February 2002 (kn) Original submission ## Author Notes ## Revision History 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation 11 June 2015 (aa) Revision: 18 September 2014 (me) Comprehensive update posted live 15 March 2012 (me) Comprehensive update posted live 21 October 2010 (cd) Revision: deletion/duplication analysis for 17 August 2010 (me) Comprehensive update posted live 2 April 2009 (me) Comprehensive update posted live 16 October 2006 (me) Comprehensive update posted live 17 June 2004 (me) Comprehensive update posted live 25 November 2002 (kn) Revisions 19 June 2002 (me) Review posted live 24 February 2002 (kn) Original submission • 7 November 2019 (ma) Chapter retired: histologic diagnosis without strong genetic correlation • 11 June 2015 (aa) Revision: • 18 September 2014 (me) Comprehensive update posted live • 15 March 2012 (me) Comprehensive update posted live • 21 October 2010 (cd) Revision: deletion/duplication analysis for • 17 August 2010 (me) Comprehensive update posted live • 2 April 2009 (me) Comprehensive update posted live • 16 October 2006 (me) Comprehensive update posted live • 17 June 2004 (me) Comprehensive update posted live • 25 November 2002 (kn) Revisions • 19 June 2002 (me) Review posted live • 24 February 2002 (kn) Original submission Pathology of nemaline myopathy. Gomori trichrome staining of frozen muscle from an affected individual shows the nemaline bodies (rods) as dark blue/purple structures scattered throughout the muscle fibers (a: arrow, 60x magnification). The rods appear as electron-dense structures at the electron microscopy level (b: arrow, 15,000x magnification).	[]	19/6/2002	18/9/2014	11/6/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nephron-ov	nephron-ov	[ "NPHP-RC", "NPHP-RC", "Ankyrin repeat and SAM domain-containing protein 6", "Centrosomal protein of 164 kDa", "Centrosomal protein of 290 kDa", "Centrosomal protein of 83 kDa", "Doublecortin domain-containing protein 2", "Intraflagellar transport protein 172 homolog", "Inversin", "IQ calmodulin-binding motif-containing protein 1", "Meckelin", "Nephrocystin-1", "Nephrocystin-3", "Nephrocystin-4", "Protein fantom", "Serine/threonine-protein kinase Nek8", "Serologically defined colon cancer antigen 8", "Tetratricopeptide repeat protein 21B", "WD repeat-containing protein 19", "Zinc finger protein 423", "Zinc finger protein GLIS2", "ANKS6", "CEP164", "CEP290", "CEP83", "DCDC2", "GLIS2", "IFT172", "INVS", "IQCB1", "NEK8", "NPHP1", "NPHP3", "NPHP4", "RPGRIP1L", "SDCCAG8", "TMEM67", "TTC21B", "WDR19", "ZNF423", "Nephronophthisis-Related Ciliopathies", "Overview" ]	Nephronophthisis-Related Ciliopathies	Marijn Stokman, Marc Lilien, Nine Knoers	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform	## Clinical Characteristics of Nephronophthisis-Related Ciliopathies Nephronophthisis (NPH) is characterized by polyuria and polydipsia resulting from reduced urine-concentrating ability, chronic tubulointerstitial nephritis, and progression to end-stage kidney disease (ESKD) typically before age 30 years (although later-onset ESKD has been reported). Common associated findings are chronic anemia resistant to therapy and growth restriction. NPH is suspected in the absence of congenital anomalies of the kidneys and/or urinary tract (CAKUT) and signs or symptoms of glomerular kidney disease. Two general age-based clinical phenotypes for NPH are recognized: an infantile-onset phenotype and a juvenile-, adolescent-, or adult-onset phenotypic continuum. However, within a phenotype, inter- and intrafamilial variability in rate of progression to ESKD can be considerable. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with severe hypertension and kidney manifestations that progress to ESKD before age three years. It is characterized by a rapid disease course. Kidney ultrasound findings are moderately enlarged cystic kidneys with cortical hyperechogenicity. Histologic findings (which might be of interest should a kidney biopsy have been obtained but are not necessary to make the diagnosis of NPH) include cortical cysts, absence of thickened tubular basement membranes, and minimal fibrosis [ Juvenile-, adolescent-, or adult-onset NPH is more common than infantile NPH. It typically presents with polydipsia and polyuria, growth restriction in children, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD), such as metabolic bone disease, metabolic acidosis, and uremic symptoms (e.g., nausea, anorexia, and weakness) [ At the juvenile-onset end of the continuum the median age that ESKD develops is 13 years [ Kidney ultrasound findings are small to normal-sized kidneys, increased echogenicity, reduced corticomedullary differentiation, and – in 50% of individuals – renal cyst formation on the corticomedullary border later in the disease course. In some instances, the bladder (but not the urinary tract) is dilated as a result of chronic polyuria. Histologic findings (which might be of interest should a kidney biopsy have been obtained but are not necessary to make the diagnosis of NPH) include tubulointerstitial fibrosis, thickened and disrupted tubular basement membranes, and sporadic corticomedullary cysts [ The term "nephronophthisis-related ciliopathies (NPH-RC)" is used to describe isolated nephronophthisis, nephronophthisis with extrarenal features that do not constitute a recognizable syndrome, and syndromic nephronophthisis. The term "ciliopathy" refers to the group of disorders characterized by defects in the formation or function of primary cilia, signaling organelles present on the surface of nearly all cell types. This chapter focuses on clinical features of NPH in NPH-RC. For the purpose of this overview, the genetic causes of NPH-RC are limited to genes classified as ## Infantile NPH Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with severe hypertension and kidney manifestations that progress to ESKD before age three years. It is characterized by a rapid disease course. Kidney ultrasound findings are moderately enlarged cystic kidneys with cortical hyperechogenicity. Histologic findings (which might be of interest should a kidney biopsy have been obtained but are not necessary to make the diagnosis of NPH) include cortical cysts, absence of thickened tubular basement membranes, and minimal fibrosis [ ## Juvenile-, Adolescent-, or Adult-Onset NPH Juvenile-, adolescent-, or adult-onset NPH is more common than infantile NPH. It typically presents with polydipsia and polyuria, growth restriction in children, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD), such as metabolic bone disease, metabolic acidosis, and uremic symptoms (e.g., nausea, anorexia, and weakness) [ At the juvenile-onset end of the continuum the median age that ESKD develops is 13 years [ Kidney ultrasound findings are small to normal-sized kidneys, increased echogenicity, reduced corticomedullary differentiation, and – in 50% of individuals – renal cyst formation on the corticomedullary border later in the disease course. In some instances, the bladder (but not the urinary tract) is dilated as a result of chronic polyuria. Histologic findings (which might be of interest should a kidney biopsy have been obtained but are not necessary to make the diagnosis of NPH) include tubulointerstitial fibrosis, thickened and disrupted tubular basement membranes, and sporadic corticomedullary cysts [ ## Nomenclature The term "nephronophthisis-related ciliopathies (NPH-RC)" is used to describe isolated nephronophthisis, nephronophthisis with extrarenal features that do not constitute a recognizable syndrome, and syndromic nephronophthisis. The term "ciliopathy" refers to the group of disorders characterized by defects in the formation or function of primary cilia, signaling organelles present on the surface of nearly all cell types. This chapter focuses on clinical features of NPH in NPH-RC. For the purpose of this overview, the genetic causes of NPH-RC are limited to genes classified as ## Genetic Causes of Nephronophthisis-Related Ciliopathies At the time of the initial presentation, approximately 80%-90% of individuals with nephronophthisis (NPH) appear to have isolated NPH (i.e., all evident clinical findings are secondary to kidney dysfunction), and approximately 10%-20% of individuals have extrarenal manifestations that can be indicative of a syndrome (e.g., Bardet-Biedl syndrome and Joubert syndrome). With time, some individuals who originally presented with apparent isolated NPH will manifest syndromic features. Biallelic pathogenic variants in one of the 21 genes included in Genes Classified as CHD = congenital heart disease; DD = developmental delay; dz = disease; RP = retinitis pigmentosa Genes are listed first by frequency of causation of nephronophthisis-related ciliopathies, and then alphabetically. Adapted from Non-obligatory extrarenal features that may be present at the time of diagnosis or appear over time Presence of supernumerary fingers and/or toes. Postaxial polydactyly is most prevalent in ciliopathies. Condition in which the organs in the thorax and abdomen are positioned in a mirror image of their normal position Skeletal anomalies include short stature, narrow thorax, brachydactyly, and polydactyly. Tentative association in one (scoliosis) and two (facial dysmorphisms) families Pancreas anomalies include cystic enlargement of the pancreas or fibrosis depending on the type of mutation. Underdevelopment of genital organs, such as cryptorchidism and micropenis in males and hypoplasia of labia minora in females Although all of the syndromes listed below are associated with nephronophthisis-related ciliopathies (NPH-RC), the prevalence of renal disease varies. Kidney disease (including NPH) has been reported in 23%-35% of individuals with JS [ Renal changes visible on ultrasound examination may occur late in the course and consist of small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction. In early-onset kidney disease, findings may be consistent with cystic dysplasia (i.e., multiple variably sized cysts in immature kidneys with fetal lobulations). Pathogenic variants in more than 30 genes are known to cause JS (see Tables 1a and The renal phenotype of BBS is highly variable and can include structural anomalies, hydronephrosis and vesicoureteral reflux, and progressive renal parenchymal disease that is commonly associated with urinary concentration defects (symptoms of polyuria and polydipsia). Chronic kidney disease (CKD) is a major contributor of morbidity and mortality in individuals with BBS. In one study, CKD was present in 31% of children and 42% of adults; 6% of children and 8% of adults developed ESKD requiring dialysis and/or transplantation. In the majority of children with BBS with advanced (Stage 4-5) CKD, the initial diagnosis of kidney disease was made within the first year of life and almost all were diagnosed by age five years [ Pathogenic variants in at least 26 genes are known to be associated with BBS (see Bardet-Biedl Syndrome Overview, Other skeletal ciliopathies include ## Syndromic Nephronophthisis-Related Ciliopathies Although all of the syndromes listed below are associated with nephronophthisis-related ciliopathies (NPH-RC), the prevalence of renal disease varies. Kidney disease (including NPH) has been reported in 23%-35% of individuals with JS [ Renal changes visible on ultrasound examination may occur late in the course and consist of small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction. In early-onset kidney disease, findings may be consistent with cystic dysplasia (i.e., multiple variably sized cysts in immature kidneys with fetal lobulations). Pathogenic variants in more than 30 genes are known to cause JS (see Tables 1a and The renal phenotype of BBS is highly variable and can include structural anomalies, hydronephrosis and vesicoureteral reflux, and progressive renal parenchymal disease that is commonly associated with urinary concentration defects (symptoms of polyuria and polydipsia). Chronic kidney disease (CKD) is a major contributor of morbidity and mortality in individuals with BBS. In one study, CKD was present in 31% of children and 42% of adults; 6% of children and 8% of adults developed ESKD requiring dialysis and/or transplantation. In the majority of children with BBS with advanced (Stage 4-5) CKD, the initial diagnosis of kidney disease was made within the first year of life and almost all were diagnosed by age five years [ Pathogenic variants in at least 26 genes are known to be associated with BBS (see Bardet-Biedl Syndrome Overview, Other skeletal ciliopathies include ## Differential Diagnosis of Nephronophthisis-Related Ciliopathies Tubulointerstitial kidney diseases, cystic kidney diseases, and conditions associated with a urine-concentrating defect and growth restriction (e.g., nephrogenic diabetes insipidus and other tubulopathies) can mimic the nephronophthisis (NPH) phenotype. For example, whole-exome sequencing in 79 families (including consanguineous families) with childhood-onset chronic kidney disease (CKD) and a nephronophthisis-related ciliopathy (NPH-RC) suspected on kidney ultrasound examination identified pathogenic variants in NPH-RC-related genes in 32 individuals and pathogenic variants in other monogenic kidney disease-associated genes in 18 individuals, including genes involved in renal tubulopathies (e.g., Bartter syndrome), Monogenic Kidney Disorders in the Differential Diagnosis of Nephronophthisis-Related Ciliopathies AD = autosomal dominant; ADTKD = autosomal dominant tubulointerstitial kidney disease; AR = autosomal recessive; ARPKD = autosomal recessive polycystic kidney; CAKUT = congenital anomalies of the kidneys and urinary tract; CKD = chronic kidney disease; ESKD = end-stage kidney disease; MODY = maturity-onset diabetes of the young; MOI = mode of inheritance; NPH = nephronophthisis; SNHL = sensorineural hearing loss; XL = X-linked ## Evaluation Strategies to Identify the Genetic Cause of a Nephronophthisis-Related Ciliopathy in a Proband Establishing a specific genetic cause of a nephronophthisis-related ciliopathy (NPH-RC): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. A three-generation family history should be taken, with attention to relatives with manifestations of NPH-RC and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing. Family history is typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: Gene-targeted deletion/duplication analysis (e.g., MLPA) or genomic testing (e.g., SNP array) is necessary to identify the common 290-kb For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. • A three-generation family history should be taken, with attention to relatives with manifestations of NPH-RC and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing. • Family history is typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. • Note: Gene-targeted deletion/duplication analysis (e.g., MLPA) or genomic testing (e.g., SNP array) is necessary to identify the common 290-kb • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management of Nephronophthisis-Related Ciliopathies To establish the extent of kidney disease and screening for the presence of multisystem involvement in an individual diagnosed with a nephronophthisis-related ciliopathy (NPH-RC), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Perform an abdominal ultrasound examination to evaluate kidney size and parenchymal aspect, and possible situs inversus and/or anomalies of the liver, bile duct, spleen, or pancreas. Evaluate blood pressure, growth parameters, and development. Perform urinalysis to measure proteinuria. Assess kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count. Assess for chronic kidney disease (CKD)-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity. Assess liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time. When indicated based on genetic diagnosis or clinical signs or symptoms, evaluate extrarenal manifestations of syndromic NPH-RC (see Neurologic evaluation including brain MRI (e.g., for the presence of molar tooth sign, suggesting Echocardiogram for congenital heart disease Ophthalmologic examination to assess visual acuity and visual fields, as well as evidence of retinal dystrophy Endocrinologic/metabolic evaluation including sex hormones and thyroid hormones, lipid spectrum, fasting glucose, and hemoglobin A1c Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of NPH-RC in order to facilitate medical and personal decision making is recommended. Assess need for community or This section discusses only the management of nephronophthisis-related CKD (i.e., NPH). Note that management of extrarenal findings in nephronophthisis-related ciliopathies (NPH-RC) included in Currently there is no cure for NPH. Treatment of NPH is aimed at slowing the progression of CKD and its complications. According to international clinical practice guidelines for CKD [ Correction of water and electrolyte imbalances, especially during intercurrent illness Treatment of anemia, hypertension, proteinuria, and CKD-related mineral and bone disorder if present Note: Preferred therapy may differ between adults and children. Growth hormone treatment for children who have severe growth restriction as a result of chronic renal insufficiency and meet criteria for treatment [ Dialysis or kidney transplantation when individuals reach end-stage kidney disease (ESKD) Note: Kidney transplantation is the preferred treatment, as NPH does not recur in the transplanted kidney [ Vaccination schedules in adults and children according to international and regional recommendations The following evaluations to identify progression of NPH are recommended for all individuals at least annually (unless more frequent monitoring by the treating nephrologist is recommended for individuals with advanced CKD and individuals at higher risk of disease progression, and for therapeutic decision making) [ Monitoring of blood pressure, growth parameters, and development Urinalysis to monitor proteinuria Assessment of kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count Assessment for CKD-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity Assessment of liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time Evaluation of extrarenal manifestations of syndromic NPH-RC when indicated (See Nephrotoxic agents such as nonsteroidal anti-inflammatory drugs and aminoglycosides should be avoided. Individuals with an estimated glomerular filtration rate below 60 mL/min per 1.73 m If the NPH-causing pathogenic variants have been identified in an affected family member, options for family members include: If the NPH-causing pathogenic variants in the family are not known, it seems prudent to instruct parents/caregivers to be aware of polydipsia, polyuria, and other signs of NPH, and to offer annual monitoring of blood pressure and protein-to-creatinine ratio when this is not part of regular healthy child visits. This recommendation is experience based and not supported by literature [Authors, personal observation]. See • Perform an abdominal ultrasound examination to evaluate kidney size and parenchymal aspect, and possible situs inversus and/or anomalies of the liver, bile duct, spleen, or pancreas. • Evaluate blood pressure, growth parameters, and development. • Perform urinalysis to measure proteinuria. • Assess kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count. • Assess for chronic kidney disease (CKD)-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity. • Assess liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time. • Neurologic evaluation including brain MRI (e.g., for the presence of molar tooth sign, suggesting • Echocardiogram for congenital heart disease • Ophthalmologic examination to assess visual acuity and visual fields, as well as evidence of retinal dystrophy • Endocrinologic/metabolic evaluation including sex hormones and thyroid hormones, lipid spectrum, fasting glucose, and hemoglobin A1c • Correction of water and electrolyte imbalances, especially during intercurrent illness • Treatment of anemia, hypertension, proteinuria, and CKD-related mineral and bone disorder if present • Note: Preferred therapy may differ between adults and children. • Growth hormone treatment for children who have severe growth restriction as a result of chronic renal insufficiency and meet criteria for treatment [ • Dialysis or kidney transplantation when individuals reach end-stage kidney disease (ESKD) • Note: Kidney transplantation is the preferred treatment, as NPH does not recur in the transplanted kidney [ • Vaccination schedules in adults and children according to international and regional recommendations • Monitoring of blood pressure, growth parameters, and development • Urinalysis to monitor proteinuria • Assessment of kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count • Assessment for CKD-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity • Assessment of liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time • Evaluation of extrarenal manifestations of syndromic NPH-RC when indicated (See ## Evaluations Following Initial Diagnosis To establish the extent of kidney disease and screening for the presence of multisystem involvement in an individual diagnosed with a nephronophthisis-related ciliopathy (NPH-RC), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Perform an abdominal ultrasound examination to evaluate kidney size and parenchymal aspect, and possible situs inversus and/or anomalies of the liver, bile duct, spleen, or pancreas. Evaluate blood pressure, growth parameters, and development. Perform urinalysis to measure proteinuria. Assess kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count. Assess for chronic kidney disease (CKD)-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity. Assess liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time. When indicated based on genetic diagnosis or clinical signs or symptoms, evaluate extrarenal manifestations of syndromic NPH-RC (see Neurologic evaluation including brain MRI (e.g., for the presence of molar tooth sign, suggesting Echocardiogram for congenital heart disease Ophthalmologic examination to assess visual acuity and visual fields, as well as evidence of retinal dystrophy Endocrinologic/metabolic evaluation including sex hormones and thyroid hormones, lipid spectrum, fasting glucose, and hemoglobin A1c Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of NPH-RC in order to facilitate medical and personal decision making is recommended. Assess need for community or • Perform an abdominal ultrasound examination to evaluate kidney size and parenchymal aspect, and possible situs inversus and/or anomalies of the liver, bile duct, spleen, or pancreas. • Evaluate blood pressure, growth parameters, and development. • Perform urinalysis to measure proteinuria. • Assess kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count. • Assess for chronic kidney disease (CKD)-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity. • Assess liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time. • Neurologic evaluation including brain MRI (e.g., for the presence of molar tooth sign, suggesting • Echocardiogram for congenital heart disease • Ophthalmologic examination to assess visual acuity and visual fields, as well as evidence of retinal dystrophy • Endocrinologic/metabolic evaluation including sex hormones and thyroid hormones, lipid spectrum, fasting glucose, and hemoglobin A1c ## Treatment of Manifestations This section discusses only the management of nephronophthisis-related CKD (i.e., NPH). Note that management of extrarenal findings in nephronophthisis-related ciliopathies (NPH-RC) included in Currently there is no cure for NPH. Treatment of NPH is aimed at slowing the progression of CKD and its complications. According to international clinical practice guidelines for CKD [ Correction of water and electrolyte imbalances, especially during intercurrent illness Treatment of anemia, hypertension, proteinuria, and CKD-related mineral and bone disorder if present Note: Preferred therapy may differ between adults and children. Growth hormone treatment for children who have severe growth restriction as a result of chronic renal insufficiency and meet criteria for treatment [ Dialysis or kidney transplantation when individuals reach end-stage kidney disease (ESKD) Note: Kidney transplantation is the preferred treatment, as NPH does not recur in the transplanted kidney [ Vaccination schedules in adults and children according to international and regional recommendations • Correction of water and electrolyte imbalances, especially during intercurrent illness • Treatment of anemia, hypertension, proteinuria, and CKD-related mineral and bone disorder if present • Note: Preferred therapy may differ between adults and children. • Growth hormone treatment for children who have severe growth restriction as a result of chronic renal insufficiency and meet criteria for treatment [ • Dialysis or kidney transplantation when individuals reach end-stage kidney disease (ESKD) • Note: Kidney transplantation is the preferred treatment, as NPH does not recur in the transplanted kidney [ • Vaccination schedules in adults and children according to international and regional recommendations ## Surveillance The following evaluations to identify progression of NPH are recommended for all individuals at least annually (unless more frequent monitoring by the treating nephrologist is recommended for individuals with advanced CKD and individuals at higher risk of disease progression, and for therapeutic decision making) [ Monitoring of blood pressure, growth parameters, and development Urinalysis to monitor proteinuria Assessment of kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count Assessment for CKD-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity Assessment of liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time Evaluation of extrarenal manifestations of syndromic NPH-RC when indicated (See • Monitoring of blood pressure, growth parameters, and development • Urinalysis to monitor proteinuria • Assessment of kidney function, including serum creatinine concentration and estimated glomerular filtration rate, cystatin C when indicated, electrolytes, and complete blood count • Assessment for CKD-related mineral and bone disease, including serum calcium, phosphate, parathyroid hormone, and alkaline phosphatase activity • Assessment of liver function, including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time • Evaluation of extrarenal manifestations of syndromic NPH-RC when indicated (See ## Agents/Circumstances to Avoid Nephrotoxic agents such as nonsteroidal anti-inflammatory drugs and aminoglycosides should be avoided. Individuals with an estimated glomerular filtration rate below 60 mL/min per 1.73 m ## Evaluation of Relatives at Risk If the NPH-causing pathogenic variants have been identified in an affected family member, options for family members include: If the NPH-causing pathogenic variants in the family are not known, it seems prudent to instruct parents/caregivers to be aware of polydipsia, polyuria, and other signs of NPH, and to offer annual monitoring of blood pressure and protein-to-creatinine ratio when this is not part of regular healthy child visits. This recommendation is experience based and not supported by literature [Authors, personal observation]. See ## Genetic Counseling of Nephronophthisis-Related Ciliopathies Genetic counseling regarding risk to family members depends on accurate diagnosis, confirmation of the mode of inheritance in each family, and the results of molecular genetic testing. Nephronophthisis-related ciliopathies (NPH-RC) are typically inherited in an autosomal recessive manner [ The exception to autosomal recessive inheritance in NPH-RC is Dominant inheritance has been reported infrequently in individuals with Joubert syndrome and variants in The parents of an affected individual are presumed to be heterozygous for an NPH-RC-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an NPH-RC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. See Management, Once both causative pathogenic variants have been identified in a family member with autosomal recessive NPH-RC, prenatal and preimplantation genetic testing for NPH-RC are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an NPH-RC-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an NPH-RC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Mode of Inheritance Genetic counseling regarding risk to family members depends on accurate diagnosis, confirmation of the mode of inheritance in each family, and the results of molecular genetic testing. Nephronophthisis-related ciliopathies (NPH-RC) are typically inherited in an autosomal recessive manner [ The exception to autosomal recessive inheritance in NPH-RC is Dominant inheritance has been reported infrequently in individuals with Joubert syndrome and variants in ## Risk to Family Members (Autosomal Recessive Inheritance) The parents of an affected individual are presumed to be heterozygous for an NPH-RC-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an NPH-RC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. See Management, • The parents of an affected individual are presumed to be heterozygous for an NPH-RC-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an NPH-RC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Prenatal Testing and Preimplantation Genetic Testing Once both causative pathogenic variants have been identified in a family member with autosomal recessive NPH-RC, prenatal and preimplantation genetic testing for NPH-RC are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Canada • • • • • • United Kingdom • • • • • Canada • • • • • ## Chapter Notes Dr Marijn Stokman ( For more information on NPH-RC, see: Radboudumc Center of Expertise: UMC Utrecht: Contact Dr Dorien Lugtenberg ( We are grateful to the patients with NPH-RC and their families for their participation in ongoing research. 2 March 2023 (bp) Comprehensive update posted live 23 June 2016 (bp) Overview posted live 7 August 2015 (ms) Original submission • Radboudumc Center of Expertise: • UMC Utrecht: • 2 March 2023 (bp) Comprehensive update posted live • 23 June 2016 (bp) Overview posted live • 7 August 2015 (ms) Original submission ## Author Notes Dr Marijn Stokman ( For more information on NPH-RC, see: Radboudumc Center of Expertise: UMC Utrecht: Contact Dr Dorien Lugtenberg ( • Radboudumc Center of Expertise: • UMC Utrecht: ## Acknowledgments We are grateful to the patients with NPH-RC and their families for their participation in ongoing research. ## Revision History 2 March 2023 (bp) Comprehensive update posted live 23 June 2016 (bp) Overview posted live 7 August 2015 (ms) Original submission • 2 March 2023 (bp) Comprehensive update posted live • 23 June 2016 (bp) Overview posted live • 7 August 2015 (ms) Original submission ## References ## Literature Cited	[]	23/6/2016	2/3/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
neuroferritin	neuroferritin	[ "Hereditary Ferritinopathy", "Hereditary Ferritinopathy", "Ferritin light chain", "FTL", "Neuroferritinopathy" ]	Neuroferritinopathy	Patrick F Chinnery	Summary Neuroferritinopathy is an adult-onset progressive movement disorder characterized by chorea or dystonia and speech and swallowing deficits. The movement disorder typically affects one or two limbs and progresses to become more generalized within 20 years of disease onset. When present, asymmetry in the movement abnormalities remains throughout the course of the disorder. Most individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity and orolingual dyskinesia are common. Cognitive deficits and behavioral issues become major problems with time. The diagnosis of neuroferritinopathy is established in a proband with typical clinical findings and/or identification of a heterozygous pathogenic variant in Neuroferritinopathy is inherited in an autosomal dominant manner with 100% penetrance. Most individuals diagnosed with neuroferritinopathy have an affected parent; the proportion of individuals with neuroferritinopathy caused by a	## Diagnosis No consensus clinical diagnostic criteria for neuroferritinopathy have been published. Neuroferritinopathy The diagnosis of neuroferritinopathy Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the clinical and brain imaging findings suggest the diagnosis of neuroferritinopathy, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by abnormal movements or neurodegenerative features more broadly, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Neuroferritinopathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Neuroferritinopathy occurs through a gain-of-function mechanism; therefore, large intragenic deletions or duplications are unlikely to cause neuroferritinopathy. Large • For an introduction to multigene panels click ## Suggestive Findings Neuroferritinopathy ## Establishing the Diagnosis The diagnosis of neuroferritinopathy Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the clinical and brain imaging findings suggest the diagnosis of neuroferritinopathy, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by abnormal movements or neurodegenerative features more broadly, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Neuroferritinopathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Neuroferritinopathy occurs through a gain-of-function mechanism; therefore, large intragenic deletions or duplications are unlikely to cause neuroferritinopathy. Large • For an introduction to multigene panels click ## Option 1 When the clinical and brain imaging findings suggest the diagnosis of neuroferritinopathy, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by abnormal movements or neurodegenerative features more broadly, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Neuroferritinopathy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Neuroferritinopathy occurs through a gain-of-function mechanism; therefore, large intragenic deletions or duplications are unlikely to cause neuroferritinopathy. Large ## Clinical Characteristics To date, more than 100 individuals have been identified with a pathogenic variant in Neuroferritinopathy: Frequency of Select Features Affects 1 or 2 limbs at time of onset Age of onset in adulthood 82% of males 100% postmenopausal females 23% of premenopausal females EOM = extraocular muscle (function) In 40 individuals with the Unusual presentations have also been described, related to an underlying dystonic gait [ The movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years, and may lead to becoming wheelchair bound [ Some individuals have striking asymmetry, which remains throughout the course of the disorder. Most individuals develop a characteristic orofacial action-specific dystonia related to speech and leading to dysarthrophonia. Frontalis overactivity is common, as is orolingual dyskinesia [ Cognitive issues are usually subtle but progressively worsen through the course of the disease [ Formal neuropsychological evaluation reveals frontal/subcortical deficits that are not as prominent as those seen in Neuroferritinopathy-associated variants in Penetrance is 100% [ Prevalence is unknown. The vast majority of affected individuals described to date have the same pathogenic variant in • Affects 1 or 2 limbs at time of onset • Age of onset in adulthood • 82% of males • 100% postmenopausal females • 23% of premenopausal females • Unusual presentations have also been described, related to an underlying dystonic gait [ • The movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years, and may lead to becoming wheelchair bound [ • Some individuals have striking asymmetry, which remains throughout the course of the disorder. • Most individuals develop a characteristic orofacial action-specific dystonia related to speech and leading to dysarthrophonia. • Frontalis overactivity is common, as is orolingual dyskinesia [ • Cognitive issues are usually subtle but progressively worsen through the course of the disease [ • Formal neuropsychological evaluation reveals frontal/subcortical deficits that are not as prominent as those seen in ## Clinical Description To date, more than 100 individuals have been identified with a pathogenic variant in Neuroferritinopathy: Frequency of Select Features Affects 1 or 2 limbs at time of onset Age of onset in adulthood 82% of males 100% postmenopausal females 23% of premenopausal females EOM = extraocular muscle (function) In 40 individuals with the Unusual presentations have also been described, related to an underlying dystonic gait [ The movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years, and may lead to becoming wheelchair bound [ Some individuals have striking asymmetry, which remains throughout the course of the disorder. Most individuals develop a characteristic orofacial action-specific dystonia related to speech and leading to dysarthrophonia. Frontalis overactivity is common, as is orolingual dyskinesia [ Cognitive issues are usually subtle but progressively worsen through the course of the disease [ Formal neuropsychological evaluation reveals frontal/subcortical deficits that are not as prominent as those seen in • Affects 1 or 2 limbs at time of onset • Age of onset in adulthood • 82% of males • 100% postmenopausal females • 23% of premenopausal females • Unusual presentations have also been described, related to an underlying dystonic gait [ • The movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years, and may lead to becoming wheelchair bound [ • Some individuals have striking asymmetry, which remains throughout the course of the disorder. • Most individuals develop a characteristic orofacial action-specific dystonia related to speech and leading to dysarthrophonia. • Frontalis overactivity is common, as is orolingual dyskinesia [ • Cognitive issues are usually subtle but progressively worsen through the course of the disease [ • Formal neuropsychological evaluation reveals frontal/subcortical deficits that are not as prominent as those seen in ## Genotype-Phenotype Correlations Neuroferritinopathy-associated variants in ## Penetrance Penetrance is 100% [ ## Prevalence Prevalence is unknown. The vast majority of affected individuals described to date have the same pathogenic variant in ## Genetically Related (Allelic) Disorders An additional family of four individuals was reported with hypoferritinemia but no neurologic features have been described. Affected individuals in this family had a deletion involving exons 3 and 4 of ## Differential Diagnosis Disorders of Interest in the Differential Diagnosis of Neuroferritinopathy AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SCA = spinocerebellar ataxia; XL = X-linked ## Management To establish the extent of disease and needs in an individual diagnosed with neuroferritinopathy, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Neuroferritinopathy Social work involvement & support; Home nursing referral in later stages. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Neuroferritinopathy Best administered & managed by mvmt disorders specialist Response to these treatments is only seen in some persons, as mvmt disorders can be resistant to conventional therapy; no formal treatment trials have been completed. Drug therapy is empiric based on predominant symptoms, which may change over time. Anecdotal reports describe improvement w/oral iron chelation agent deferriprone. May be required for cognitive & neurobehavioral features. May require psychotropic medication to manage behavioral symptoms. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Recommended Surveillance for Individuals with Neuroferritinopathy Iron supplements are not recommended for affected individuals and those at risk [ See Search It has been proposed that administration of deferiprone, an orally administered bidentate iron chelator that passes through the blood-brain barrier, might confer clinical and neuroradiologic improvement in individuals with neuroferritinopathy [ • Social work involvement & support; • Home nursing referral in later stages. • Best administered & managed by mvmt disorders specialist • Response to these treatments is only seen in some persons, as mvmt disorders can be resistant to conventional therapy; no formal treatment trials have been completed. • Drug therapy is empiric based on predominant symptoms, which may change over time. • Anecdotal reports describe improvement w/oral iron chelation agent deferriprone. • May be required for cognitive & neurobehavioral features. • May require psychotropic medication to manage behavioral symptoms. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with neuroferritinopathy, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Neuroferritinopathy Social work involvement & support; Home nursing referral in later stages. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Social work involvement & support; • Home nursing referral in later stages. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Neuroferritinopathy Best administered & managed by mvmt disorders specialist Response to these treatments is only seen in some persons, as mvmt disorders can be resistant to conventional therapy; no formal treatment trials have been completed. Drug therapy is empiric based on predominant symptoms, which may change over time. Anecdotal reports describe improvement w/oral iron chelation agent deferriprone. May be required for cognitive & neurobehavioral features. May require psychotropic medication to manage behavioral symptoms. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Best administered & managed by mvmt disorders specialist • Response to these treatments is only seen in some persons, as mvmt disorders can be resistant to conventional therapy; no formal treatment trials have been completed. • Drug therapy is empiric based on predominant symptoms, which may change over time. • Anecdotal reports describe improvement w/oral iron chelation agent deferriprone. • May be required for cognitive & neurobehavioral features. • May require psychotropic medication to manage behavioral symptoms. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Recommended Surveillance for Individuals with Neuroferritinopathy ## Agents/Circumstances to Avoid Iron supplements are not recommended for affected individuals and those at risk [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search It has been proposed that administration of deferiprone, an orally administered bidentate iron chelator that passes through the blood-brain barrier, might confer clinical and neuroradiologic improvement in individuals with neuroferritinopathy [ ## Genetic Counseling Neuroferritinopathy is inherited in an autosomal dominant manner. Most individuals diagnosed with neuroferritinopathy have an affected parent. A proband with neuroferritinopathy may have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include: Brain MRI and measurement of serum ferritin concentration; Molecular genetic testing (if the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with neuroferritinopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of neuroferritinopathy is 100%; however, there may be differences in the age of onset and rate of progression in heterozygous sibs. If the proband has a known If the parents have not been tested for the Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the There may be differences in the age of onset and rate of progression of the disorder between heterozygous members of the same family. Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of neuroferritinopathy, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors • Most individuals diagnosed with neuroferritinopathy have an affected parent. • A proband with neuroferritinopathy may have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include: • Brain MRI and measurement of serum ferritin concentration; • Molecular genetic testing (if the • Brain MRI and measurement of serum ferritin concentration; • Molecular genetic testing (if the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with neuroferritinopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • Brain MRI and measurement of serum ferritin concentration; • Molecular genetic testing (if the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of neuroferritinopathy is 100%; however, there may be differences in the age of onset and rate of progression in heterozygous sibs. • If the proband has a known • If the parents have not been tested for the • Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the • There may be differences in the age of onset and rate of progression of the disorder between heterozygous members of the same family. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Neuroferritinopathy is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with neuroferritinopathy have an affected parent. A proband with neuroferritinopathy may have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include: Brain MRI and measurement of serum ferritin concentration; Molecular genetic testing (if the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with neuroferritinopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of neuroferritinopathy is 100%; however, there may be differences in the age of onset and rate of progression in heterozygous sibs. If the proband has a known If the parents have not been tested for the Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the There may be differences in the age of onset and rate of progression of the disorder between heterozygous members of the same family. • Most individuals diagnosed with neuroferritinopathy have an affected parent. • A proband with neuroferritinopathy may have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband include: • Brain MRI and measurement of serum ferritin concentration; • Molecular genetic testing (if the • Brain MRI and measurement of serum ferritin concentration; • Molecular genetic testing (if the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with neuroferritinopathy may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • Brain MRI and measurement of serum ferritin concentration; • Molecular genetic testing (if the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of neuroferritinopathy is 100%; however, there may be differences in the age of onset and rate of progression in heterozygous sibs. • If the proband has a known • If the parents have not been tested for the • Each child of an individual with neuroferritinopathy has a 50% chance of inheriting the • There may be differences in the age of onset and rate of progression of the disorder between heterozygous members of the same family. ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of neuroferritinopathy, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors ## Resources Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • Germany • ## Molecular Genetics Neuroferritinopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Neuroferritinopathy ( Ferritin is an iron storage protein that has two main subunits, ferritin heavy chain (FTH) and ferritin light chain (FTL), and plays an important role in maintaining iron homeostasis. A functional ferritin molecule can store up to 4,500 iron molecules. The proportion of H and L subunits varies among tissues. The most common Notable Variants listed in the table have been provided by the author. ## Molecular Pathogenesis Ferritin is an iron storage protein that has two main subunits, ferritin heavy chain (FTH) and ferritin light chain (FTL), and plays an important role in maintaining iron homeostasis. A functional ferritin molecule can store up to 4,500 iron molecules. The proportion of H and L subunits varies among tissues. The most common Notable Variants listed in the table have been provided by the author. ## Chapter Notes 20 October 2022 (sw/gm) Comprehensive update posted live 18 January 2018 (ha) Comprehensive update posted live 23 December 2010 (me) Comprehensive update posted live 8 August 2007 (me) Comprehensive update posted live 30 November 2006 (pfc) Revision: sequence analysis clinically available; addition of relevant material from author's new paper, 25 April 2005 (me) Review posted live 1 September 2004 (pfc) Original submission • 20 October 2022 (sw/gm) Comprehensive update posted live • 18 January 2018 (ha) Comprehensive update posted live • 23 December 2010 (me) Comprehensive update posted live • 8 August 2007 (me) Comprehensive update posted live • 30 November 2006 (pfc) Revision: sequence analysis clinically available; addition of relevant material from author's new paper, • 25 April 2005 (me) Review posted live • 1 September 2004 (pfc) Original submission ## Revision History 20 October 2022 (sw/gm) Comprehensive update posted live 18 January 2018 (ha) Comprehensive update posted live 23 December 2010 (me) Comprehensive update posted live 8 August 2007 (me) Comprehensive update posted live 30 November 2006 (pfc) Revision: sequence analysis clinically available; addition of relevant material from author's new paper, 25 April 2005 (me) Review posted live 1 September 2004 (pfc) Original submission • 20 October 2022 (sw/gm) Comprehensive update posted live • 18 January 2018 (ha) Comprehensive update posted live • 23 December 2010 (me) Comprehensive update posted live • 8 August 2007 (me) Comprehensive update posted live • 30 November 2006 (pfc) Revision: sequence analysis clinically available; addition of relevant material from author's new paper, • 25 April 2005 (me) Review posted live • 1 September 2004 (pfc) Original submission ## References Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Published Guidelines / Consensus Statements Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. 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Mov Disord. 2022;37:1948-52", "A McNeill, D Birchall, SJ Hayflick, A Gregory, JF Schenk, EA Zimmerman, H Shang, H Miyajima, PF Chinnery. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation.. Neurology. 2008;70:1614-9", "A McNeill, G Gorman, A Khan, R Horvath, AM Blamire, PF Chinnery. Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate.. AJNR Am J Neuroradiol. 2012;33:1810-3", "P Mir, MJ Edwards, AR Curtis, KP Bhatia, NP Quinn. Adult-onset generalized dystonia due to a mutation in the neuroferritinopathy gene.. Mov Disord. 2005;20:243-5", "S Moutton, P Fergelot, JM Trocello, V Plante-Bordeneuve, N Houcinat, E Wenisch, V Larue, P Brugières, F Clot, D Lacombe, B Arveiler, C Goizet. A novel FTL mutation responsible for neuroferritinopathy with asymmetric clinical features and brain anomalies.. Parkinsonism Relat Disord. 2014;20:935-7", "W Ni, HF Li, YC Zheng, ZY Wu. FTL mutation in a Chinese pedigree with neuroferritinopathy.. Neurol Genet. 2016;2", "K Nishida, HJ Garringer, N Futamura, I Funakawa, K Jinnai, R Vidal, M Takao. A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation.. J Neurol Sci. 2014;342:173-7", "E Ohta, T Nagasaka, K Shindo, S Toma, K Nagasaka, K Ohta, Z. Shiozawa. Neuroferritinopathy in a Japanese family with a duplication in the ferritin light chain gene.. Neurology. 2008;70:1493-4", "WG Ondo, OR Adam, J Jankovic, PF Chinnery. Dramatic response of facial stereotype/tic to tetrabenazine in the first reported cases of neuroferritinopathy in the United States.. Mov Disord. 2010;25:2470-2", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "N Romano, G Baiardi, VM Pinto, S Quintino, B Gianesin, R Sasso, A Diociasi, F Mattioli, R Marchese, G Abbruzzese, A Castaldi, GL Forni. Long-term neuroradiological and clinical evaluation of NBIA patients treated with a deferiprone based iron-chelation therapy.. J Clin Med. 2022;11:4524", "SO Shah, H Mehta, R Fekete. Late-onset neurodegeneration with brain iron accumulation with diffusion tensor magnetic resonance imaging.. Case Rep Neurol. 2012;4:216-23", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "E Storti, F Cortese, R Di Fabio, C Fiorillo, A Pierallini, A Tessa, A Valleriani, F Pierelli, FM Santorelli, C Casali. De novo FTL mutation: a clinical, neuroimaging, and molecular study.. Mov Disord. 2013;28:252-3", "S Turner, C Dress, VK. A Misra. 3'-truncating FTL mutation associated with hypoferritinemia without neuroferritinopathy.. Eur J Med Genet. 2021;64", "R Vidal, B Ghetti, M Takao, C Brefel-Courbon, E Uro-Coste, BS Glazier, V Siani, MD Benson, P Calvas, L Miravalle, O Rascol, MB Delisle. Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene.. J Neuropathol Exp Neurol 2004;63:363-80", "AJ Wills, GV Sawle, PR Guilbert, AR Curtis. Palatal tremor and cognitive decline in neuroferritinopathy.. J Neurol Neurosurg Psychiatry 2002;73:91-2", "SH Yoon, NY Kim, YJ Kim, CH Lyoo. Novel ferritin light chain gene mutation in a Korean patient with neuroferritinopathy.. J Mov Disord. 2019;12:63-5" ]	25/4/2005	20/10/2022	30/11/2006	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nf1	nf1	[ "NF1", "Von Recklinghausen Disease", "Von Recklinghausen's Neurofibromatosis", "NF1", "Von Recklinghausen Disease", "Von Recklinghausen's Neurofibromatosis", "Neurofibromin", "NF1", "Neurofibromatosis 1" ]	Neurofibromatosis 1	Jan M Friedman	Summary Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease. The diagnosis of NF1 is established in a proband with two or more of the characteristic clinical features or one characteristic clinical feature and a heterozygous NF1 is inherited in an autosomal dominant manner. Approximately half of affected individuals have NF1 as the result of a	## Diagnosis Neurofibromatosis 1 (NF1) Six or more Freckling in the axillary or inguinal regions Two or more Optic pathway glioma Two or more Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging) A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone A parent who meets the diagnostic criteria for NF1 A germline The diagnosis of NF1 Note: About half of individuals with Legius syndrome (see CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas. A germline Negative Note: If an A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Neurofibromatosis 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, or splice site variants and small intragenic deletions/insertions. Deletion/duplication analysis is often included in NF1 molecular analysis; If exome sequencing is used, confirm that deletion/duplcaiton analysis is included (usually performed by read-depth analysis of next generation sequencing data). For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. If deletion/duplication analysis is not performed with sequence analysis (e.g., read-depth analysis), alternate methods may include quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), or FISH. Whole-gene deletions occur in 5%-11% of individuals with NF1 [ Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • Six or more • Freckling in the axillary or inguinal regions • Two or more • Optic pathway glioma • Two or more Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging) • A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone • A parent who meets the diagnostic criteria for NF1 • A germline • About half of individuals with Legius syndrome (see • CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of • Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas. • A germline • Negative • If an • A ## Suggestive Findings Neurofibromatosis 1 (NF1) Six or more Freckling in the axillary or inguinal regions Two or more Optic pathway glioma Two or more Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging) A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone A parent who meets the diagnostic criteria for NF1 A germline • Six or more • Freckling in the axillary or inguinal regions • Two or more • Optic pathway glioma • Two or more Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (bright, patchy nodules imaged by optical coherence tomography/near-infrared reflectance imaging) • A distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone • A parent who meets the diagnostic criteria for NF1 • A germline ## Establishing the Diagnosis The diagnosis of NF1 Note: About half of individuals with Legius syndrome (see CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas. A germline Negative Note: If an A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Neurofibromatosis 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, or splice site variants and small intragenic deletions/insertions. Deletion/duplication analysis is often included in NF1 molecular analysis; If exome sequencing is used, confirm that deletion/duplcaiton analysis is included (usually performed by read-depth analysis of next generation sequencing data). For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. If deletion/duplication analysis is not performed with sequence analysis (e.g., read-depth analysis), alternate methods may include quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), or FISH. Whole-gene deletions occur in 5%-11% of individuals with NF1 [ Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • About half of individuals with Legius syndrome (see • CALMs, intertriginous freckling, cutaneous neurofibromas, and Lisch nodules are usually bilateral in NF1. A diagnosis of • Sphenoid wing dysplasia is not a separate criterion in those with ipsilateral orbital plexiform neurofibromas. • A germline • Negative • If an • A ## Clinical Characteristics Neurofibromatosis 1 (NF1) is an extremely variable multisystem disease; the progression and severity may differ throughout life in an affected individual as well as in affected family members with the same Neurofibromatosis 1: Frequency of Select Features Many of the features listed in this table have different frequencies at different ages. The table gives life-time cumulative incidence figures that may be higher, and sometimes much higher, than the prevalence at any given age. Most frequencies in this table are from CALMs are flat and flush with the surrounding skin; if the skin of the lesion is raised or has an unusually soft or irregular texture in comparison to the surrounding skin, an underlying plexiform neurofibroma is likely. The darker pigmentation of CALMs may be difficult to see in people with very fair skin or very dark skin, where the color of the lesions is similar to that of the rest of the skin. A Wood's light is useful in such individuals to demonstrate the pigmented macules. CALMs are not seen on the palms or soles in people with NF1 but can occur almost anywhere else on the body. Increased tortuosity of the optic nerve can be seen on brain MRI in children with NF1, but optic nerve tortuosity is not associated with the occurrence of optic pathway glioma among individuals with NF1 [ Subcutaneous neurofibromas lie under the skin (the skin can be moved over them). Most feel rubbery and are nodular, but they may be diffuse, with indistinct borders, and of soft or heterogeneous consistency. The skin overlying a superficial diffuse neurofibroma may exhibit unusual pigmentation or hair patterning. Subcutaneous neurofibromas may be isolated or occur in clusters or continuously like beads on a string along a nerve. Most are small, but subcutaneous neurofibromas can grow to be 5 cm in diameter or more. They may be tender and are sometimes painful. Subcutaneous neurofibromas are uncommon in children but present in about 15% of adults with NF1 on clinical examination. Cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. The total number of neurofibromas seen on clinical examination in adults with NF1 varies from a few to hundreds or even thousands. Some women experience a rapid increase in the number and size of neurofibromas during pregnancy, but this does not appear to produce a persistent increase in the tumor burden in comparison to those of child-bearing age with NF1 who have not been pregnant [ Superficial diffuse plexiform neurofibromas are soft and irregular; they are often associated with thickening, hypertrophy, and/or hyperpigmentation of the associated skin. More extensive diffuse plexiform neurofibromas may have a characteristic “bag of worms” feel on palpation, indicating involvement of multiple nerves and branches. Plexiform neurofibromas may also be firm and nodular, occurring singly or extending for some distance or even along the entire extent of a nerve, producing a “beads on a string” feel on palpation. Deeper plexiform neurofibromas that are not apparent on clinical examination may also be diffuse or nodular, and singular or clustered on any nerve, nerve root, or nerve plexus. Individuals with NF1 who have a At least 20% of people with NF1 who have one non-optic glioma have two or more of these tumors [ The approach to treating epilepsy in individuals with NF1 is similar to that used in those who do not have NF1 [ Enlargement of the corpus callosum is seen in some children with NF1 and has been associated with learning disabilities [ MRI is the imaging method of choice for demonstrating optic gliomas, brain tumors, and neurofibromas of cranial, spinal, or peripheral nerves, as well as diffuse or nodular neurofibromas anywhere in the body. Positron emission tomography is useful in recognizing MPNST [ Although much more frequent in people with NF1 than in the general population, pheochromocytomas or paragangliomas are found in fewer than 1% of adults with NF1. These tumors are usually asymptomatic, but they can cause arterial hypertension [ Congenital anomalies of the circulatory system were observed 3.35 times (95% confidence interval 1.64-6.83x) more often than expected among children with NF1 in a study performed through Finnish population-based registries [ NF1-associated diffuse lung disease occurs in 10%-20% of adults [ Individuals with NF1 tend to be below average in height and above average in head circumference for age [ In contrast, individuals with whole-gene Pubertal development is usually normal, although decreased pubertal growth velocity occurs in both girls and boys [ The median life expectancy of individuals with NF1 is at least eight years lower than in the general population [ Quality of life assessments are lower in both children and adults with NF1 than in comparison groups [ Symptomatic Several allele-phenotype correlations have been observed in NF1: An unusually severe phenotype with frequent plexiform or spinal neurofibromas, optic pathway gliomas, malignant neoplasms, and skeletal abnormalities has been observed in adults with missense variants of one of five codons between 844 and 848 [ Missense variants affecting Missense variants affecting Missense variants affecting Several missense variants affecting Pedigree studies demonstrate that the penetrance of NF1 is nearly complete after childhood [ NF1 was previously referred to as peripheral neurofibromatosis, to distinguish it from "Neurofibromatosis" without further specification is sometimes used in the literature to refer to NF1, but this usage is confusing because other authors employ the term "neurofibromatosis" to designate a group of conditions that includes (in addition to NF1) Legius syndrome, NF2, and A Finnish register-based total population study estimated the prevalence of NF1 at 1:2,052 between ages 0 and 74 years [ Almost half of all affected individuals have the disorder as the result of • An unusually severe phenotype with frequent plexiform or spinal neurofibromas, optic pathway gliomas, malignant neoplasms, and skeletal abnormalities has been observed in adults with missense variants of one of five codons between 844 and 848 [ • Missense variants affecting • Missense variants affecting • Missense variants affecting • Several missense variants affecting ## Clinical Description Neurofibromatosis 1 (NF1) is an extremely variable multisystem disease; the progression and severity may differ throughout life in an affected individual as well as in affected family members with the same Neurofibromatosis 1: Frequency of Select Features Many of the features listed in this table have different frequencies at different ages. The table gives life-time cumulative incidence figures that may be higher, and sometimes much higher, than the prevalence at any given age. Most frequencies in this table are from CALMs are flat and flush with the surrounding skin; if the skin of the lesion is raised or has an unusually soft or irregular texture in comparison to the surrounding skin, an underlying plexiform neurofibroma is likely. The darker pigmentation of CALMs may be difficult to see in people with very fair skin or very dark skin, where the color of the lesions is similar to that of the rest of the skin. A Wood's light is useful in such individuals to demonstrate the pigmented macules. CALMs are not seen on the palms or soles in people with NF1 but can occur almost anywhere else on the body. Increased tortuosity of the optic nerve can be seen on brain MRI in children with NF1, but optic nerve tortuosity is not associated with the occurrence of optic pathway glioma among individuals with NF1 [ Subcutaneous neurofibromas lie under the skin (the skin can be moved over them). Most feel rubbery and are nodular, but they may be diffuse, with indistinct borders, and of soft or heterogeneous consistency. The skin overlying a superficial diffuse neurofibroma may exhibit unusual pigmentation or hair patterning. Subcutaneous neurofibromas may be isolated or occur in clusters or continuously like beads on a string along a nerve. Most are small, but subcutaneous neurofibromas can grow to be 5 cm in diameter or more. They may be tender and are sometimes painful. Subcutaneous neurofibromas are uncommon in children but present in about 15% of adults with NF1 on clinical examination. Cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. The total number of neurofibromas seen on clinical examination in adults with NF1 varies from a few to hundreds or even thousands. Some women experience a rapid increase in the number and size of neurofibromas during pregnancy, but this does not appear to produce a persistent increase in the tumor burden in comparison to those of child-bearing age with NF1 who have not been pregnant [ Superficial diffuse plexiform neurofibromas are soft and irregular; they are often associated with thickening, hypertrophy, and/or hyperpigmentation of the associated skin. More extensive diffuse plexiform neurofibromas may have a characteristic “bag of worms” feel on palpation, indicating involvement of multiple nerves and branches. Plexiform neurofibromas may also be firm and nodular, occurring singly or extending for some distance or even along the entire extent of a nerve, producing a “beads on a string” feel on palpation. Deeper plexiform neurofibromas that are not apparent on clinical examination may also be diffuse or nodular, and singular or clustered on any nerve, nerve root, or nerve plexus. Individuals with NF1 who have a At least 20% of people with NF1 who have one non-optic glioma have two or more of these tumors [ The approach to treating epilepsy in individuals with NF1 is similar to that used in those who do not have NF1 [ Enlargement of the corpus callosum is seen in some children with NF1 and has been associated with learning disabilities [ MRI is the imaging method of choice for demonstrating optic gliomas, brain tumors, and neurofibromas of cranial, spinal, or peripheral nerves, as well as diffuse or nodular neurofibromas anywhere in the body. Positron emission tomography is useful in recognizing MPNST [ Although much more frequent in people with NF1 than in the general population, pheochromocytomas or paragangliomas are found in fewer than 1% of adults with NF1. These tumors are usually asymptomatic, but they can cause arterial hypertension [ Congenital anomalies of the circulatory system were observed 3.35 times (95% confidence interval 1.64-6.83x) more often than expected among children with NF1 in a study performed through Finnish population-based registries [ NF1-associated diffuse lung disease occurs in 10%-20% of adults [ Individuals with NF1 tend to be below average in height and above average in head circumference for age [ In contrast, individuals with whole-gene Pubertal development is usually normal, although decreased pubertal growth velocity occurs in both girls and boys [ The median life expectancy of individuals with NF1 is at least eight years lower than in the general population [ Quality of life assessments are lower in both children and adults with NF1 than in comparison groups [ Symptomatic ## Cutaneous Features CALMs are flat and flush with the surrounding skin; if the skin of the lesion is raised or has an unusually soft or irregular texture in comparison to the surrounding skin, an underlying plexiform neurofibroma is likely. The darker pigmentation of CALMs may be difficult to see in people with very fair skin or very dark skin, where the color of the lesions is similar to that of the rest of the skin. A Wood's light is useful in such individuals to demonstrate the pigmented macules. CALMs are not seen on the palms or soles in people with NF1 but can occur almost anywhere else on the body. ## Ocular Findings Increased tortuosity of the optic nerve can be seen on brain MRI in children with NF1, but optic nerve tortuosity is not associated with the occurrence of optic pathway glioma among individuals with NF1 [ ## Other Tumors Subcutaneous neurofibromas lie under the skin (the skin can be moved over them). Most feel rubbery and are nodular, but they may be diffuse, with indistinct borders, and of soft or heterogeneous consistency. The skin overlying a superficial diffuse neurofibroma may exhibit unusual pigmentation or hair patterning. Subcutaneous neurofibromas may be isolated or occur in clusters or continuously like beads on a string along a nerve. Most are small, but subcutaneous neurofibromas can grow to be 5 cm in diameter or more. They may be tender and are sometimes painful. Subcutaneous neurofibromas are uncommon in children but present in about 15% of adults with NF1 on clinical examination. Cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. The total number of neurofibromas seen on clinical examination in adults with NF1 varies from a few to hundreds or even thousands. Some women experience a rapid increase in the number and size of neurofibromas during pregnancy, but this does not appear to produce a persistent increase in the tumor burden in comparison to those of child-bearing age with NF1 who have not been pregnant [ Superficial diffuse plexiform neurofibromas are soft and irregular; they are often associated with thickening, hypertrophy, and/or hyperpigmentation of the associated skin. More extensive diffuse plexiform neurofibromas may have a characteristic “bag of worms” feel on palpation, indicating involvement of multiple nerves and branches. Plexiform neurofibromas may also be firm and nodular, occurring singly or extending for some distance or even along the entire extent of a nerve, producing a “beads on a string” feel on palpation. Deeper plexiform neurofibromas that are not apparent on clinical examination may also be diffuse or nodular, and singular or clustered on any nerve, nerve root, or nerve plexus. Individuals with NF1 who have a At least 20% of people with NF1 who have one non-optic glioma have two or more of these tumors [ ## Other Neurologic Manifestations The approach to treating epilepsy in individuals with NF1 is similar to that used in those who do not have NF1 [ Enlargement of the corpus callosum is seen in some children with NF1 and has been associated with learning disabilities [ MRI is the imaging method of choice for demonstrating optic gliomas, brain tumors, and neurofibromas of cranial, spinal, or peripheral nerves, as well as diffuse or nodular neurofibromas anywhere in the body. Positron emission tomography is useful in recognizing MPNST [ ## Musculoskeletal Features ## Vascular Involvement Although much more frequent in people with NF1 than in the general population, pheochromocytomas or paragangliomas are found in fewer than 1% of adults with NF1. These tumors are usually asymptomatic, but they can cause arterial hypertension [ ## Cardiac Issues Congenital anomalies of the circulatory system were observed 3.35 times (95% confidence interval 1.64-6.83x) more often than expected among children with NF1 in a study performed through Finnish population-based registries [ ## Pulmonary Disease NF1-associated diffuse lung disease occurs in 10%-20% of adults [ ## Growth Individuals with NF1 tend to be below average in height and above average in head circumference for age [ In contrast, individuals with whole-gene Pubertal development is usually normal, although decreased pubertal growth velocity occurs in both girls and boys [ ## Life Expectancy The median life expectancy of individuals with NF1 is at least eight years lower than in the general population [ ## Quality of Life Quality of life assessments are lower in both children and adults with NF1 than in comparison groups [ ## NF1 Phenotypic Variants Symptomatic ## Genotype-Phenotype Correlations Several allele-phenotype correlations have been observed in NF1: An unusually severe phenotype with frequent plexiform or spinal neurofibromas, optic pathway gliomas, malignant neoplasms, and skeletal abnormalities has been observed in adults with missense variants of one of five codons between 844 and 848 [ Missense variants affecting Missense variants affecting Missense variants affecting Several missense variants affecting • An unusually severe phenotype with frequent plexiform or spinal neurofibromas, optic pathway gliomas, malignant neoplasms, and skeletal abnormalities has been observed in adults with missense variants of one of five codons between 844 and 848 [ • Missense variants affecting • Missense variants affecting • Missense variants affecting • Several missense variants affecting ## Penetrance Pedigree studies demonstrate that the penetrance of NF1 is nearly complete after childhood [ ## Nomenclature NF1 was previously referred to as peripheral neurofibromatosis, to distinguish it from "Neurofibromatosis" without further specification is sometimes used in the literature to refer to NF1, but this usage is confusing because other authors employ the term "neurofibromatosis" to designate a group of conditions that includes (in addition to NF1) Legius syndrome, NF2, and ## Prevalence A Finnish register-based total population study estimated the prevalence of NF1 at 1:2,052 between ages 0 and 74 years [ Almost half of all affected individuals have the disorder as the result of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis More than 100 genetic conditions and multiple congenital anomaly syndromes that include café au lait macules (CALMs) or other individual features of neurofibromatosis 1 (NF1) have been described, but few of these disorders are ever confused with NF1. The conditions to consider in the differential diagnosis of NF1 are summarized in Genes of Interest in the Differential Diagnosis of Neurofibromatosis 1 AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; CALMs = café au lait macules; DD = developmental delay; MOI = mode of inheritance; NS = Noonan syndrome A somatic mosaic NS is most often inherited in an AD manner. NS caused by pathogenic variants in FD/MAS is the result of early embryonic postzygotic somatic activating mutation of Clinically distinguishing Legius syndrome from NF1 may be impossible in a young child because neurofibromas and Lisch nodules do not usually arise until later in childhood or adolescence in those with NF1. Examination of the parents for signs of Legius syndrome or NF1 may distinguish the two conditions, but in simplex cases, reevaluation of the individual after adolescence or molecular testing may be necessary to establish the diagnosis [ Isolated familial multiple CALMs (OMIM Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face, and marfanoid habitus [ • Isolated familial multiple CALMs (OMIM • Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face, and marfanoid habitus [ ## Management The American Academy of Pediatrics and American College of Medical Genetics and Genomics (ACMG) have published management guidelines for children with NF1 [ To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 1 (NF1), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Neurofibromatosis 1 MOI = mode of inheritance Proponents state that brain MRI is useful to identify structural anomalies of the brain or skull, tumors, or vascular disease before it becomes clinically apparent. Those who oppose head MRI in asymptomatic individuals point to the uncertain clinical significance of unidentified bright objects (UBOs), increased cost, requirement for sedation in small children, and findings resulting in repeating imaging for reassurance. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is currently no cure for NF1. Specialist medical or surgical management is available for many NF1-associated morbidities, and targeted therapy with MEK inhibitors is available for NF1-related inoperable plexiform neurofibromas. Treatment of Manifestations in Individuals with Neurofibromatosis 1 Monitoring by brain MRI & mgmt per ophthalmologist & oncologist w/experience in NF1 Chemotherapy for progressive OPG, although the results are mixed Surgical treatment is usually reserved for cosmetic palliation in a blind eye. Children w/NF1 & low-grade progressive gliomas (most of which were OPG) had better survival w/carboplatin & vincristine than children w/o NF1 who had similar tumors [ Treatments for NF1-assoc OPG w/MEK inhibitors, other targeted therapies, immunotherapies, & other approaches are currently being investigated [ Radiotherapy is usually avoided due to ↑ risk of inducing malignancy or moya moya vasculopathy in the exposed field. Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ Other non-surgical methods may be used to ablate cutaneous neurofibromas [Richie et at 2025]. See Assess size, extent, & monitor growth w/MRI. Monitor for pain, neurologic deficit, &/or tumor growth (which suggests MPNST). Exam by MRI, PET, or PET/CT when MPNST is suspected; definitive diagnosis of MPNST requires biopsy. Surgical removal of nodular & many plexiform neurofibromas is possible. Surgical treatment of larger plexiform tumors is often unsatisfactory because of involvement w/nerves & tendency to grow back. Radiotherapy is contraindicated due to risk of inducing MPNST. Mgmt per surgical &/or medical oncologists familiar w/NF1 Complete surgical excision, when possible, is the only treatment that offers the possibility of cure. Adjuvant chemotherapy or radiotherapy may be helpful in some. Brain stem & cerebellar gliomas in those w/NF1 are usually less aggressive than in persons w/o NF1 [ Treatments for NF1-assoc gliomas w/MEK inhibitors, other targeted therapies, immunotherapies, gene therapies, & other approaches are currently being investigated [ Avoid radiation therapy, as MPNST or other gliomas may develop w/in treatment field [ Depends on nature, severity, & degree to which it interferes w/ADL [ Is empiric & similar to that in those w/o NF1. Assess by x-ray when suspected on clinical exam. Consider CT or 3D-CT reconstructions when surgical treatment is planned. Vitamin D & calcium supplementation to ↓ risk of developing osteoporosis Bisphosphonate treatment of osteoporosis may be helpful [ MR angiography to assess NF1 vasculopathy [ Treatment per neurologist & vascular surgeon ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; MPNST = malignant peripheral nerve sheath tumor; OPG = optic pathway glioma Treatment with selumetinib has been shown to reduce the size and symptoms associated with inoperable plexiform neurofibromas in most individuals with NF1 age two years and older [ Reduction of the size and symptoms associated with inoperable plexiform neurofibromas was produced by treatment of many individuals with NF1 with mirdametinib [ MRI is the method of choice for demonstrating the size and extent of plexiform neurofibromas [ Surveillance recommendations for children and adults with NF1 have been published by ACMG [ Recommended Surveillance for Children with Neurofibromatosis 1 Developmental assessment by screening questionnaire Neuropsychiatric assessment Blood pressure assessment Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications Monitoring of known cardiac &/or vascular disease per cardiologist/vascular specialist Persons with Recommended Surveillance for Adults with Neurofibromatosis 1 Blood pressure assessment Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications Monitoring known cardiac &/or vascular disease per cardiologist / vascular specialist The efficacy and cost-effectiveness of such screening have not yet been demonstrated [ Activity restrictions may be required in those with tibial dysplasia or dystrophic scoliosis if recommended by orthopedic specialist. Radiotherapy of individuals with NF1 appears to be associated with a high risk of developing malignant peripheral nerve sheath tumors within the field of treatment [ See Although most pregnancies in individuals with NF1 are normal, preterm delivery, delivery by cesarean section, hypertension, and placental abruptions are more common than expected [ Therapy of NF1-related MPNST by interfering with various critical cell signaling pathways is under active investigation in preclinical models and early clinical trials [ Many preclinical and clinical investigations of NF1-related gliomas are under way [ Gene therapy to correct the primary disease-causing Clinical studies are in progress to assess treatments for NF1-associated scoliosis, leukemia, cutaneous neurofibromas, pain, constipation, and hypertension, as well as for cognitive, learning, behavioral, social, and motor impairments. See • Monitoring by brain MRI & mgmt per ophthalmologist & oncologist w/experience in NF1 • Chemotherapy for progressive OPG, although the results are mixed • Surgical treatment is usually reserved for cosmetic palliation in a blind eye. • Children w/NF1 & low-grade progressive gliomas (most of which were OPG) had better survival w/carboplatin & vincristine than children w/o NF1 who had similar tumors [ • Treatments for NF1-assoc OPG w/MEK inhibitors, other targeted therapies, immunotherapies, & other approaches are currently being investigated [ • Radiotherapy is usually avoided due to ↑ risk of inducing malignancy or moya moya vasculopathy in the exposed field. • Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ • Other non-surgical methods may be used to ablate cutaneous neurofibromas [Richie et at 2025]. • See • Assess size, extent, & monitor growth w/MRI. • Monitor for pain, neurologic deficit, &/or tumor growth (which suggests MPNST). • Exam by MRI, PET, or PET/CT when MPNST is suspected; definitive diagnosis of MPNST requires biopsy. • Surgical removal of nodular & many plexiform neurofibromas is possible. • Surgical treatment of larger plexiform tumors is often unsatisfactory because of involvement w/nerves & tendency to grow back. • Radiotherapy is contraindicated due to risk of inducing MPNST. • Mgmt per surgical &/or medical oncologists familiar w/NF1 • Complete surgical excision, when possible, is the only treatment that offers the possibility of cure. • Adjuvant chemotherapy or radiotherapy may be helpful in some. • Brain stem & cerebellar gliomas in those w/NF1 are usually less aggressive than in persons w/o NF1 [ • Treatments for NF1-assoc gliomas w/MEK inhibitors, other targeted therapies, immunotherapies, gene therapies, & other approaches are currently being investigated [ • Avoid radiation therapy, as MPNST or other gliomas may develop w/in treatment field [ • Depends on nature, severity, & degree to which it interferes w/ADL [ • Is empiric & similar to that in those w/o NF1. • Assess by x-ray when suspected on clinical exam. • Consider CT or 3D-CT reconstructions when surgical treatment is planned. • Vitamin D & calcium supplementation to ↓ risk of developing osteoporosis • Bisphosphonate treatment of osteoporosis may be helpful [ • MR angiography to assess NF1 vasculopathy [ • Treatment per neurologist & vascular surgeon • Developmental assessment by screening questionnaire • Neuropsychiatric assessment • Blood pressure assessment • Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications • Monitoring of known cardiac &/or vascular disease per cardiologist/vascular specialist • Blood pressure assessment • Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications • Monitoring known cardiac &/or vascular disease per cardiologist / vascular specialist ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 1 (NF1), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Neurofibromatosis 1 MOI = mode of inheritance Proponents state that brain MRI is useful to identify structural anomalies of the brain or skull, tumors, or vascular disease before it becomes clinically apparent. Those who oppose head MRI in asymptomatic individuals point to the uncertain clinical significance of unidentified bright objects (UBOs), increased cost, requirement for sedation in small children, and findings resulting in repeating imaging for reassurance. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations There is currently no cure for NF1. Specialist medical or surgical management is available for many NF1-associated morbidities, and targeted therapy with MEK inhibitors is available for NF1-related inoperable plexiform neurofibromas. Treatment of Manifestations in Individuals with Neurofibromatosis 1 Monitoring by brain MRI & mgmt per ophthalmologist & oncologist w/experience in NF1 Chemotherapy for progressive OPG, although the results are mixed Surgical treatment is usually reserved for cosmetic palliation in a blind eye. Children w/NF1 & low-grade progressive gliomas (most of which were OPG) had better survival w/carboplatin & vincristine than children w/o NF1 who had similar tumors [ Treatments for NF1-assoc OPG w/MEK inhibitors, other targeted therapies, immunotherapies, & other approaches are currently being investigated [ Radiotherapy is usually avoided due to ↑ risk of inducing malignancy or moya moya vasculopathy in the exposed field. Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ Other non-surgical methods may be used to ablate cutaneous neurofibromas [Richie et at 2025]. See Assess size, extent, & monitor growth w/MRI. Monitor for pain, neurologic deficit, &/or tumor growth (which suggests MPNST). Exam by MRI, PET, or PET/CT when MPNST is suspected; definitive diagnosis of MPNST requires biopsy. Surgical removal of nodular & many plexiform neurofibromas is possible. Surgical treatment of larger plexiform tumors is often unsatisfactory because of involvement w/nerves & tendency to grow back. Radiotherapy is contraindicated due to risk of inducing MPNST. Mgmt per surgical &/or medical oncologists familiar w/NF1 Complete surgical excision, when possible, is the only treatment that offers the possibility of cure. Adjuvant chemotherapy or radiotherapy may be helpful in some. Brain stem & cerebellar gliomas in those w/NF1 are usually less aggressive than in persons w/o NF1 [ Treatments for NF1-assoc gliomas w/MEK inhibitors, other targeted therapies, immunotherapies, gene therapies, & other approaches are currently being investigated [ Avoid radiation therapy, as MPNST or other gliomas may develop w/in treatment field [ Depends on nature, severity, & degree to which it interferes w/ADL [ Is empiric & similar to that in those w/o NF1. Assess by x-ray when suspected on clinical exam. Consider CT or 3D-CT reconstructions when surgical treatment is planned. Vitamin D & calcium supplementation to ↓ risk of developing osteoporosis Bisphosphonate treatment of osteoporosis may be helpful [ MR angiography to assess NF1 vasculopathy [ Treatment per neurologist & vascular surgeon ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; MPNST = malignant peripheral nerve sheath tumor; OPG = optic pathway glioma Treatment with selumetinib has been shown to reduce the size and symptoms associated with inoperable plexiform neurofibromas in most individuals with NF1 age two years and older [ Reduction of the size and symptoms associated with inoperable plexiform neurofibromas was produced by treatment of many individuals with NF1 with mirdametinib [ • Monitoring by brain MRI & mgmt per ophthalmologist & oncologist w/experience in NF1 • Chemotherapy for progressive OPG, although the results are mixed • Surgical treatment is usually reserved for cosmetic palliation in a blind eye. • Children w/NF1 & low-grade progressive gliomas (most of which were OPG) had better survival w/carboplatin & vincristine than children w/o NF1 who had similar tumors [ • Treatments for NF1-assoc OPG w/MEK inhibitors, other targeted therapies, immunotherapies, & other approaches are currently being investigated [ • Radiotherapy is usually avoided due to ↑ risk of inducing malignancy or moya moya vasculopathy in the exposed field. • Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ • Other non-surgical methods may be used to ablate cutaneous neurofibromas [Richie et at 2025]. • See • Assess size, extent, & monitor growth w/MRI. • Monitor for pain, neurologic deficit, &/or tumor growth (which suggests MPNST). • Exam by MRI, PET, or PET/CT when MPNST is suspected; definitive diagnosis of MPNST requires biopsy. • Surgical removal of nodular & many plexiform neurofibromas is possible. • Surgical treatment of larger plexiform tumors is often unsatisfactory because of involvement w/nerves & tendency to grow back. • Radiotherapy is contraindicated due to risk of inducing MPNST. • Mgmt per surgical &/or medical oncologists familiar w/NF1 • Complete surgical excision, when possible, is the only treatment that offers the possibility of cure. • Adjuvant chemotherapy or radiotherapy may be helpful in some. • Brain stem & cerebellar gliomas in those w/NF1 are usually less aggressive than in persons w/o NF1 [ • Treatments for NF1-assoc gliomas w/MEK inhibitors, other targeted therapies, immunotherapies, gene therapies, & other approaches are currently being investigated [ • Avoid radiation therapy, as MPNST or other gliomas may develop w/in treatment field [ • Depends on nature, severity, & degree to which it interferes w/ADL [ • Is empiric & similar to that in those w/o NF1. • Assess by x-ray when suspected on clinical exam. • Consider CT or 3D-CT reconstructions when surgical treatment is planned. • Vitamin D & calcium supplementation to ↓ risk of developing osteoporosis • Bisphosphonate treatment of osteoporosis may be helpful [ • MR angiography to assess NF1 vasculopathy [ • Treatment per neurologist & vascular surgeon ## Standard Medical and Surgical Care Treatment of Manifestations in Individuals with Neurofibromatosis 1 Monitoring by brain MRI & mgmt per ophthalmologist & oncologist w/experience in NF1 Chemotherapy for progressive OPG, although the results are mixed Surgical treatment is usually reserved for cosmetic palliation in a blind eye. Children w/NF1 & low-grade progressive gliomas (most of which were OPG) had better survival w/carboplatin & vincristine than children w/o NF1 who had similar tumors [ Treatments for NF1-assoc OPG w/MEK inhibitors, other targeted therapies, immunotherapies, & other approaches are currently being investigated [ Radiotherapy is usually avoided due to ↑ risk of inducing malignancy or moya moya vasculopathy in the exposed field. Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ Other non-surgical methods may be used to ablate cutaneous neurofibromas [Richie et at 2025]. See Assess size, extent, & monitor growth w/MRI. Monitor for pain, neurologic deficit, &/or tumor growth (which suggests MPNST). Exam by MRI, PET, or PET/CT when MPNST is suspected; definitive diagnosis of MPNST requires biopsy. Surgical removal of nodular & many plexiform neurofibromas is possible. Surgical treatment of larger plexiform tumors is often unsatisfactory because of involvement w/nerves & tendency to grow back. Radiotherapy is contraindicated due to risk of inducing MPNST. Mgmt per surgical &/or medical oncologists familiar w/NF1 Complete surgical excision, when possible, is the only treatment that offers the possibility of cure. Adjuvant chemotherapy or radiotherapy may be helpful in some. Brain stem & cerebellar gliomas in those w/NF1 are usually less aggressive than in persons w/o NF1 [ Treatments for NF1-assoc gliomas w/MEK inhibitors, other targeted therapies, immunotherapies, gene therapies, & other approaches are currently being investigated [ Avoid radiation therapy, as MPNST or other gliomas may develop w/in treatment field [ Depends on nature, severity, & degree to which it interferes w/ADL [ Is empiric & similar to that in those w/o NF1. Assess by x-ray when suspected on clinical exam. Consider CT or 3D-CT reconstructions when surgical treatment is planned. Vitamin D & calcium supplementation to ↓ risk of developing osteoporosis Bisphosphonate treatment of osteoporosis may be helpful [ MR angiography to assess NF1 vasculopathy [ Treatment per neurologist & vascular surgeon ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; MPNST = malignant peripheral nerve sheath tumor; OPG = optic pathway glioma • Monitoring by brain MRI & mgmt per ophthalmologist & oncologist w/experience in NF1 • Chemotherapy for progressive OPG, although the results are mixed • Surgical treatment is usually reserved for cosmetic palliation in a blind eye. • Children w/NF1 & low-grade progressive gliomas (most of which were OPG) had better survival w/carboplatin & vincristine than children w/o NF1 who had similar tumors [ • Treatments for NF1-assoc OPG w/MEK inhibitors, other targeted therapies, immunotherapies, & other approaches are currently being investigated [ • Radiotherapy is usually avoided due to ↑ risk of inducing malignancy or moya moya vasculopathy in the exposed field. • Laser ablation is rapid & effective for removing large numbers of neurofibromas w/satisfactory cosmetic results [ • Other non-surgical methods may be used to ablate cutaneous neurofibromas [Richie et at 2025]. • See • Assess size, extent, & monitor growth w/MRI. • Monitor for pain, neurologic deficit, &/or tumor growth (which suggests MPNST). • Exam by MRI, PET, or PET/CT when MPNST is suspected; definitive diagnosis of MPNST requires biopsy. • Surgical removal of nodular & many plexiform neurofibromas is possible. • Surgical treatment of larger plexiform tumors is often unsatisfactory because of involvement w/nerves & tendency to grow back. • Radiotherapy is contraindicated due to risk of inducing MPNST. • Mgmt per surgical &/or medical oncologists familiar w/NF1 • Complete surgical excision, when possible, is the only treatment that offers the possibility of cure. • Adjuvant chemotherapy or radiotherapy may be helpful in some. • Brain stem & cerebellar gliomas in those w/NF1 are usually less aggressive than in persons w/o NF1 [ • Treatments for NF1-assoc gliomas w/MEK inhibitors, other targeted therapies, immunotherapies, gene therapies, & other approaches are currently being investigated [ • Avoid radiation therapy, as MPNST or other gliomas may develop w/in treatment field [ • Depends on nature, severity, & degree to which it interferes w/ADL [ • Is empiric & similar to that in those w/o NF1. • Assess by x-ray when suspected on clinical exam. • Consider CT or 3D-CT reconstructions when surgical treatment is planned. • Vitamin D & calcium supplementation to ↓ risk of developing osteoporosis • Bisphosphonate treatment of osteoporosis may be helpful [ • MR angiography to assess NF1 vasculopathy [ • Treatment per neurologist & vascular surgeon ## Targeted Therapy Treatment with selumetinib has been shown to reduce the size and symptoms associated with inoperable plexiform neurofibromas in most individuals with NF1 age two years and older [ Reduction of the size and symptoms associated with inoperable plexiform neurofibromas was produced by treatment of many individuals with NF1 with mirdametinib [ ## Imaging MRI is the method of choice for demonstrating the size and extent of plexiform neurofibromas [ ## Surveillance Surveillance recommendations for children and adults with NF1 have been published by ACMG [ Recommended Surveillance for Children with Neurofibromatosis 1 Developmental assessment by screening questionnaire Neuropsychiatric assessment Blood pressure assessment Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications Monitoring of known cardiac &/or vascular disease per cardiologist/vascular specialist Persons with Recommended Surveillance for Adults with Neurofibromatosis 1 Blood pressure assessment Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications Monitoring known cardiac &/or vascular disease per cardiologist / vascular specialist The efficacy and cost-effectiveness of such screening have not yet been demonstrated [ • Developmental assessment by screening questionnaire • Neuropsychiatric assessment • Blood pressure assessment • Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications • Monitoring of known cardiac &/or vascular disease per cardiologist/vascular specialist • Blood pressure assessment • Clinical assessment for cardiac disease; assess for signs & symptoms of vascular complications • Monitoring known cardiac &/or vascular disease per cardiologist / vascular specialist ## Agents/Circumstances to Avoid Activity restrictions may be required in those with tibial dysplasia or dystrophic scoliosis if recommended by orthopedic specialist. Radiotherapy of individuals with NF1 appears to be associated with a high risk of developing malignant peripheral nerve sheath tumors within the field of treatment [ ## Evaluation of Relatives at Risk See ## Pregnancy Management Although most pregnancies in individuals with NF1 are normal, preterm delivery, delivery by cesarean section, hypertension, and placental abruptions are more common than expected [ ## Therapies Under Investigation Therapy of NF1-related MPNST by interfering with various critical cell signaling pathways is under active investigation in preclinical models and early clinical trials [ Many preclinical and clinical investigations of NF1-related gliomas are under way [ Gene therapy to correct the primary disease-causing Clinical studies are in progress to assess treatments for NF1-associated scoliosis, leukemia, cutaneous neurofibromas, pain, constipation, and hypertension, as well as for cognitive, learning, behavioral, social, and motor impairments. See ## Genetic Counseling Neurofibromatosis 1 (NF1) is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with NF1 have an affected parent. Approximately 50% of individuals diagnosed with NF1 have the disorder as the result of a Recommendations for the evaluation of both parents of a proband with an apparent Medical history and physical examination with particular attention to dermal and other features of NF1; and Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. If neither parent of an individual with NF1 has features that meet the clinical diagnostic criteria for NF1 [ Note: Parental somatic and germline mosaicism may be present even if there are no clinical signs of NF1 and no evidence of the proband’s disease-causing The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms. Therefore, an apparently negative family history cannot be confirmed unless both parents have undergone detailed clinical examination for signs of NF1. Note: An individual in whom NF1 appears to have arisen as the result of If a parent is affected, the risk to the sibs is 50%; a sib who inherits an If a parent of a proband has mosaicism for a disease-causing If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of parental germline mosaicism. Germline mosaicism for an Each child of an individual with NF1 has a 50% chance of inheriting the Penetrance is close to 100%; thus, a child who inherits an The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Approximately 50% of individuals diagnosed with NF1 have an affected parent. • Approximately 50% of individuals diagnosed with NF1 have the disorder as the result of a • Recommendations for the evaluation of both parents of a proband with an apparent • Medical history and physical examination with particular attention to dermal and other features of NF1; and • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. • Medical history and physical examination with particular attention to dermal and other features of NF1; and • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. • If neither parent of an individual with NF1 has features that meet the clinical diagnostic criteria for NF1 [ • Note: Parental somatic and germline mosaicism may be present even if there are no clinical signs of NF1 and no evidence of the proband’s disease-causing • The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms. Therefore, an apparently negative family history cannot be confirmed unless both parents have undergone detailed clinical examination for signs of NF1. • Note: An individual in whom NF1 appears to have arisen as the result of • Medical history and physical examination with particular attention to dermal and other features of NF1; and • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. • If a parent is affected, the risk to the sibs is 50%; a sib who inherits an • If a parent of a proband has mosaicism for a disease-causing • If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of parental germline mosaicism. Germline mosaicism for an • Each child of an individual with NF1 has a 50% chance of inheriting the • Penetrance is close to 100%; thus, a child who inherits an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk. ## Mode of Inheritance Neurofibromatosis 1 (NF1) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 50% of individuals diagnosed with NF1 have an affected parent. Approximately 50% of individuals diagnosed with NF1 have the disorder as the result of a Recommendations for the evaluation of both parents of a proband with an apparent Medical history and physical examination with particular attention to dermal and other features of NF1; and Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. If neither parent of an individual with NF1 has features that meet the clinical diagnostic criteria for NF1 [ Note: Parental somatic and germline mosaicism may be present even if there are no clinical signs of NF1 and no evidence of the proband’s disease-causing The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms. Therefore, an apparently negative family history cannot be confirmed unless both parents have undergone detailed clinical examination for signs of NF1. Note: An individual in whom NF1 appears to have arisen as the result of If a parent is affected, the risk to the sibs is 50%; a sib who inherits an If a parent of a proband has mosaicism for a disease-causing If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of parental germline mosaicism. Germline mosaicism for an Each child of an individual with NF1 has a 50% chance of inheriting the Penetrance is close to 100%; thus, a child who inherits an • Approximately 50% of individuals diagnosed with NF1 have an affected parent. • Approximately 50% of individuals diagnosed with NF1 have the disorder as the result of a • Recommendations for the evaluation of both parents of a proband with an apparent • Medical history and physical examination with particular attention to dermal and other features of NF1; and • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. • Medical history and physical examination with particular attention to dermal and other features of NF1; and • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. • If neither parent of an individual with NF1 has features that meet the clinical diagnostic criteria for NF1 [ • Note: Parental somatic and germline mosaicism may be present even if there are no clinical signs of NF1 and no evidence of the proband’s disease-causing • The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms. Therefore, an apparently negative family history cannot be confirmed unless both parents have undergone detailed clinical examination for signs of NF1. • Note: An individual in whom NF1 appears to have arisen as the result of • Medical history and physical examination with particular attention to dermal and other features of NF1; and • Ophthalmologic examination (including slit lamp examination and infrared reflectance imaging or optical coherence tomography) to look for Lisch nodules, choroidal freckling, or other ophthalmologic signs of NF1. • If a parent is affected, the risk to the sibs is 50%; a sib who inherits an • If a parent of a proband has mosaicism for a disease-causing • If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of parental germline mosaicism. Germline mosaicism for an • Each child of an individual with NF1 has a 50% chance of inheriting the • Penetrance is close to 100%; thus, a child who inherits an ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Children’s Tumor Foundation • • • • • • • • • • United Kingdom • • • • • • • • Children’s Tumor Foundation • ## Molecular Genetics Neurofibromatosis 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Neurofibromatosis 1 ( Notable Variants listed in the table have been provided by the author. Type 1 deletion of the entire Several kinds of tumors that occur with increased frequency among persons with NF1 may exhibit somatic (but not germline) ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the author. Type 1 deletion of the entire ## Cancer and Benign Tumors Several kinds of tumors that occur with increased frequency among persons with NF1 may exhibit somatic (but not germline) ## Chapter Notes 3 April 2025 (sw) Revision: MEK inhibitor mirdametinib approved by FDA as 21 April 2022 (sw) Comprehensive update posted live 2 November 2017 (ha) Comprehensive update posted live 4 September 2014 (me) Comprehensive update posted live 3 May 2012 (me) Comprehensive update posted live 2 June 2009 (me) Comprehensive update posted live 31 January 2007 (me) Comprehensive update posted live 5 October 2004 (me) Comprehensive update posted live 30 September 2002 (me) Comprehensive update posted live 2 October 1998 (pb) Review posted live Spring 1996 (jmf) Original submission • 3 April 2025 (sw) Revision: MEK inhibitor mirdametinib approved by FDA as • 21 April 2022 (sw) Comprehensive update posted live • 2 November 2017 (ha) Comprehensive update posted live • 4 September 2014 (me) Comprehensive update posted live • 3 May 2012 (me) Comprehensive update posted live • 2 June 2009 (me) Comprehensive update posted live • 31 January 2007 (me) Comprehensive update posted live • 5 October 2004 (me) Comprehensive update posted live • 30 September 2002 (me) Comprehensive update posted live • 2 October 1998 (pb) Review posted live • Spring 1996 (jmf) Original submission ## Revision History 3 April 2025 (sw) Revision: MEK inhibitor mirdametinib approved by FDA as 21 April 2022 (sw) Comprehensive update posted live 2 November 2017 (ha) Comprehensive update posted live 4 September 2014 (me) Comprehensive update posted live 3 May 2012 (me) Comprehensive update posted live 2 June 2009 (me) Comprehensive update posted live 31 January 2007 (me) Comprehensive update posted live 5 October 2004 (me) Comprehensive update posted live 30 September 2002 (me) Comprehensive update posted live 2 October 1998 (pb) Review posted live Spring 1996 (jmf) Original submission • 3 April 2025 (sw) Revision: MEK inhibitor mirdametinib approved by FDA as • 21 April 2022 (sw) Comprehensive update posted live • 2 November 2017 (ha) Comprehensive update posted live • 4 September 2014 (me) Comprehensive update posted live • 3 May 2012 (me) Comprehensive update posted live • 2 June 2009 (me) Comprehensive update posted live • 31 January 2007 (me) Comprehensive update posted live • 5 October 2004 (me) Comprehensive update posted live • 30 September 2002 (me) Comprehensive update posted live • 2 October 1998 (pb) Review posted live • Spring 1996 (jmf) Original submission ## Key Sections in This ## References ## Literature Cited Café au lait macules Neurofibromas Plexiform neurofibroma	[]	2/10/1998	21/4/2022	3/4/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nf2	nf2	[ "Neurofibromatosis 2", "Neurofibromatosis Type II", "Neurofibromatosis Type II", "Neurofibromatosis 2", "Merlin", "NF2", "NF2-Related Schwannomatosis" ]		D Gareth Evans	Summary The diagnosis of NF2 is established in a proband with bilateral vestibular schwannomas, an identical NF2 is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with NF2 have an affected parent. Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a	## Diagnosis Updated clinical diagnostic criteria for NF2 A schwannoma at any location including intradermal Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology) A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin A cortical wedge cataract A retinal hamartoma A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy Bilateral vestibular schwannomas Unilateral vestibular schwannoma accompanied by ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract Multiple meningiomas accompanied by EITHER of the following: Unilateral vestibular schwannoma ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years The diagnosis of NF2 Bilateral vestibular schwannomas An identical Note: If the variant allele fraction (VAF) in an unaffected tissue (e.g., blood) is clearly <50%, the diagnosis is mosaic NF2. Two major criteria One major and two minor criteria Unilateral vestibular schwannoma A first-degree relative other than a sib with NF2 Two or more meningiomas Note: If the VAF is clearly <50%, the diagnosis is mosaic NF2. Ependymoma, schwannoma (non-vestibular) Note: Two ependymomas or two non-vestibular schwannomas count as two minor criteria. A single meningioma Note: Two meningiomas count as a major criterion. Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person age <40 years Note: Each ocular manifestation that occurs bilaterally only counts as one minor criterion. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the clinical findings suggest the diagnosis of NF2, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of NF2 is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including When tumor DNA is tested, pathogenic variants in both • A schwannoma at any location including intradermal • Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology) • A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin • A cortical wedge cataract • A retinal hamartoma • A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy • Bilateral vestibular schwannomas • Unilateral vestibular schwannoma accompanied by ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract • Multiple meningiomas accompanied by EITHER of the following: • Unilateral vestibular schwannoma • ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years • Unilateral vestibular schwannoma • ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years • Unilateral vestibular schwannoma • ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years • Bilateral vestibular schwannomas • An identical • Note: If the variant allele fraction (VAF) in an unaffected tissue (e.g., blood) is clearly <50%, the diagnosis is mosaic NF2. • Two major criteria • One major and two minor criteria • Unilateral vestibular schwannoma • A first-degree relative other than a sib with NF2 • Two or more meningiomas • Note: If the VAF is clearly <50%, the diagnosis is mosaic NF2. • Ependymoma, schwannoma (non-vestibular) • Note: Two ependymomas or two non-vestibular schwannomas count as two minor criteria. • A single meningioma • Note: Two meningiomas count as a major criterion. • Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person age <40 years • Note: Each ocular manifestation that occurs bilaterally only counts as one minor criterion. • For an introduction to multigene panels click ## Suggestive Findings NF2 A schwannoma at any location including intradermal Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology) A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin A cortical wedge cataract A retinal hamartoma A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy Bilateral vestibular schwannomas Unilateral vestibular schwannoma accompanied by ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract Multiple meningiomas accompanied by EITHER of the following: Unilateral vestibular schwannoma ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years • A schwannoma at any location including intradermal • Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology) • A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin • A cortical wedge cataract • A retinal hamartoma • A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy • Bilateral vestibular schwannomas • Unilateral vestibular schwannoma accompanied by ANY TWO of the following: meningioma, schwannoma, glioma, neurofibroma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract • Multiple meningiomas accompanied by EITHER of the following: • Unilateral vestibular schwannoma • ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years • Unilateral vestibular schwannoma • ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years • Unilateral vestibular schwannoma • ANY TWO of the following: schwannoma, ependymoma, cataract in the form of subcapsular lenticular opacities or cortical wedge cataract diagnosed in an individual age <40 years ## Establishing the Diagnosis The diagnosis of NF2 Bilateral vestibular schwannomas An identical Note: If the variant allele fraction (VAF) in an unaffected tissue (e.g., blood) is clearly <50%, the diagnosis is mosaic NF2. Two major criteria One major and two minor criteria Unilateral vestibular schwannoma A first-degree relative other than a sib with NF2 Two or more meningiomas Note: If the VAF is clearly <50%, the diagnosis is mosaic NF2. Ependymoma, schwannoma (non-vestibular) Note: Two ependymomas or two non-vestibular schwannomas count as two minor criteria. A single meningioma Note: Two meningiomas count as a major criterion. Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person age <40 years Note: Each ocular manifestation that occurs bilaterally only counts as one minor criterion. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the clinical findings suggest the diagnosis of NF2, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of NF2 is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including When tumor DNA is tested, pathogenic variants in both • Bilateral vestibular schwannomas • An identical • Note: If the variant allele fraction (VAF) in an unaffected tissue (e.g., blood) is clearly <50%, the diagnosis is mosaic NF2. • Two major criteria • One major and two minor criteria • Unilateral vestibular schwannoma • A first-degree relative other than a sib with NF2 • Two or more meningiomas • Note: If the VAF is clearly <50%, the diagnosis is mosaic NF2. • Ependymoma, schwannoma (non-vestibular) • Note: Two ependymomas or two non-vestibular schwannomas count as two minor criteria. • A single meningioma • Note: Two meningiomas count as a major criterion. • Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person age <40 years • Note: Each ocular manifestation that occurs bilaterally only counts as one minor criterion. • For an introduction to multigene panels click ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in ## Option 1 When the clinical findings suggest the diagnosis of NF2, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of NF2 is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including When tumor DNA is tested, pathogenic variants in both ## Clinical Characteristics The average age of onset of findings in individuals with Adapted from Includes percentage of 353 individuals with Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings may be the first manifestations [ Retinal hamartoma Thickened optic nerves Cortical wedge cataracts that may be congenital and associated with amblyopia Third cranial nerve palsy Epiretinal membranes Retinal tufts on optical coherence tomography A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause An isolated meningioma, or a schwannoma at any site [ With time, vestibular tumors extend medially into the cerebellar pontine angle and, if left untreated, cause compression of the brain stem and hydrocephalus. Significant facial palsy is rare even in individuals with large vestibular schwannomas. Schwannomas may also develop on other cranial and peripheral nerves, with sensory nerves more frequently affected than motor nerves. Children and young adults with an apparently isolated vestibular or other cranial nerve schwannoma should be considered at risk for See Retinal hamartoma and epiretinal membrane are seen in up to one third of individuals. Rarely, other ocular manifestations may occur; persistent hyperplastic primary vitreous has been reported in a father and son [ Intracranial and intraorbital tumors may result in decreased visual acuity and diplopia. A progressive polyneuropathy of adulthood not directly related to tumor masses is also recognized [ Further evidence for the mononeuropathy of childhood and the polyneuropathy of adulthood has come from sural nerve biopsies [ NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2. Intrafamilial variability is much lower than interfamilial variability, suggesting a strong effect of the underlying genotype on the resulting phenotype. Large deletions of The type of Nonsense and frameshift variants have been associated with severe disease regardless of their position within the gene [ Splice site variants have been associated with both mild and severe disease [ Missense variants are usually associated with a mild phenotype, often causing the mildest form of NF2 [ Truncating variants are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating variants (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site variants or deletions [ Pathogenic variants in the 3' half of Somatic mosaicism (even when detected in lymphocyte DNA) for typical pathogenic truncating variants that would normally cause severe NF2 may result in a milder phenotype [ Penetrance is close to 100%. Virtually all individuals who have a germline pathogenic variant develop the disease in an average lifetime. The term " The estimated prevalence of NF2 is 1:50,000 [ • Retinal hamartoma • Thickened optic nerves • Cortical wedge cataracts that may be congenital and associated with amblyopia • Third cranial nerve palsy • Epiretinal membranes • Retinal tufts on optical coherence tomography • A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause • An isolated meningioma, or a schwannoma at any site [ • NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. • NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. • No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2. • Nonsense and frameshift variants have been associated with severe disease regardless of their position within the gene [ • Splice site variants have been associated with both mild and severe disease [ • Missense variants are usually associated with a mild phenotype, often causing the mildest form of NF2 [ • Truncating variants are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating variants (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site variants or deletions [ • Pathogenic variants in the 3' half of ## Clinical Description The average age of onset of findings in individuals with Adapted from Includes percentage of 353 individuals with Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings may be the first manifestations [ Retinal hamartoma Thickened optic nerves Cortical wedge cataracts that may be congenital and associated with amblyopia Third cranial nerve palsy Epiretinal membranes Retinal tufts on optical coherence tomography A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause An isolated meningioma, or a schwannoma at any site [ With time, vestibular tumors extend medially into the cerebellar pontine angle and, if left untreated, cause compression of the brain stem and hydrocephalus. Significant facial palsy is rare even in individuals with large vestibular schwannomas. Schwannomas may also develop on other cranial and peripheral nerves, with sensory nerves more frequently affected than motor nerves. Children and young adults with an apparently isolated vestibular or other cranial nerve schwannoma should be considered at risk for See Retinal hamartoma and epiretinal membrane are seen in up to one third of individuals. Rarely, other ocular manifestations may occur; persistent hyperplastic primary vitreous has been reported in a father and son [ Intracranial and intraorbital tumors may result in decreased visual acuity and diplopia. A progressive polyneuropathy of adulthood not directly related to tumor masses is also recognized [ Further evidence for the mononeuropathy of childhood and the polyneuropathy of adulthood has come from sural nerve biopsies [ NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2. • Retinal hamartoma • Thickened optic nerves • Cortical wedge cataracts that may be congenital and associated with amblyopia • Third cranial nerve palsy • Epiretinal membranes • Retinal tufts on optical coherence tomography • A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause • An isolated meningioma, or a schwannoma at any site [ • NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. • NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. • No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2. ## Presenting Features of NF2 in Childhood Retinal hamartoma Thickened optic nerves Cortical wedge cataracts that may be congenital and associated with amblyopia Third cranial nerve palsy Epiretinal membranes Retinal tufts on optical coherence tomography A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause An isolated meningioma, or a schwannoma at any site [ • Retinal hamartoma • Thickened optic nerves • Cortical wedge cataracts that may be congenital and associated with amblyopia • Third cranial nerve palsy • Epiretinal membranes • Retinal tufts on optical coherence tomography • A mononeuropathy (e.g., a facial nerve palsy, foot or wrist drop) with no obvious tumor cause • An isolated meningioma, or a schwannoma at any site [ ## Details of Typical Clinical Findings in NF2 With time, vestibular tumors extend medially into the cerebellar pontine angle and, if left untreated, cause compression of the brain stem and hydrocephalus. Significant facial palsy is rare even in individuals with large vestibular schwannomas. Schwannomas may also develop on other cranial and peripheral nerves, with sensory nerves more frequently affected than motor nerves. Children and young adults with an apparently isolated vestibular or other cranial nerve schwannoma should be considered at risk for See Retinal hamartoma and epiretinal membrane are seen in up to one third of individuals. Rarely, other ocular manifestations may occur; persistent hyperplastic primary vitreous has been reported in a father and son [ Intracranial and intraorbital tumors may result in decreased visual acuity and diplopia. A progressive polyneuropathy of adulthood not directly related to tumor masses is also recognized [ Further evidence for the mononeuropathy of childhood and the polyneuropathy of adulthood has come from sural nerve biopsies [ NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2. • NF2-associated vestibular schwannomas tend to be more invasive and to have a higher degree of dividing cells than non-NF2 tumors. • NF2-associated meningiomas have a higher degree of dividing cells than non-NF2 meningiomas. NF2 meningiomas are usually of the fibroblastic variety. • No histologic differences have been observed between glial tumors in individuals with NF2 and individuals who do not have NF2. ## Genotype-Phenotype Correlations Intrafamilial variability is much lower than interfamilial variability, suggesting a strong effect of the underlying genotype on the resulting phenotype. Large deletions of The type of Nonsense and frameshift variants have been associated with severe disease regardless of their position within the gene [ Splice site variants have been associated with both mild and severe disease [ Missense variants are usually associated with a mild phenotype, often causing the mildest form of NF2 [ Truncating variants are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating variants (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site variants or deletions [ Pathogenic variants in the 3' half of Somatic mosaicism (even when detected in lymphocyte DNA) for typical pathogenic truncating variants that would normally cause severe NF2 may result in a milder phenotype [ • Nonsense and frameshift variants have been associated with severe disease regardless of their position within the gene [ • Splice site variants have been associated with both mild and severe disease [ • Missense variants are usually associated with a mild phenotype, often causing the mildest form of NF2 [ • Truncating variants are associated with earlier onset and greater number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors. In general, truncating variants (frameshift and nonsense) are associated with greater disease-related mortality than missense and splice site variants or deletions [ • Pathogenic variants in the 3' half of ## Penetrance Penetrance is close to 100%. Virtually all individuals who have a germline pathogenic variant develop the disease in an average lifetime. ## Nomenclature The term " ## Prevalence The estimated prevalence of NF2 is 1:50,000 [ ## Genetically Related (Allelic) Disorders No other phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; MOI = mode of inheritance; NF2 = The great majority of individuals with multiple meningiomas do not have a ## Management Clinical practice guidelines for For NF specialists, see For NF2 service centers in the UK, see To establish the extent of disease and needs in an individual diagnosed with NF2, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with BAER = brain stem auditory evoked response; MOI = mode of inheritance; NF2 = Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for NF2. The VEGF (vascular endothelial growth factor) antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ Bevacizumab has also shown some clinical benefit in some individuals with ependymoma [ Small vestibular tumors (<1.5 mm) that are completely intracanalicular can often be completely resected, with preservation of both hearing and facial nerve function. Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [ Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [ Malignant transformation is a possible (though not common) sequela [ More recently, targeted therapy with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ There is some promise with targeted therapy with the tyrosine kinase inhibitor brigatinib [ Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. A cervical spine MRI should be performed before cranial surgery to prevent complications from manipulation under anesthesia [ Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral MRI should be performed before regional analgesia is given [ Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [ Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [ Lipreading skills may be enhanced by instruction. Sign language may often be more effectively acquired before the individual loses hearing. Hearing aids may be helpful early in the course of the disease [ Auditory habilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in affected individuals and at-risk individuals in whom the known pathogenic variant in the family has been identified or whose genetic status cannot be clarified by molecular genetic testing, the evaluations summarized in Recommended Surveillance for Individuals with BAER = brain stem auditory evoked response; NF2 = Annual brain MRI can start at an older age in individuals from families in which the onset of tumors is known to be later [ It is not clear if earlier surveillance (e.g., brain MRI before age 10 years) is beneficial, and it is not known at what age surveillance by brain MRI can be safely stopped. May be useful in detecting changes in auditory nerve function before changes can be visualized by brain MRI. Radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher [ Once the germline See Although there is no convincing evidence that schwannomas increase in size during pregnancy, hormonal effects on meningiomas are possible; therefore, assessment of the potential risk of increased intracranial pressure is important for women considering pregnancy. Search • For NF specialists, see • For NF2 service centers in the UK, see • Small vestibular tumors (<1.5 mm) that are completely intracanalicular can often be completely resected, with preservation of both hearing and facial nerve function. • Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [ • Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [ • Malignant transformation is a possible (though not common) sequela [ • More recently, targeted therapy with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ • There is some promise with targeted therapy with the tyrosine kinase inhibitor brigatinib [ • Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. • A cervical spine MRI should be performed before cranial surgery to prevent complications from manipulation under anesthesia [ • Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral MRI should be performed before regional analgesia is given [ • Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [ • Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [ • Lipreading skills may be enhanced by instruction. • Sign language may often be more effectively acquired before the individual loses hearing. • Hearing aids may be helpful early in the course of the disease [ • Auditory habilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NF2, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with BAER = brain stem auditory evoked response; MOI = mode of inheritance; NF2 = Medical geneticist, certified genetic counselor, certified advanced genetic nurse ## Treatment of Manifestations There is no cure for NF2. The VEGF (vascular endothelial growth factor) antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ Bevacizumab has also shown some clinical benefit in some individuals with ependymoma [ Small vestibular tumors (<1.5 mm) that are completely intracanalicular can often be completely resected, with preservation of both hearing and facial nerve function. Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [ Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [ Malignant transformation is a possible (though not common) sequela [ More recently, targeted therapy with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ There is some promise with targeted therapy with the tyrosine kinase inhibitor brigatinib [ Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. A cervical spine MRI should be performed before cranial surgery to prevent complications from manipulation under anesthesia [ Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral MRI should be performed before regional analgesia is given [ Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [ Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [ Lipreading skills may be enhanced by instruction. Sign language may often be more effectively acquired before the individual loses hearing. Hearing aids may be helpful early in the course of the disease [ Auditory habilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [ • Small vestibular tumors (<1.5 mm) that are completely intracanalicular can often be completely resected, with preservation of both hearing and facial nerve function. • Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [ • Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [ • Malignant transformation is a possible (though not common) sequela [ • More recently, targeted therapy with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ • There is some promise with targeted therapy with the tyrosine kinase inhibitor brigatinib [ • Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. • A cervical spine MRI should be performed before cranial surgery to prevent complications from manipulation under anesthesia [ • Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral MRI should be performed before regional analgesia is given [ • Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [ • Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [ • Lipreading skills may be enhanced by instruction. • Sign language may often be more effectively acquired before the individual loses hearing. • Hearing aids may be helpful early in the course of the disease [ • Auditory habilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [ ## Targeted Therapy The VEGF (vascular endothelial growth factor) antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ Bevacizumab has also shown some clinical benefit in some individuals with ependymoma [ ## Supportive Care Small vestibular tumors (<1.5 mm) that are completely intracanalicular can often be completely resected, with preservation of both hearing and facial nerve function. Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [ Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [ Malignant transformation is a possible (though not common) sequela [ More recently, targeted therapy with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ There is some promise with targeted therapy with the tyrosine kinase inhibitor brigatinib [ Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. A cervical spine MRI should be performed before cranial surgery to prevent complications from manipulation under anesthesia [ Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral MRI should be performed before regional analgesia is given [ Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [ Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [ Lipreading skills may be enhanced by instruction. Sign language may often be more effectively acquired before the individual loses hearing. Hearing aids may be helpful early in the course of the disease [ Auditory habilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [ • Small vestibular tumors (<1.5 mm) that are completely intracanalicular can often be completely resected, with preservation of both hearing and facial nerve function. • Larger tumors are probably best managed expectantly, with debulking or decompression carried out only when brain stem compression, deterioration of hearing, and/or facial nerve dysfunction occur [ • Stereotactic radiosurgery, most commonly with the gamma knife, has been offered as an alternative to surgery in select individuals with vestibular schwannoma. However, the outcomes from radiation treatment in individuals with NF2 are not as good as for individuals with sporadic unilateral vestibular schwannoma, with only approximately 60% long-term tumor control [ • Malignant transformation is a possible (though not common) sequela [ • More recently, targeted therapy with the VEGF antibody bevacizumab has shown promise in the treatment of rapidly growing vestibular schwannomas, with some individuals regaining hearing [ • There is some promise with targeted therapy with the tyrosine kinase inhibitor brigatinib [ • Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. • A cervical spine MRI should be performed before cranial surgery to prevent complications from manipulation under anesthesia [ • Spinal tumors may make epidural analgesia difficult; therefore, lumbosacral MRI should be performed before regional analgesia is given [ • Although ependymoma in individuals without NF2 is optimally treated with complete resection, and occasionally with radiotherapy and chemotherapy, it is unclear whether ependymoma in individuals with NF2 warrants aggressive management. However, bevacizumab has shown some clinical benefit in some individuals [ • Use of radiation therapy for NF2-associated tumors should be carefully considered because radiation exposure may induce, accelerate, or transform tumors in an individual (especially a child) with an inactive tumor suppressor gene [ • Lipreading skills may be enhanced by instruction. • Sign language may often be more effectively acquired before the individual loses hearing. • Hearing aids may be helpful early in the course of the disease [ • Auditory habilitation with a cochlear or brain stem implant should be discussed with those who have lost hearing [ ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in affected individuals and at-risk individuals in whom the known pathogenic variant in the family has been identified or whose genetic status cannot be clarified by molecular genetic testing, the evaluations summarized in Recommended Surveillance for Individuals with BAER = brain stem auditory evoked response; NF2 = Annual brain MRI can start at an older age in individuals from families in which the onset of tumors is known to be later [ It is not clear if earlier surveillance (e.g., brain MRI before age 10 years) is beneficial, and it is not known at what age surveillance by brain MRI can be safely stopped. May be useful in detecting changes in auditory nerve function before changes can be visualized by brain MRI. ## Agents/Circumstances to Avoid Radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher [ ## Evaluation of Relatives at Risk Once the germline See ## Pregnancy Management Although there is no convincing evidence that schwannomas increase in size during pregnancy, hormonal effects on meningiomas are possible; therefore, assessment of the potential risk of increased intracranial pressure is important for women considering pregnancy. ## Therapies Under Investigation Search ## Genetic Counseling Approximately 50% of individuals diagnosed with NF2 have an affected parent. While there is a strong genotype-phenotype correlation, significant variability within families and even between identical twins can be seen. Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a As many as 25% to 50% of individuals with a If the proband is the only family member known to have NF2 and molecular genetic testing does not suggest that the The proband has The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. The incidence of pure germline mosaicism in NF2 is extremely low, as thus far all parents having more than one affected child have had a detectable pathogenic variant in Because the age of onset of symptoms is typically consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents. The family history of some individuals diagnosed with NF2 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless the proband has mosaic NF2 or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the germline If the proband has a known germline If the proband has a known germline If the proband has mosaic NF2, it is presumed that the parents do not have the If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. If the proband is the only affected individual in the family: The proband may have a The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ See Management, Predictive testing for at-risk asymptomatic family members requires prior identification of the germline Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Approximately 50% of individuals diagnosed with NF2 have an affected parent. While there is a strong genotype-phenotype correlation, significant variability within families and even between identical twins can be seen. • Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a • As many as 25% to 50% of individuals with a • If the proband is the only family member known to have NF2 and molecular genetic testing does not suggest that the • The proband has • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The incidence of pure germline mosaicism in NF2 is extremely low, as thus far all parents having more than one affected child have had a detectable pathogenic variant in • Because the age of onset of symptoms is typically consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents. • The family history of some individuals diagnosed with NF2 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless the proband has mosaic NF2 or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the germline • If the proband has a known germline • If the proband has a known germline • If the proband has mosaic NF2, it is presumed that the parents do not have the • If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. • If the proband is the only affected individual in the family: • The proband may have a • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. • Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ • The proband may have a • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. • Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ • The proband may have a • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. • Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ • Predictive testing for at-risk asymptomatic family members requires prior identification of the germline • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Approximately 50% of individuals diagnosed with NF2 have an affected parent. While there is a strong genotype-phenotype correlation, significant variability within families and even between identical twins can be seen. Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a As many as 25% to 50% of individuals with a If the proband is the only family member known to have NF2 and molecular genetic testing does not suggest that the The proband has The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. The incidence of pure germline mosaicism in NF2 is extremely low, as thus far all parents having more than one affected child have had a detectable pathogenic variant in Because the age of onset of symptoms is typically consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents. The family history of some individuals diagnosed with NF2 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless the proband has mosaic NF2 or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the germline If the proband has a known germline If the proband has a known germline If the proband has mosaic NF2, it is presumed that the parents do not have the If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. If the proband is the only affected individual in the family: The proband may have a The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ • Approximately 50% of individuals diagnosed with NF2 have an affected parent. While there is a strong genotype-phenotype correlation, significant variability within families and even between identical twins can be seen. • Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a • As many as 25% to 50% of individuals with a • If the proband is the only family member known to have NF2 and molecular genetic testing does not suggest that the • The proband has • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The incidence of pure germline mosaicism in NF2 is extremely low, as thus far all parents having more than one affected child have had a detectable pathogenic variant in • Because the age of onset of symptoms is typically consistent within families, it is usually not necessary to offer surveillance to asymptomatic parents. • The family history of some individuals diagnosed with NF2 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless the proband has mosaic NF2 or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the germline • If the proband has a known germline • If the proband has a known germline • If the proband has mosaic NF2, it is presumed that the parents do not have the • If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. • If the proband is the only affected individual in the family: • The proband may have a • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. • Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ • The proband may have a • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. • Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ • The proband may have a • The proband may have somatic mosaicism for the pathogenic variant. Offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the pathogenic variant. • Persons with somatic mosaicism and bilateral vestibular tumors have a less than 50% chance of having an affected child [ ## Related Genetic Counseling Issues See Management, Predictive testing for at-risk asymptomatic family members requires prior identification of the germline Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk asymptomatic family members requires prior identification of the germline • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • Because early detection of at-risk individuals affects medical management, testing of at-risk asymptomatic individuals younger than age 18 years is beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Children’s Tumor Foundation • • • • • • • • United Kingdom • • • • • • • • • • Children’s Tumor Foundation • ## Molecular Genetics NF2-Related Schwannomatosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NF2-Related Schwannomatosis ( Abnormal merlin is caused by either somatic or constitutional ## Molecular Pathogenesis Abnormal merlin is caused by either somatic or constitutional ## Chapter Notes Professor D Gareth Evans ( Contact Dr Miriam J Smith ( The author would like to thank Dr Andrew J Wallace and Dr Miriam J Smith for their enormous help in characterizing the molecular pathology of NF2-related schwannomatosis and Dr Scott Plotkin for driving (with Dr Evans) the name change to D Gareth Evans, MD, FRCP (2004-present)Mia MacCollin, MD; Harvard Medical School (1998-2004) 20 April 2023 (sw) Comprehensive update posted live 15 March 2018 (ha) Comprehensive update posted live 18 August 2011 (me) Comprehensive update posted live 19 May 2009 (me) Comprehensive update posted live 6 June 2006 (me) Comprehensive update posted live 6 April 2004 (me) Comprehensive update posted live 29 October 2001 (me) Comprehensive update posted live 14 October 1998 (pb) Review posted live 5 August 1998 (mm) Original submission • 20 April 2023 (sw) Comprehensive update posted live • 15 March 2018 (ha) Comprehensive update posted live • 18 August 2011 (me) Comprehensive update posted live • 19 May 2009 (me) Comprehensive update posted live • 6 June 2006 (me) Comprehensive update posted live • 6 April 2004 (me) Comprehensive update posted live • 29 October 2001 (me) Comprehensive update posted live • 14 October 1998 (pb) Review posted live • 5 August 1998 (mm) Original submission ## Author Notes Professor D Gareth Evans ( Contact Dr Miriam J Smith ( ## Acknowledgments The author would like to thank Dr Andrew J Wallace and Dr Miriam J Smith for their enormous help in characterizing the molecular pathology of NF2-related schwannomatosis and Dr Scott Plotkin for driving (with Dr Evans) the name change to ## Author History D Gareth Evans, MD, FRCP (2004-present)Mia MacCollin, MD; Harvard Medical School (1998-2004) ## Revision History 20 April 2023 (sw) Comprehensive update posted live 15 March 2018 (ha) Comprehensive update posted live 18 August 2011 (me) Comprehensive update posted live 19 May 2009 (me) Comprehensive update posted live 6 June 2006 (me) Comprehensive update posted live 6 April 2004 (me) Comprehensive update posted live 29 October 2001 (me) Comprehensive update posted live 14 October 1998 (pb) Review posted live 5 August 1998 (mm) Original submission • 20 April 2023 (sw) Comprehensive update posted live • 15 March 2018 (ha) Comprehensive update posted live • 18 August 2011 (me) Comprehensive update posted live • 19 May 2009 (me) Comprehensive update posted live • 6 June 2006 (me) Comprehensive update posted live • 6 April 2004 (me) Comprehensive update posted live • 29 October 2001 (me) Comprehensive update posted live • 14 October 1998 (pb) Review posted live • 5 August 1998 (mm) Original submission ## Key Sections in this ## References ## Literature Cited The position of pathogenic variants in A. The Kaplan-Meier plot shows the risk of meningioma within each functional domain. Gene regions are divided into exons 1-3, 4-6, 7-9, 10-13, and 14-15. B. The bar graph shows the overall risk for meningioma conferred by pathogenic variants in individual exons. 5' regions confer a higher risk than 3' regions, and exons encoding the junctions between functional domains confer a higher relative risk than the rest of the domain.	[]	14/10/1998	20/4/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nfia-dis	nfia-dis	[ "NFIA Haploinsufficiency", "NFIA Haploinsufficiency", "Nuclear factor 1 A-type", "NFIA", "NFIA-Related Disorder" ]		T Niroshini Senaratne, Fabiola Quintero-Rivera	Summary For the purposes of this chapter, The diagnosis of	## Diagnosis An Macrocephaly Seizures including: Generalized tonic-clonic Pseudo-seizures Nonspecific seizure disorders Hypotonia (generalized/neonatal) Developmental delay Frequent urinary tract infections Nonspecific dysmorphic features (See Other, less common findings, including eye abnormalities (e.g., strabismus) or cutis marmorata Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum Ventriculomegaly (typically non-progressive) Hydrocephalus Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage Vesicoureteral reflux Hydronephrosis Renal cysts The diagnosis of Heterozygous intragenic Heterozygous deletion of the 1p31.3 region that includes part or all of Chromosome translocation / other rearrangement with a 1p31.3 breakpoint that disrupts Note: (1) Molecular testing by CMA or karyotyping may detect a large and/or complex heterozygous rearrangement that inactivates Molecular genetic testing approaches can include a combination of If not already performed, For an introduction to multigene panels click More comprehensive genomic testing (when available) including For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The number of probands is 13; some probands have other affected family members. The total number of individuals reported with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Intragenic deletions that affect one or multiple exons within NFIA but disrupt no other genes have been identified in five probands [ Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use typically cover the 1p31.3 region. Karyotype can detect balanced chromosome rearrangements that are not detectable through chromosomal microarray analysis. Chromosome rearrangements, including translocations and inversions, which disrupt Note: For • Macrocephaly • Seizures including: • Generalized tonic-clonic • Pseudo-seizures • Nonspecific seizure disorders • Generalized tonic-clonic • Pseudo-seizures • Nonspecific seizure disorders • Hypotonia (generalized/neonatal) • Developmental delay • Frequent urinary tract infections • Nonspecific dysmorphic features (See • Other, less common findings, including eye abnormalities (e.g., strabismus) or cutis marmorata • Generalized tonic-clonic • Pseudo-seizures • Nonspecific seizure disorders • • Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum • Ventriculomegaly (typically non-progressive) • Hydrocephalus • Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage • Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum • Ventriculomegaly (typically non-progressive) • Hydrocephalus • Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage • • Vesicoureteral reflux • Hydronephrosis • Renal cysts • Vesicoureteral reflux • Hydronephrosis • Renal cysts • Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum • Ventriculomegaly (typically non-progressive) • Hydrocephalus • Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage • Vesicoureteral reflux • Hydronephrosis • Renal cysts • Heterozygous intragenic • Heterozygous deletion of the 1p31.3 region that includes part or all of • Chromosome translocation / other rearrangement with a 1p31.3 breakpoint that disrupts • If not already performed, • For an introduction to multigene panels click • More comprehensive genomic testing (when available) including • For an introduction to comprehensive genomic testing click ## Suggestive Findings An Macrocephaly Seizures including: Generalized tonic-clonic Pseudo-seizures Nonspecific seizure disorders Hypotonia (generalized/neonatal) Developmental delay Frequent urinary tract infections Nonspecific dysmorphic features (See Other, less common findings, including eye abnormalities (e.g., strabismus) or cutis marmorata Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum Ventriculomegaly (typically non-progressive) Hydrocephalus Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage Vesicoureteral reflux Hydronephrosis Renal cysts • Macrocephaly • Seizures including: • Generalized tonic-clonic • Pseudo-seizures • Nonspecific seizure disorders • Generalized tonic-clonic • Pseudo-seizures • Nonspecific seizure disorders • Hypotonia (generalized/neonatal) • Developmental delay • Frequent urinary tract infections • Nonspecific dysmorphic features (See • Other, less common findings, including eye abnormalities (e.g., strabismus) or cutis marmorata • Generalized tonic-clonic • Pseudo-seizures • Nonspecific seizure disorders • • Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum • Ventriculomegaly (typically non-progressive) • Hydrocephalus • Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage • Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum • Ventriculomegaly (typically non-progressive) • Hydrocephalus • Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage • • Vesicoureteral reflux • Hydronephrosis • Renal cysts • Vesicoureteral reflux • Hydronephrosis • Renal cysts • Abnormalities of the corpus callosum including agenesis or hypoplasia of the corpus callosum • Ventriculomegaly (typically non-progressive) • Hydrocephalus • Less commonly, Chiari type I malformation and/or subarachnoid hemorrhage • Vesicoureteral reflux • Hydronephrosis • Renal cysts ## Establishing the Diagnosis The diagnosis of Heterozygous intragenic Heterozygous deletion of the 1p31.3 region that includes part or all of Chromosome translocation / other rearrangement with a 1p31.3 breakpoint that disrupts Note: (1) Molecular testing by CMA or karyotyping may detect a large and/or complex heterozygous rearrangement that inactivates Molecular genetic testing approaches can include a combination of If not already performed, For an introduction to multigene panels click More comprehensive genomic testing (when available) including For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The number of probands is 13; some probands have other affected family members. The total number of individuals reported with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Intragenic deletions that affect one or multiple exons within NFIA but disrupt no other genes have been identified in five probands [ Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use typically cover the 1p31.3 region. Karyotype can detect balanced chromosome rearrangements that are not detectable through chromosomal microarray analysis. Chromosome rearrangements, including translocations and inversions, which disrupt Note: For • Heterozygous intragenic • Heterozygous deletion of the 1p31.3 region that includes part or all of • Chromosome translocation / other rearrangement with a 1p31.3 breakpoint that disrupts • If not already performed, • For an introduction to multigene panels click • More comprehensive genomic testing (when available) including • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Note: Cutis marmorata has been described in multiple individuals with deletions that include No genotype-phenotype correlations have been identified to date, with the exception of individuals who have larger, nonrecurrent 1p31.3 deletions that include Early reports that identified deletions affecting ## Clinical Description Note: Cutis marmorata has been described in multiple individuals with deletions that include ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified to date, with the exception of individuals who have larger, nonrecurrent 1p31.3 deletions that include ## Nomenclature Early reports that identified deletions affecting ## Prevalence ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Macrocephaly Ventriculomegaly DD Brain malformations incl partial-to-complete agenesis of corpus callosum No urinary tract defects Sotos syndrome typically includes distinctive facial appearance & overgrowth. Macrocephaly DD Minor dysmorphic features Brain malformations incl dysgenesis of corpus callosum Neurodevelopmental phenotypes Macrocephaly Ventriculomegaly DD Brain malformations incl hypoplasia of corpus callosum Ventriculomegaly w/seizures in some affected individuals Agenesis of corpus callosum Hydrocephalus Kidney disease Typically more severe than Characteristic MRI findings ("molar tooth sign") Eye abnormalities Hydrocephalus Agenesis of corpus callosum Renal abnormalities incl hydronephrosis Typically more severe than Intestinal atresia Ocular abnormalities Microcephaly Cardiac involvement AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance Because Sotos syndrome and Malan syndrome have overlapping features, Sotos syndrome is sometimes referred to as Sotos syndrome 1. Malan syndrome is also referred to as Sotos syndrome 2. • Macrocephaly • Ventriculomegaly • DD • Brain malformations incl partial-to-complete agenesis of corpus callosum • No urinary tract defects • Sotos syndrome typically includes distinctive facial appearance & overgrowth. • Macrocephaly • DD • Minor dysmorphic features • Brain malformations incl dysgenesis of corpus callosum • Neurodevelopmental phenotypes • Macrocephaly • Ventriculomegaly • DD • Brain malformations incl hypoplasia of corpus callosum • Ventriculomegaly w/seizures in some affected individuals • Agenesis of corpus callosum • Hydrocephalus • Kidney disease • Typically more severe than • Characteristic MRI findings ("molar tooth sign") • Eye abnormalities • Hydrocephalus • Agenesis of corpus callosum • Renal abnormalities incl hydronephrosis • Typically more severe than • Intestinal atresia • Ocular abnormalities • Microcephaly • Cardiac involvement ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder The choice of imaging depends on the age of the affected individuals. In infants age 3 months, typically spinal MRI is required. Treatment of Manifestations in Individuals with NFIA-Related Disorder ASM = anti-seizure medication The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Following initial evaluation, affected individuals should be followed by the appropriate specialists (e.g., neurologist, urologist, and/or clinical geneticist) as needed based on their particular features. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the genetic alteration identified in the proband in order to identify as early as possible those who would benefit from prompt initiation of treatment. See Search • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder The choice of imaging depends on the age of the affected individuals. In infants age 3 months, typically spinal MRI is required. ## Treatment of Manifestations Treatment of Manifestations in Individuals with NFIA-Related Disorder ASM = anti-seizure medication The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. ## Surveillance Following initial evaluation, affected individuals should be followed by the appropriate specialists (e.g., neurologist, urologist, and/or clinical geneticist) as needed based on their particular features. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the genetic alteration identified in the proband in order to identify as early as possible those who would benefit from prompt initiation of treatment. See ## Therapies Under Investigation Search ## Genetic Counseling The majority of individuals diagnosed with Approximately 20%-25% of reported individuals inherited an Recommendations for the evaluation of parents of an individual with If the genetic alteration identified in the proband cannot be detected in either parent, the most likely explanation is that the genetic alteration is If a parent of the proband has the genetic alteration identified in the proband, the risk to the sibs is 50%. However, the disorder is known to have variable expressivity; i.e., a sib who inherits the same genetic alteration may not have the same manifestation of the phenotype as the proband. Intrafamilial variation of the phenotype for the same genetic variant has been reported [ If a parent of the proband has a chromosome translocation, recurrence risk to sibs depends on the specific structural variant. If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism. Parental germline mosaicism for Each child of an individual with an Risk to offspring of an individual with a chromosome translocation depends on the specific structural variant. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child. • The majority of individuals diagnosed with • Approximately 20%-25% of reported individuals inherited an • Recommendations for the evaluation of parents of an individual with • If the genetic alteration identified in the proband cannot be detected in either parent, the most likely explanation is that the genetic alteration is • If a parent of the proband has the genetic alteration identified in the proband, the risk to the sibs is 50%. However, the disorder is known to have variable expressivity; i.e., a sib who inherits the same genetic alteration may not have the same manifestation of the phenotype as the proband. Intrafamilial variation of the phenotype for the same genetic variant has been reported [ • If a parent of the proband has a chromosome translocation, recurrence risk to sibs depends on the specific structural variant. • If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism. Parental germline mosaicism for • Each child of an individual with an • Risk to offspring of an individual with a chromosome translocation depends on the specific structural variant. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child. ## Mode of Inheritance ## Risk to Family Members The majority of individuals diagnosed with Approximately 20%-25% of reported individuals inherited an Recommendations for the evaluation of parents of an individual with If the genetic alteration identified in the proband cannot be detected in either parent, the most likely explanation is that the genetic alteration is If a parent of the proband has the genetic alteration identified in the proband, the risk to the sibs is 50%. However, the disorder is known to have variable expressivity; i.e., a sib who inherits the same genetic alteration may not have the same manifestation of the phenotype as the proband. Intrafamilial variation of the phenotype for the same genetic variant has been reported [ If a parent of the proband has a chromosome translocation, recurrence risk to sibs depends on the specific structural variant. If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism. Parental germline mosaicism for Each child of an individual with an Risk to offspring of an individual with a chromosome translocation depends on the specific structural variant. • The majority of individuals diagnosed with • Approximately 20%-25% of reported individuals inherited an • Recommendations for the evaluation of parents of an individual with • If the genetic alteration identified in the proband cannot be detected in either parent, the most likely explanation is that the genetic alteration is • If a parent of the proband has the genetic alteration identified in the proband, the risk to the sibs is 50%. However, the disorder is known to have variable expressivity; i.e., a sib who inherits the same genetic alteration may not have the same manifestation of the phenotype as the proband. Intrafamilial variation of the phenotype for the same genetic variant has been reported [ • If a parent of the proband has a chromosome translocation, recurrence risk to sibs depends on the specific structural variant. • If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism. Parental germline mosaicism for • Each child of an individual with an • Risk to offspring of an individual with a chromosome translocation depends on the specific structural variant. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child. ## Prenatal Testing and Preimplantation Genetic Testing ## Resources No specific resources for ## Molecular Genetics NFIA-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NFIA-Related Disorder ( Numerous sporadic tumors (e.g., glioblastoma) occurring as single tumors in the absence of any other findings of ## Cancer and Benign Tumors Numerous sporadic tumors (e.g., glioblastoma) occurring as single tumors in the absence of any other findings of ## Chapter Notes Fabiola Quintero-Rivera, MD 13 June 2019 (ma) Review posted live 2 March 2018 (fqr) Original submission • 13 June 2019 (ma) Review posted live • 2 March 2018 (fqr) Original submission ## Author Notes Fabiola Quintero-Rivera, MD ## Revision History 13 June 2019 (ma) Review posted live 2 March 2018 (fqr) Original submission • 13 June 2019 (ma) Review posted live • 2 March 2018 (fqr) Original submission ## References ## Literature Cited	[]	13/6/2019			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nfix-malan	nfix-malan	[ "Sotos-Like Syndrome", "Sotos Syndrome 2", "Sotos-Like Syndrome", "Sotos Syndrome 2", "Nuclear factor 1 X-type", "NFIX", "NFIX-Related Malan Syndrome" ]		Manuela Priolo	Summary The diagnosis of MALNS is established in a proband with suggestive findings and either a heterozygous pathogenic variant in MALNS is an autosomal dominant disorder typically caused by a	## Diagnosis No consensus clinical diagnostic criteria for MALNS Prenatal overgrowth, often with a diagnosis of being large for gestational age Postnatal overgrowth (length/height and/or head circumference ≥2 standard deviations [SD] above mean for age and sex) Developmental delay / intellectual disability Behavioral problems Distinctive facial features (See Advanced bone age and/or skeletal anomalies, such as scoliosis, pes planus, and pectus anomaly Slender body habitus Ocular findings, most commonly strabismus, refractive errors, and blue sclerae The diagnosis of MALNS A heterozygous pathogenic (or likely pathogenic) variant in A heterozygous deletion of 19p13.2 that includes Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of MALNS, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by overgrowth and intellectual disability, comprehensive genomic testing may be considered. For an introduction to CMA click If CMA is not diagnostic, Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene. Gene-targeted deletion/duplication analysis may be useful to detect an additional 2%-5% of partial-gene deletions [M Priolo, personal observation; Sanford CoRDS patient registry for Malan syndrome]. However, it should be noted that targeted deletion/duplication analysis should also be able to detect any chromosomal deletion that includes • Prenatal overgrowth, often with a diagnosis of being large for gestational age • Postnatal overgrowth (length/height and/or head circumference ≥2 standard deviations [SD] above mean for age and sex) • Developmental delay / intellectual disability • Behavioral problems • Distinctive facial features (See • Advanced bone age and/or skeletal anomalies, such as scoliosis, pes planus, and pectus anomaly • Slender body habitus • Ocular findings, most commonly strabismus, refractive errors, and blue sclerae • A heterozygous pathogenic (or likely pathogenic) variant in • A heterozygous deletion of 19p13.2 that includes • For an introduction to multigene panels click • For an introduction to CMA click • If CMA is not diagnostic, ## Suggestive Findings MALNS Prenatal overgrowth, often with a diagnosis of being large for gestational age Postnatal overgrowth (length/height and/or head circumference ≥2 standard deviations [SD] above mean for age and sex) Developmental delay / intellectual disability Behavioral problems Distinctive facial features (See Advanced bone age and/or skeletal anomalies, such as scoliosis, pes planus, and pectus anomaly Slender body habitus Ocular findings, most commonly strabismus, refractive errors, and blue sclerae • Prenatal overgrowth, often with a diagnosis of being large for gestational age • Postnatal overgrowth (length/height and/or head circumference ≥2 standard deviations [SD] above mean for age and sex) • Developmental delay / intellectual disability • Behavioral problems • Distinctive facial features (See • Advanced bone age and/or skeletal anomalies, such as scoliosis, pes planus, and pectus anomaly • Slender body habitus • Ocular findings, most commonly strabismus, refractive errors, and blue sclerae ## Establishing the Diagnosis The diagnosis of MALNS A heterozygous pathogenic (or likely pathogenic) variant in A heterozygous deletion of 19p13.2 that includes Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of MALNS, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by overgrowth and intellectual disability, comprehensive genomic testing may be considered. For an introduction to CMA click If CMA is not diagnostic, Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene. Gene-targeted deletion/duplication analysis may be useful to detect an additional 2%-5% of partial-gene deletions [M Priolo, personal observation; Sanford CoRDS patient registry for Malan syndrome]. However, it should be noted that targeted deletion/duplication analysis should also be able to detect any chromosomal deletion that includes • A heterozygous pathogenic (or likely pathogenic) variant in • A heterozygous deletion of 19p13.2 that includes • For an introduction to multigene panels click • For an introduction to CMA click • If CMA is not diagnostic, ## Option 1 When the phenotypic findings suggest the diagnosis of MALNS, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by overgrowth and intellectual disability, comprehensive genomic testing may be considered. For an introduction to CMA click If CMA is not diagnostic, Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene. Gene-targeted deletion/duplication analysis may be useful to detect an additional 2%-5% of partial-gene deletions [M Priolo, personal observation; Sanford CoRDS patient registry for Malan syndrome]. However, it should be noted that targeted deletion/duplication analysis should also be able to detect any chromosomal deletion that includes • For an introduction to CMA click • If CMA is not diagnostic, ## Clinical Characteristics Adapted from BMI = body mass index; CHD = congenital heart defects; SD = standard deviations Percentages refer to individuals with a pathogenic variant in When a fraction is specified, the percentage refers to a specific cohort of affected individuals who underwent a deep phenotyping analysis by an experienced team [ Low-grade mitral valve regurgitation has been recorded in at least one third of individuals. However, this data should be considered a minor anomaly and not sufficient to classify MALNS as a condition predisposing to cardiovascular disease and/or heart anomalies. Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. At least 77% of adults maintain a head circumference >2 SD above the mean for sex. About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. About one third of affected individuals’ final adult height is >2 SD above the mean [ Typically, affected individuals show both low cognitive and adaptive functioning, with communication skills being the most affected. The level of intellectual impairment generally remains stable throughout life. A dedicated diagnostic battery of tests has been proposed to carefully assess the impairment in different domains (for a full review of the battery of tests recommended, see Aadaptive functioning is usually lower than normal, generally ranging from moderately to severely impaired, with communication skills the most affected. Verbal language skills are usually the most severely impacted, with receptive language more preserved than expressive language [ The same signs, sometimes associated with gait disturbances (e.g., broad-based gait, toe-walking), have also been occasionally described in affected individuals with Chiari I malformations, but they may be also observed in individuals with MALNS who do not have Chiari I malformations. For this reason, individuals with MALNS should be first assessed for Chiari I malformations through neuorimaging and then for other causes (e.g., cardiac/otologic evaluation) of these nonspecific symptoms. The most prevalent psychiatric comorbidities include generalized anxiety disorder; separation anxiety with specific phobias; attention-deficit/hyperactivity disorder; and behavioral issues (e.g., impaired socialization) that may resemble those of individuals with autism but are different from classic autistic behavior. Some affected individuals may be given a clinical diagnosis of an autism spectrum disorder primarily because of their expressive language difficulties. However, most affected individuals do not have true impairment in social interactions outside of their deficient communication skills [ Additional neuropsychiatric hallmarks include difficulty with visuomotor integration; hypersensitivity to visual and auditory stimuli (noise hypersensitivity and photophobia), both of which may contribute to psychopathology; and challenging behaviors with panic crises and, rarely, outbursts of hetero-aggression and self-injurious behavior. Slender body habitus (almost all individuals) Advanced bone age (at least 76%) Scoliosis (75%) Hyperkyphosis or hyperlordosis (~30%) Pes planus (69%) Pectus anomaly (excavatum, carinatum, or mixed) (63%) Long bone fracture Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D Nystagmus (31%) Polar posterior cataract (13%) Optic nerve hypoplasia and optic disk pallor (25%) Different degrees of constipation, sometimes requiring pharmacologic therapy (see Based on the number of known affected individuals, the prevalence of • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. • At least 77% of adults maintain a head circumference >2 SD above the mean for sex. • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. • At least 77% of adults maintain a head circumference >2 SD above the mean for sex. • • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. • About one third of affected individuals’ final adult height is >2 SD above the mean [ • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. • About one third of affected individuals’ final adult height is >2 SD above the mean [ • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. • At least 77% of adults maintain a head circumference >2 SD above the mean for sex. • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. • About one third of affected individuals’ final adult height is >2 SD above the mean [ • Typically, affected individuals show both low cognitive and adaptive functioning, with communication skills being the most affected. • The level of intellectual impairment generally remains stable throughout life. • A dedicated diagnostic battery of tests has been proposed to carefully assess the impairment in different domains (for a full review of the battery of tests recommended, see • Aadaptive functioning is usually lower than normal, generally ranging from moderately to severely impaired, with communication skills the most affected. • Verbal language skills are usually the most severely impacted, with receptive language more preserved than expressive language [ • The same signs, sometimes associated with gait disturbances (e.g., broad-based gait, toe-walking), have also been occasionally described in affected individuals with Chiari I malformations, but they may be also observed in individuals with MALNS who do not have Chiari I malformations. For this reason, individuals with MALNS should be first assessed for Chiari I malformations through neuorimaging and then for other causes (e.g., cardiac/otologic evaluation) of these nonspecific symptoms. • Slender body habitus (almost all individuals) • Advanced bone age (at least 76%) • Scoliosis (75%) • Hyperkyphosis or hyperlordosis (~30%) • Pes planus (69%) • Pectus anomaly (excavatum, carinatum, or mixed) (63%) • Long bone fracture • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D • Nystagmus (31%) • Polar posterior cataract (13%) • Optic nerve hypoplasia and optic disk pallor (25%) ## Clinical Description Adapted from BMI = body mass index; CHD = congenital heart defects; SD = standard deviations Percentages refer to individuals with a pathogenic variant in When a fraction is specified, the percentage refers to a specific cohort of affected individuals who underwent a deep phenotyping analysis by an experienced team [ Low-grade mitral valve regurgitation has been recorded in at least one third of individuals. However, this data should be considered a minor anomaly and not sufficient to classify MALNS as a condition predisposing to cardiovascular disease and/or heart anomalies. Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. At least 77% of adults maintain a head circumference >2 SD above the mean for sex. About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. About one third of affected individuals’ final adult height is >2 SD above the mean [ Typically, affected individuals show both low cognitive and adaptive functioning, with communication skills being the most affected. The level of intellectual impairment generally remains stable throughout life. A dedicated diagnostic battery of tests has been proposed to carefully assess the impairment in different domains (for a full review of the battery of tests recommended, see Aadaptive functioning is usually lower than normal, generally ranging from moderately to severely impaired, with communication skills the most affected. Verbal language skills are usually the most severely impacted, with receptive language more preserved than expressive language [ The same signs, sometimes associated with gait disturbances (e.g., broad-based gait, toe-walking), have also been occasionally described in affected individuals with Chiari I malformations, but they may be also observed in individuals with MALNS who do not have Chiari I malformations. For this reason, individuals with MALNS should be first assessed for Chiari I malformations through neuorimaging and then for other causes (e.g., cardiac/otologic evaluation) of these nonspecific symptoms. The most prevalent psychiatric comorbidities include generalized anxiety disorder; separation anxiety with specific phobias; attention-deficit/hyperactivity disorder; and behavioral issues (e.g., impaired socialization) that may resemble those of individuals with autism but are different from classic autistic behavior. Some affected individuals may be given a clinical diagnosis of an autism spectrum disorder primarily because of their expressive language difficulties. However, most affected individuals do not have true impairment in social interactions outside of their deficient communication skills [ Additional neuropsychiatric hallmarks include difficulty with visuomotor integration; hypersensitivity to visual and auditory stimuli (noise hypersensitivity and photophobia), both of which may contribute to psychopathology; and challenging behaviors with panic crises and, rarely, outbursts of hetero-aggression and self-injurious behavior. Slender body habitus (almost all individuals) Advanced bone age (at least 76%) Scoliosis (75%) Hyperkyphosis or hyperlordosis (~30%) Pes planus (69%) Pectus anomaly (excavatum, carinatum, or mixed) (63%) Long bone fracture Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D Nystagmus (31%) Polar posterior cataract (13%) Optic nerve hypoplasia and optic disk pallor (25%) Different degrees of constipation, sometimes requiring pharmacologic therapy (see • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. • At least 77% of adults maintain a head circumference >2 SD above the mean for sex. • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. • At least 77% of adults maintain a head circumference >2 SD above the mean for sex. • • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. • About one third of affected individuals’ final adult height is >2 SD above the mean [ • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. • About one third of affected individuals’ final adult height is >2 SD above the mean [ • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex. • At least 77% of adults maintain a head circumference >2 SD above the mean for sex. • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns. • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals. • About one third of affected individuals’ final adult height is >2 SD above the mean [ • Typically, affected individuals show both low cognitive and adaptive functioning, with communication skills being the most affected. • The level of intellectual impairment generally remains stable throughout life. • A dedicated diagnostic battery of tests has been proposed to carefully assess the impairment in different domains (for a full review of the battery of tests recommended, see • Aadaptive functioning is usually lower than normal, generally ranging from moderately to severely impaired, with communication skills the most affected. • Verbal language skills are usually the most severely impacted, with receptive language more preserved than expressive language [ • The same signs, sometimes associated with gait disturbances (e.g., broad-based gait, toe-walking), have also been occasionally described in affected individuals with Chiari I malformations, but they may be also observed in individuals with MALNS who do not have Chiari I malformations. For this reason, individuals with MALNS should be first assessed for Chiari I malformations through neuorimaging and then for other causes (e.g., cardiac/otologic evaluation) of these nonspecific symptoms. • Slender body habitus (almost all individuals) • Advanced bone age (at least 76%) • Scoliosis (75%) • Hyperkyphosis or hyperlordosis (~30%) • Pes planus (69%) • Pectus anomaly (excavatum, carinatum, or mixed) (63%) • Long bone fracture • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [ • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D • Nystagmus (31%) • Polar posterior cataract (13%) • Optic nerve hypoplasia and optic disk pallor (25%) ## Genotype-Phenotype Correlations ## Nomenclature ## Prevalence Based on the number of known affected individuals, the prevalence of ## Genetically Related (Allelic) Disorders Heterozygous pathogenic variants in Typically, truncating pathogenic variants affecting exons 6-10 of ## Differential Diagnosis See Genes of Interest in the Differential Diagnosis of Generalized prenatal & postnatal overgrowth Macrocephaly, long philtrum, retrognathia (usually resolves w/age), & prominent chin crease Round face, increased bifrontal diameter Flattened occipitus Generalized prenatal & postnatal overgrowth Macrocephaly Hypertelorism, downslanting palpebral fissures Hypotonia Agenesis of corpus callosum, enlargement of cerebral ventricles Distinctive facial features more resembling Weaver syndrome Although large hands & feet have been reported, arachnodactyly has not been described. Scoliosis Ligamentous hyperlaxity Neonatal hypotonia Generalized prenatal & postnatal overgrowth Macrocephaly Long face, downslanting palpebral fissures, pointed chin Speech delay Anxiety disorder, behavioral difficulties incl ASD &/or outbursts of aggression Chiari I malformation, ventriculomegaly Malar hypoplasia Hyperphagia Seizures are reported more frequently than in MALNS. Marfanoid habitus, pectus excavatum, long fingers High-arched palate, prominent forehead, long face Macrocephaly Ascending aortic aneurysm Behavioral manifestations (Affected persons are commonly hyperactive, aggressive, shy, & attention seeking.) Low-set ears, long nose, high & narrow nasal bridge Seizures are reported more frequently than in MALNS. Marfanoid habitus, kyphoscoliosis, pectus excavatum/carinatum, arachnodactyly High-arched palate Psychiatric problems incl personality disorder, anxiety, depression, obsessive-compulsive behavior, & psychotic episodes Ectopia lentis, glaucoma Thromboembolism Seizures are reported more frequently than in MALNS. Homocystinuria, methioninuria, cystathionine beta-synthase deficiency Marfanoid habitus, pectus excavatum/carinatum, kyphoscoliosis, arachnodactyly High, narrow palate Multiple fractures Facial asymmetry, asymmetric dysplastic ears Short, webbed neck Seizures are reported more frequently than in MALNS. Marfanoid habitus, pectus excavatum/carinatum, kyphoscoliosis, arachnodactyly High-arched palate, downslanting palpebral fissures ↓ subcutaneous fat Ectopia lentis, retinal detachment, glaucoma Aortic root dilatation/aneurism/dissection No DD/ID AD = autosomal dominant; AR= autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MALNS = Rows are ordered by degree of phenotypic overlap with MALNS; disorders with the most phenotypic overlap are listed first. In addition to DD/ID (with the exception of Many affected individuals have a • Generalized prenatal & postnatal overgrowth • Macrocephaly, long philtrum, retrognathia (usually resolves w/age), & prominent chin crease • Round face, increased bifrontal diameter • Flattened occipitus • Generalized prenatal & postnatal overgrowth • Macrocephaly • Hypertelorism, downslanting palpebral fissures • Hypotonia • Agenesis of corpus callosum, enlargement of cerebral ventricles • Distinctive facial features more resembling Weaver syndrome • Although large hands & feet have been reported, arachnodactyly has not been described. • Scoliosis • Ligamentous hyperlaxity • Neonatal hypotonia • Generalized prenatal & postnatal overgrowth • Macrocephaly • Long face, downslanting palpebral fissures, pointed chin • Speech delay • Anxiety disorder, behavioral difficulties incl ASD &/or outbursts of aggression • Chiari I malformation, ventriculomegaly • Malar hypoplasia • Hyperphagia • Seizures are reported more frequently than in MALNS. • Marfanoid habitus, pectus excavatum, long fingers • High-arched palate, prominent forehead, long face • Macrocephaly • Ascending aortic aneurysm • Behavioral manifestations (Affected persons are commonly hyperactive, aggressive, shy, & attention seeking.) • Low-set ears, long nose, high & narrow nasal bridge • Seizures are reported more frequently than in MALNS. • Marfanoid habitus, kyphoscoliosis, pectus excavatum/carinatum, arachnodactyly • High-arched palate • Psychiatric problems incl personality disorder, anxiety, depression, obsessive-compulsive behavior, & psychotic episodes • Ectopia lentis, glaucoma • Thromboembolism • Seizures are reported more frequently than in MALNS. • Homocystinuria, methioninuria, cystathionine beta-synthase deficiency • Marfanoid habitus, pectus excavatum/carinatum, kyphoscoliosis, arachnodactyly • High, narrow palate • Multiple fractures • Facial asymmetry, asymmetric dysplastic ears • Short, webbed neck • Seizures are reported more frequently than in MALNS. • Marfanoid habitus, pectus excavatum/carinatum, kyphoscoliosis, arachnodactyly • High-arched palate, downslanting palpebral fissures • ↓ subcutaneous fat • Ectopia lentis, retinal detachment, glaucoma • Aortic root dilatation/aneurism/dissection • No DD/ID ## Management Suggested management and follow up recommendations for individuals with To establish the extent of disease and needs in an individual diagnosed with MALNS, the evaluations summarized in Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. If BMI is >2 SD below mean for age & sex, reevaluate appropriateness of reported caloric intake. To screen for hepatomegaly, although most hepatomegaly described to date has not been assoc w/liver dysfunction Consider abdominal ultrasound if hepatomegaly is suspected by physical exam. Consider EEG if seizures are a concern. In absence of clinical seizures, a watch & wait strategy is reasonable if EEG demonstrates nonspecific changes, esp in those w/intragenic Such as vomiting/nausea, dizziness, & fainting If present, assessment for potential causes (Chiari I malformation, cardiac, otolaryngologic) is indicated. Consider possible triggering events. Incl complete motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education services Define cognitive & adaptive behavior profile. Verify visuomotor abilities, noise hypersensitivity, & photophobia. Gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Kyphoscoliosis Pes planus Pectus excavatum/carinatum History of frequent fractures In those w/severe pectus anomalies, consider overnight pulse oximetry test. Consider baseline DXA scan around time of puberty or if person sustains multiple fractures. Consider referral to orthopedist. Consider referral to endocrinologist. To assess for refractive errors, nystagmus, strabismus, polar cataract, & optic disk pallor Consider VEP & ERG to assess conduction in visual pathway. Narrow (ogival) palate Tooth overgrowth Malocclusion Dental caries Community or Social work involvement for parental support Home nursing referral BMI = body mass index; DXA = dual-energy x-ray absorptiometry; ERG = electroretinogram; MALNS = Which may include severe headaches, neck pain, poor balance, dizziness, numbness or tingling in the hands/feet, and/or swallowing issues See Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for MALNS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Persons w/o clinical signs of seizures who have nonspecific EEG changes may not require medical therapy Cognitive behavioral therapy to treat anxiety & ADHD Standard treatment for visuomotor abilities, photophobia, & noise sensitivity Symptomatic aids (i.e., colored glasses, low voice tone) may reduce anxiety ↓. Consider introducing AAC when expressive language difficulties are a concern. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or AAC = augmentative alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Particularly in individuals with an intragenic The following information represents typical management recommendations for individuals with developmental delay /intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder (ASD), including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Cognitive behavioral therapy (CBT) has been proven effective in treating anxiety disorders, ASD, and ADHD; therefore, early initiation of CBT should be considered in those with adequate cognitive skills. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. However, any drug therapy to treat psychiatric symptoms should be weighed against the age of the affected person (child or adolescent) and the specific medical comorbidities of individuals with MALNS, with close consideration for possible current or future drug interactions that may be given to treat MALNS-specific medical issues. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in At each visit 1st BMI eval should be performed after age 2 yrs. Eval of nutritional status & safety of oral intake Assessment for signs/symptoms of constipation Monitor those w/seizures as clinically indicated. Assess for new manifestations such as changes in tone, signs/symptoms of Chari I malformation, Assess for subtle & nonspecific autonomic signs/symptoms. From age 12 mos to approximatively 36 mos: annually From age 3 yrs to adulthood: every 2 yrs Annually until puberty Periodic eval should be performed in adults to evaluate for late-onset optic nerve degeneration. BMI = body mass index; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy Those with a BMI of >2 standard deviations below the mean require reassessment of their caloric intake and the appropriateness of their food intake. Including severe headaches, neck pain, poor balance, dizziness, numbness or tingling in the hands/feet, and/or swallowing issues Individuals with a deletion that includes Such as vomiting/nausea, dizziness, and fainting See Search • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • If BMI is >2 SD below mean for age & sex, reevaluate appropriateness of reported caloric intake. • To screen for hepatomegaly, although most hepatomegaly described to date has not been assoc w/liver dysfunction • Consider abdominal ultrasound if hepatomegaly is suspected by physical exam. • Consider EEG if seizures are a concern. • In absence of clinical seizures, a watch & wait strategy is reasonable if EEG demonstrates nonspecific changes, esp in those w/intragenic • Such as vomiting/nausea, dizziness, & fainting • If present, assessment for potential causes (Chiari I malformation, cardiac, otolaryngologic) is indicated. • Consider possible triggering events. • Incl complete motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education services • Define cognitive & adaptive behavior profile. • Verify visuomotor abilities, noise hypersensitivity, & photophobia. • Gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Kyphoscoliosis • Pes planus • Pectus excavatum/carinatum • History of frequent fractures • In those w/severe pectus anomalies, consider overnight pulse oximetry test. • Consider baseline DXA scan around time of puberty or if person sustains multiple fractures. • Consider referral to orthopedist. • Consider referral to endocrinologist. • To assess for refractive errors, nystagmus, strabismus, polar cataract, & optic disk pallor • Consider VEP & ERG to assess conduction in visual pathway. • Narrow (ogival) palate • Tooth overgrowth • Malocclusion • Dental caries • Community or • Social work involvement for parental support • Home nursing referral • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Persons w/o clinical signs of seizures who have nonspecific EEG changes may not require medical therapy • Cognitive behavioral therapy to treat anxiety & ADHD • Standard treatment for visuomotor abilities, photophobia, & noise sensitivity • Symptomatic aids (i.e., colored glasses, low voice tone) may reduce anxiety ↓. • Consider introducing AAC when expressive language difficulties are a concern. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • At each visit • 1st BMI eval should be performed after age 2 yrs. • Eval of nutritional status & safety of oral intake • Assessment for signs/symptoms of constipation • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as changes in tone, signs/symptoms of Chari I malformation, • Assess for subtle & nonspecific autonomic signs/symptoms. • From age 12 mos to approximatively 36 mos: annually • From age 3 yrs to adulthood: every 2 yrs • Annually until puberty • Periodic eval should be performed in adults to evaluate for late-onset optic nerve degeneration. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MALNS, the evaluations summarized in Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. If BMI is >2 SD below mean for age & sex, reevaluate appropriateness of reported caloric intake. To screen for hepatomegaly, although most hepatomegaly described to date has not been assoc w/liver dysfunction Consider abdominal ultrasound if hepatomegaly is suspected by physical exam. Consider EEG if seizures are a concern. In absence of clinical seizures, a watch & wait strategy is reasonable if EEG demonstrates nonspecific changes, esp in those w/intragenic Such as vomiting/nausea, dizziness, & fainting If present, assessment for potential causes (Chiari I malformation, cardiac, otolaryngologic) is indicated. Consider possible triggering events. Incl complete motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education services Define cognitive & adaptive behavior profile. Verify visuomotor abilities, noise hypersensitivity, & photophobia. Gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Kyphoscoliosis Pes planus Pectus excavatum/carinatum History of frequent fractures In those w/severe pectus anomalies, consider overnight pulse oximetry test. Consider baseline DXA scan around time of puberty or if person sustains multiple fractures. Consider referral to orthopedist. Consider referral to endocrinologist. To assess for refractive errors, nystagmus, strabismus, polar cataract, & optic disk pallor Consider VEP & ERG to assess conduction in visual pathway. Narrow (ogival) palate Tooth overgrowth Malocclusion Dental caries Community or Social work involvement for parental support Home nursing referral BMI = body mass index; DXA = dual-energy x-ray absorptiometry; ERG = electroretinogram; MALNS = Which may include severe headaches, neck pain, poor balance, dizziness, numbness or tingling in the hands/feet, and/or swallowing issues See Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • If BMI is >2 SD below mean for age & sex, reevaluate appropriateness of reported caloric intake. • To screen for hepatomegaly, although most hepatomegaly described to date has not been assoc w/liver dysfunction • Consider abdominal ultrasound if hepatomegaly is suspected by physical exam. • Consider EEG if seizures are a concern. • In absence of clinical seizures, a watch & wait strategy is reasonable if EEG demonstrates nonspecific changes, esp in those w/intragenic • Such as vomiting/nausea, dizziness, & fainting • If present, assessment for potential causes (Chiari I malformation, cardiac, otolaryngologic) is indicated. • Consider possible triggering events. • Incl complete motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education services • Define cognitive & adaptive behavior profile. • Verify visuomotor abilities, noise hypersensitivity, & photophobia. • Gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Kyphoscoliosis • Pes planus • Pectus excavatum/carinatum • History of frequent fractures • In those w/severe pectus anomalies, consider overnight pulse oximetry test. • Consider baseline DXA scan around time of puberty or if person sustains multiple fractures. • Consider referral to orthopedist. • Consider referral to endocrinologist. • To assess for refractive errors, nystagmus, strabismus, polar cataract, & optic disk pallor • Consider VEP & ERG to assess conduction in visual pathway. • Narrow (ogival) palate • Tooth overgrowth • Malocclusion • Dental caries • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for MALNS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Persons w/o clinical signs of seizures who have nonspecific EEG changes may not require medical therapy Cognitive behavioral therapy to treat anxiety & ADHD Standard treatment for visuomotor abilities, photophobia, & noise sensitivity Symptomatic aids (i.e., colored glasses, low voice tone) may reduce anxiety ↓. Consider introducing AAC when expressive language difficulties are a concern. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or AAC = augmentative alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Particularly in individuals with an intragenic The following information represents typical management recommendations for individuals with developmental delay /intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder (ASD), including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Cognitive behavioral therapy (CBT) has been proven effective in treating anxiety disorders, ASD, and ADHD; therefore, early initiation of CBT should be considered in those with adequate cognitive skills. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. However, any drug therapy to treat psychiatric symptoms should be weighed against the age of the affected person (child or adolescent) and the specific medical comorbidities of individuals with MALNS, with close consideration for possible current or future drug interactions that may be given to treat MALNS-specific medical issues. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Persons w/o clinical signs of seizures who have nonspecific EEG changes may not require medical therapy • Cognitive behavioral therapy to treat anxiety & ADHD • Standard treatment for visuomotor abilities, photophobia, & noise sensitivity • Symptomatic aids (i.e., colored glasses, low voice tone) may reduce anxiety ↓. • Consider introducing AAC when expressive language difficulties are a concern. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay /intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder (ASD), including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Cognitive behavioral therapy (CBT) has been proven effective in treating anxiety disorders, ASD, and ADHD; therefore, early initiation of CBT should be considered in those with adequate cognitive skills. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. However, any drug therapy to treat psychiatric symptoms should be weighed against the age of the affected person (child or adolescent) and the specific medical comorbidities of individuals with MALNS, with close consideration for possible current or future drug interactions that may be given to treat MALNS-specific medical issues. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in At each visit 1st BMI eval should be performed after age 2 yrs. Eval of nutritional status & safety of oral intake Assessment for signs/symptoms of constipation Monitor those w/seizures as clinically indicated. Assess for new manifestations such as changes in tone, signs/symptoms of Chari I malformation, Assess for subtle & nonspecific autonomic signs/symptoms. From age 12 mos to approximatively 36 mos: annually From age 3 yrs to adulthood: every 2 yrs Annually until puberty Periodic eval should be performed in adults to evaluate for late-onset optic nerve degeneration. BMI = body mass index; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy Those with a BMI of >2 standard deviations below the mean require reassessment of their caloric intake and the appropriateness of their food intake. Including severe headaches, neck pain, poor balance, dizziness, numbness or tingling in the hands/feet, and/or swallowing issues Individuals with a deletion that includes Such as vomiting/nausea, dizziness, and fainting • At each visit • 1st BMI eval should be performed after age 2 yrs. • Eval of nutritional status & safety of oral intake • Assessment for signs/symptoms of constipation • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as changes in tone, signs/symptoms of Chari I malformation, • Assess for subtle & nonspecific autonomic signs/symptoms. • From age 12 mos to approximatively 36 mos: annually • From age 3 yrs to adulthood: every 2 yrs • Annually until puberty • Periodic eval should be performed in adults to evaluate for late-onset optic nerve degeneration. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Almost all individuals diagnosed with MALNS whose parents have undergone molecular genetic testing have the disorder as the result of a Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported [ If the proband appears to be the only affected family member (i.e., a simplex case), genetic testing capable of identifying the genetic alternation identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ * A parent with somatic and gonadal mosaicism for an If a parent of the proband is affected and/or is known to have the If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent and – if the proband has a deletion – neither parent has a balanced chromosome rearrangement involving the 19p13.2 region, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Once the MALNS-related genetic alternation has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Almost all individuals diagnosed with MALNS whose parents have undergone molecular genetic testing have the disorder as the result of a • Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported [ • If the proband appears to be the only affected family member (i.e., a simplex case), genetic testing capable of identifying the genetic alternation identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for an • If a parent of the proband is affected and/or is known to have the • If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent and – if the proband has a deletion – neither parent has a balanced chromosome rearrangement involving the 19p13.2 region, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance ## Risk to Family Members Almost all individuals diagnosed with MALNS whose parents have undergone molecular genetic testing have the disorder as the result of a Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported [ If the proband appears to be the only affected family member (i.e., a simplex case), genetic testing capable of identifying the genetic alternation identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ * A parent with somatic and gonadal mosaicism for an If a parent of the proband is affected and/or is known to have the If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent and – if the proband has a deletion – neither parent has a balanced chromosome rearrangement involving the 19p13.2 region, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ • Almost all individuals diagnosed with MALNS whose parents have undergone molecular genetic testing have the disorder as the result of a • Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported [ • If the proband appears to be the only affected family member (i.e., a simplex case), genetic testing capable of identifying the genetic alternation identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [ • * A parent with somatic and gonadal mosaicism for an • If a parent of the proband is affected and/or is known to have the • If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent and – if the proband has a deletion – neither parent has a balanced chromosome rearrangement involving the 19p13.2 region, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [ ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the MALNS-related genetic alternation has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Italy United Kingdom Sanford Research • • • • Italy • • • United Kingdom • • • Sanford Research • ## Molecular Genetics NFIX-Related Malan Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NFIX-Related Malan Syndrome ( Nuclear factor 1 X-type (NFIX) belongs to the nuclear factor 1 (NFI) family of transcription factors. Members of this family act as homodimers and heterodimers and bind with high affinity to the palindromic consensus sequence TTGGC(N5)GCCAA. In vertebrates, the ## Molecular Pathogenesis Nuclear factor 1 X-type (NFIX) belongs to the nuclear factor 1 (NFI) family of transcription factors. Members of this family act as homodimers and heterodimers and bind with high affinity to the palindromic consensus sequence TTGGC(N5)GCCAA. In vertebrates, the ## Chapter Notes The author gratefully acknowledges the patients, their families, and the support associations that have generously participated in the research described and referenced here. The author would also like to thank the clinician collaborator teams of physicians, genetic counselors, nurses, therapists, and trainees who have generously cared for these patients and contributed to produce guidelines for diagnosis and management of individuals with 1 August 2024 (ma) Review posted live 17 February 2023 (mp) Original submission • 1 August 2024 (ma) Review posted live • 17 February 2023 (mp) Original submission ## Acknowledgments The author gratefully acknowledges the patients, their families, and the support associations that have generously participated in the research described and referenced here. The author would also like to thank the clinician collaborator teams of physicians, genetic counselors, nurses, therapists, and trainees who have generously cared for these patients and contributed to produce guidelines for diagnosis and management of individuals with ## Revision History 1 August 2024 (ma) Review posted live 17 February 2023 (mp) Original submission • 1 August 2024 (ma) Review posted live • 17 February 2023 (mp) Original submission ## References ## Literature Cited Clinical features of individuals with Malan syndrome at different ages, with evolving facial appearance. Note long and triangular face, high anterior hair line with prominent forehead, downslanted palpebral fissures, small mouth, everted lower lip, and prominent chin. Reproduced from	[]	1/8/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ngly1-cddg	ngly1-cddg	[ "NGLY1-CDDG", "NGLY1 Deficiency", "NGLY1-Related Disorder", "NGLY1-CDDG", "NGLY1 Deficiency", "NGLY1-Related Disorder", "Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase", "NGLY1", "NGLY1-Related Congenital Disorder of Deglycosylation" ]		Christina Lam, Lynne Wolfe, Anna Need, Vandana Shashi, Gregory Enns	Summary Individuals with The diagnosis of NGLY1-CDDG is established in a proband by the identification of biallelic pathogenic variants in NGLY1-CDDG is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.	## Diagnosis Formal diagnostic criteria have not been established. Developmental delay / intellectual disability, most often in the severe to profound range Hyperkinetic movement disorder Hypo- or alacrima Note: Typical serum screening tests for congenital disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG (see The diagnosis of NGLY1-CDDG For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Developmental delay / intellectual disability, most often in the severe to profound range • Hyperkinetic movement disorder • Hypo- or alacrima ## Suggestive Findings Developmental delay / intellectual disability, most often in the severe to profound range Hyperkinetic movement disorder Hypo- or alacrima Note: Typical serum screening tests for congenital disorders of glycosylation (i.e., analysis of serum transferrin glycoforms, N and O glycan profiling) will NOT reliably detect NGLY1-CDDG (see • Developmental delay / intellectual disability, most often in the severe to profound range • Hyperkinetic movement disorder • Hypo- or alacrima ## Establishing the Diagnosis The diagnosis of NGLY1-CDDG For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Recommended Testing For an introduction to multigene panels click ## Testing to Consider For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics In addition, individuals with NGLY1-CDDG universally exhibit a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements [ Further findings may include the following: CSF laboratory results typically demonstrate: Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ Brain MRI can show: Delayed myelination during early childhood (ages 0-5), but not in older individuals; Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ Brain MRS can be significant for: Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ Nerve conduction studies most often demonstrate an axonal sensorimotor polyneuropathy with additional demyelinative features that are length dependent and appear progressive. Neuropathy has been documented in all nerves tested including the median, ulnar, radial, peroneal, tibial, and sural nerves. Individual testing typically reveals more severe neuropathy in the lower (compared to upper) extremities, with lower amplitudes and slower conduction. Needle electromyogram may show neurogenic findings with varying degrees of acute and chronic changes. QSWEAT testing can show absent sweat response, more frequently in the lower extremities than in the forearm, suggesting a length-dependent neuropathy [ Note: The QTcB is the standard clinical correction of the QT interval using Bazett's formula, calculated as QT interval divided by square root of the RR interval. The QtcF is the alternative correction based on Fridericia's formula, which is defined as the QT interval divided by the cube root of the RR interval. The QTcB is believed to overestimate the QT prolongation at higher heart rates, and the QTcF may underestimate the QT prolongation at slower heart rates [ Transaminases (AST and ALT): Are typically elevated and range from just slightly above the upper limit of normal to >1,000 U/L in the first two years of life; Usually normalize by age four years without any specific intervention. Note: In the few liver biopsies performed, findings have been normal or consistent with microvesicular steatosis, ductular proliferation, focal microvacuolation, and micronodular cirrhosis with bands of fibrosis with regenerative nodules. Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels are low in about one third of tested individuals, but particle numbers and sizes of HDL, LDL, and VLDL are normal [ Abdominal ultrasound findings can include splenomegaly, steatosis, coarse or inhomogeneous liver texture, and hepatomegaly. Fibroscan scores show evidence of liver fibrosis in a few affected individuals [ Carbohydrate-deficient transferrin analysis in blood may show small elevations in mono- and a-oligosaccharides and tri-sialo-oligosaccharides, but not to the levels typically seen in O-glycan profiling is normal. Urine quantitative mucopolysaccharides can be elevated, but with a normal pattern. Free and total carnitine, uric acid, white blood cell CoQ Lactate was normal in the majority of affected individuals, but can be mild to moderately elevated (~5 mmol/L) especially in younger affected individuals. Lactate to pyruvate ratio is typically normal. Urine amino acids can show generalized aminoaciduria, especially in older individuals [ On liver biopsy, abnormal cristae and mitochondrial proliferation was noted in one individual, while depleted cristae and mitochondrial DNA depletion was seen in another individual [ On quadriceps muscle biopsy mitochondrial proliferation and mitochondrial DNA proliferation was noted in one affected individual [ The most common pathogenic variant is A sib pair with the cryptic pathogenic NGLY1-CDDG was previously referred to as congenital disorder of glycosylation type Iv (CDG-Iv). NGLY1-CDDG is the first primary defect of N-linked A total of 18 individuals from 14 families have been described in the literature [ • CSF laboratory results typically demonstrate: • Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); • Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); • Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ • Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); • Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); • Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ • Brain MRI can show: • Delayed myelination during early childhood (ages 0-5), but not in older individuals; • Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ • Delayed myelination during early childhood (ages 0-5), but not in older individuals; • Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ • Brain MRS can be significant for: • Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; • Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ • Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; • Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ • Nerve conduction studies most often demonstrate an axonal sensorimotor polyneuropathy with additional demyelinative features that are length dependent and appear progressive. Neuropathy has been documented in all nerves tested including the median, ulnar, radial, peroneal, tibial, and sural nerves. Individual testing typically reveals more severe neuropathy in the lower (compared to upper) extremities, with lower amplitudes and slower conduction. • Needle electromyogram may show neurogenic findings with varying degrees of acute and chronic changes. • QSWEAT testing can show absent sweat response, more frequently in the lower extremities than in the forearm, suggesting a length-dependent neuropathy [ • Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); • Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); • Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ • Delayed myelination during early childhood (ages 0-5), but not in older individuals; • Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ • Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; • Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ • Are typically elevated and range from just slightly above the upper limit of normal to >1,000 U/L in the first two years of life; • Usually normalize by age four years without any specific intervention. • Note: In the few liver biopsies performed, findings have been normal or consistent with microvesicular steatosis, ductular proliferation, focal microvacuolation, and micronodular cirrhosis with bands of fibrosis with regenerative nodules. • Carbohydrate-deficient transferrin analysis in blood may show small elevations in mono- and a-oligosaccharides and tri-sialo-oligosaccharides, but not to the levels typically seen in • O-glycan profiling is normal. • Urine quantitative mucopolysaccharides can be elevated, but with a normal pattern. • Free and total carnitine, uric acid, white blood cell CoQ • Lactate was normal in the majority of affected individuals, but can be mild to moderately elevated (~5 mmol/L) especially in younger affected individuals. • Lactate to pyruvate ratio is typically normal. • Urine amino acids can show generalized aminoaciduria, especially in older individuals [ • On liver biopsy, abnormal cristae and mitochondrial proliferation was noted in one individual, while depleted cristae and mitochondrial DNA depletion was seen in another individual [ • On quadriceps muscle biopsy mitochondrial proliferation and mitochondrial DNA proliferation was noted in one affected individual [ ## Clinical Description In addition, individuals with NGLY1-CDDG universally exhibit a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements [ Further findings may include the following: CSF laboratory results typically demonstrate: Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ Brain MRI can show: Delayed myelination during early childhood (ages 0-5), but not in older individuals; Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ Brain MRS can be significant for: Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ Nerve conduction studies most often demonstrate an axonal sensorimotor polyneuropathy with additional demyelinative features that are length dependent and appear progressive. Neuropathy has been documented in all nerves tested including the median, ulnar, radial, peroneal, tibial, and sural nerves. Individual testing typically reveals more severe neuropathy in the lower (compared to upper) extremities, with lower amplitudes and slower conduction. Needle electromyogram may show neurogenic findings with varying degrees of acute and chronic changes. QSWEAT testing can show absent sweat response, more frequently in the lower extremities than in the forearm, suggesting a length-dependent neuropathy [ Note: The QTcB is the standard clinical correction of the QT interval using Bazett's formula, calculated as QT interval divided by square root of the RR interval. The QtcF is the alternative correction based on Fridericia's formula, which is defined as the QT interval divided by the cube root of the RR interval. The QTcB is believed to overestimate the QT prolongation at higher heart rates, and the QTcF may underestimate the QT prolongation at slower heart rates [ Transaminases (AST and ALT): Are typically elevated and range from just slightly above the upper limit of normal to >1,000 U/L in the first two years of life; Usually normalize by age four years without any specific intervention. Note: In the few liver biopsies performed, findings have been normal or consistent with microvesicular steatosis, ductular proliferation, focal microvacuolation, and micronodular cirrhosis with bands of fibrosis with regenerative nodules. Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels are low in about one third of tested individuals, but particle numbers and sizes of HDL, LDL, and VLDL are normal [ Abdominal ultrasound findings can include splenomegaly, steatosis, coarse or inhomogeneous liver texture, and hepatomegaly. Fibroscan scores show evidence of liver fibrosis in a few affected individuals [ Carbohydrate-deficient transferrin analysis in blood may show small elevations in mono- and a-oligosaccharides and tri-sialo-oligosaccharides, but not to the levels typically seen in O-glycan profiling is normal. Urine quantitative mucopolysaccharides can be elevated, but with a normal pattern. Free and total carnitine, uric acid, white blood cell CoQ Lactate was normal in the majority of affected individuals, but can be mild to moderately elevated (~5 mmol/L) especially in younger affected individuals. Lactate to pyruvate ratio is typically normal. Urine amino acids can show generalized aminoaciduria, especially in older individuals [ On liver biopsy, abnormal cristae and mitochondrial proliferation was noted in one individual, while depleted cristae and mitochondrial DNA depletion was seen in another individual [ On quadriceps muscle biopsy mitochondrial proliferation and mitochondrial DNA proliferation was noted in one affected individual [ • CSF laboratory results typically demonstrate: • Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); • Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); • Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ • Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); • Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); • Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ • Brain MRI can show: • Delayed myelination during early childhood (ages 0-5), but not in older individuals; • Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ • Delayed myelination during early childhood (ages 0-5), but not in older individuals; • Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ • Brain MRS can be significant for: • Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; • Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ • Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; • Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ • Nerve conduction studies most often demonstrate an axonal sensorimotor polyneuropathy with additional demyelinative features that are length dependent and appear progressive. Neuropathy has been documented in all nerves tested including the median, ulnar, radial, peroneal, tibial, and sural nerves. Individual testing typically reveals more severe neuropathy in the lower (compared to upper) extremities, with lower amplitudes and slower conduction. • Needle electromyogram may show neurogenic findings with varying degrees of acute and chronic changes. • QSWEAT testing can show absent sweat response, more frequently in the lower extremities than in the forearm, suggesting a length-dependent neuropathy [ • Low total protein (from 8 affected individuals, mean protein level was 11 mg/dL, standard error of the mean [SEM] 1) and albumin (from 9 affected individuals, mean 9 mg/dL, SEM 1); • Low CSF/serum albumin ratios (from 9 affected individuals, mean ratio was 3, SEM 1); • Low CSF 5-hydroxyindolacetic acid, homovanillic acid, and tetrahydrobiopterin levels, especially in older individuals [ • Delayed myelination during early childhood (ages 0-5), but not in older individuals; • Progressive cerebral and occasional cerebellar atrophy, which correlates with worsening function. In 10/11 affected individuals imaged cerebral volume loss was found; in 4/11 cerebellar volume loss was also seen [ • Lower N-acetylaspartylglutamate and N-acetylaspartate levels compared to normal; • Higher choline and myo-inositol levels, becoming more prominent with increasing age, worsening function, and lower brain volume [ • Are typically elevated and range from just slightly above the upper limit of normal to >1,000 U/L in the first two years of life; • Usually normalize by age four years without any specific intervention. • Note: In the few liver biopsies performed, findings have been normal or consistent with microvesicular steatosis, ductular proliferation, focal microvacuolation, and micronodular cirrhosis with bands of fibrosis with regenerative nodules. • Carbohydrate-deficient transferrin analysis in blood may show small elevations in mono- and a-oligosaccharides and tri-sialo-oligosaccharides, but not to the levels typically seen in • O-glycan profiling is normal. • Urine quantitative mucopolysaccharides can be elevated, but with a normal pattern. • Free and total carnitine, uric acid, white blood cell CoQ • Lactate was normal in the majority of affected individuals, but can be mild to moderately elevated (~5 mmol/L) especially in younger affected individuals. • Lactate to pyruvate ratio is typically normal. • Urine amino acids can show generalized aminoaciduria, especially in older individuals [ • On liver biopsy, abnormal cristae and mitochondrial proliferation was noted in one individual, while depleted cristae and mitochondrial DNA depletion was seen in another individual [ • On quadriceps muscle biopsy mitochondrial proliferation and mitochondrial DNA proliferation was noted in one affected individual [ ## Genotype-Phenotype Correlations The most common pathogenic variant is A sib pair with the cryptic pathogenic ## Nomenclature NGLY1-CDDG was previously referred to as congenital disorder of glycosylation type Iv (CDG-Iv). NGLY1-CDDG is the first primary defect of N-linked ## Prevalence A total of 18 individuals from 14 families have been described in the literature [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The tetrad of developmental delay / cognitive impairment, hyperkinetic movement disorder, hypo/alacrima, and elevated transaminases during early childhood is pathognomonic of NGLY1-CDDG [ Disorders to Consider in the Differential Diagnosis of Intrauterine growth restriction DD / cognitive impairment Neurologic dysfunction Liver disease No apparent lipodystrophy or significant cardiac manifestations Nonspecific brain imaging findings, but usually relatively mild abnormalities Multisystem involvement Pigmentary retinopathy Mild biochemical evidence of mt impairment, especially transient or mildly ↑ blood lactate levels Nonspecific electron transport chain abnormalities in skin fibroblasts, muscle, & liver, & mildly abnormal mt morphology on electron microscopy Do not typically have episodes of metabolic decompensation or clinical presentations assoc w/classic mt disorder phenotypes. Have normal CSF lactate levels. Various combinations of abnormal levels of HVA, 5-HIAA, & biopterin metabolites in neurotransmitter disorders In some cases, ↓ HVA, 5-HIAA, & tetrahydrobiopterin in NGLY1-CDDG; such findings appear to correlate w/degree of brain atrophy. Oculogyric crises not reported No diurnal fluctuation of symptoms Peripheral neuropathy common Alacrima/hypolacrima & liver dysfunction not typically seen Intellectual & cognitive function typically normal ↓ HVA may be present in hypoxic-ischemic encephalopathy, CNS infections, & some genetic disorders. ↓ HVA & 5-HIAA may occur in hypoxic-ischemic encephalopathy, congenital infections, & some genetic disorders. Are common features in May also be seen in NGLY1-CDDG. Persons w/NGLY1-CDDG have neither a period of normal development nor such rapid developmental regression. Alacrima Mild dementia Cerebellar ataxia Triple A syndrome does not feature choreoathetosis. Adrenal insufficiency is not a prominent feature of NGLY1-CDDG. Persons with Triple A syndrome may have anisocoria. Alacrima ID Variable hypotonia Ataxia Spasticity Hearing impairment Does not feature choreoathetosis. May feature anisocoria. FD & HSAN type VI do not feature choreoathetosis. Persons w/HSAN usually have normal cognitive function. 5-HIAA = 5-hydroxyindoleacetic acid; AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; HVA = homovanillic acid; ID = intellectual disability; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked See OMIM Phenotypic Series: Some individuals with Neurotransmitter disorders are associated with a wide spectrum of neurologic abnormalities including seizures, choreoathetosis, dystonia, hypotonia, oculogyric crises, and psychiatric disease [ For more information, see hyperlinked Genetic disorders that may be associated with low HVA include Genetic disorders that may be associated with low HVA and 5-HIAA include See OMIM Phenotypic Series: • Intrauterine growth restriction • DD / cognitive impairment • Neurologic dysfunction • Liver disease • No apparent lipodystrophy or significant cardiac manifestations • Nonspecific brain imaging findings, but usually relatively mild abnormalities • Multisystem involvement • Pigmentary retinopathy • Mild biochemical evidence of mt impairment, especially transient or mildly ↑ blood lactate levels • Nonspecific electron transport chain abnormalities in skin fibroblasts, muscle, & liver, & mildly abnormal mt morphology on electron microscopy • Do not typically have episodes of metabolic decompensation or clinical presentations assoc w/classic mt disorder phenotypes. • Have normal CSF lactate levels. • Various combinations of abnormal levels of HVA, 5-HIAA, & biopterin metabolites in neurotransmitter disorders • In some cases, ↓ HVA, 5-HIAA, & tetrahydrobiopterin in NGLY1-CDDG; such findings appear to correlate w/degree of brain atrophy. • Oculogyric crises not reported • No diurnal fluctuation of symptoms • Peripheral neuropathy common • Alacrima/hypolacrima & liver dysfunction not typically seen • Intellectual & cognitive function typically normal • ↓ HVA may be present in hypoxic-ischemic encephalopathy, CNS infections, & some genetic disorders. • ↓ HVA & 5-HIAA may occur in hypoxic-ischemic encephalopathy, congenital infections, & some genetic disorders. • Are common features in • May also be seen in NGLY1-CDDG. • Persons w/NGLY1-CDDG have neither a period of normal development nor such rapid developmental regression. • Alacrima • Mild dementia • Cerebellar ataxia • Triple A syndrome does not feature choreoathetosis. • Adrenal insufficiency is not a prominent feature of NGLY1-CDDG. • Persons with Triple A syndrome may have anisocoria. • Alacrima • ID • Variable hypotonia • Ataxia • Spasticity • Hearing impairment • Does not feature choreoathetosis. • May feature anisocoria. • FD & HSAN type VI do not feature choreoathetosis. • Persons w/HSAN usually have normal cognitive function. ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of NGLY1-CDDG Transaminase levels Eval for constipation Neurologic & neurodevelopmental eval of cognitive abilities Nerve conduction study DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, neurology, developmental pediatrics, ophthalmology, gastroenterology, orthopedics, and rehabilitation medicine who are knowledgeable about NGLY1-CDDG. Treatment of Manifestations in Individuals with NGLY1-CDDG AC = air conditioning The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox In the absence of formal surveillance guidelines, the authors recommend the following: Annual follow up by: Pediatrician or internist Physical medicine and rehabilitation medicine Ophthalmology Neurology Nutrition Follow up as recommended by: Developmental pediatrician Gastroenterologist/hepatologist Audiologist Clinical or biochemical geneticist Hot environment should be avoided by those with hypohydrosis. See No FDA-approved treatments for NGLY1-CDDG exist. Enzyme replacement therapy is currently being evaluated in the pre-clinical arena. Pre-clinical screens for endo-beta-N-acetylglucosaminidase (ENGase) inhibitors are underway [ Large-scale compound screens on model organisms and cell lines are being evaluated. Search • Transaminase levels • Eval for constipation • Neurologic & neurodevelopmental eval of cognitive abilities • Nerve conduction study • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox • Annual follow up by: • Pediatrician or internist • Physical medicine and rehabilitation medicine • Ophthalmology • Neurology • Nutrition • Pediatrician or internist • Physical medicine and rehabilitation medicine • Ophthalmology • Neurology • Nutrition • Follow up as recommended by: • Developmental pediatrician • Gastroenterologist/hepatologist • Audiologist • Clinical or biochemical geneticist • Developmental pediatrician • Gastroenterologist/hepatologist • Audiologist • Clinical or biochemical geneticist • Pediatrician or internist • Physical medicine and rehabilitation medicine • Ophthalmology • Neurology • Nutrition • Developmental pediatrician • Gastroenterologist/hepatologist • Audiologist • Clinical or biochemical geneticist ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of NGLY1-CDDG Transaminase levels Eval for constipation Neurologic & neurodevelopmental eval of cognitive abilities Nerve conduction study DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy • Transaminase levels • Eval for constipation • Neurologic & neurodevelopmental eval of cognitive abilities • Nerve conduction study ## Treatment of Manifestations Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, neurology, developmental pediatrics, ophthalmology, gastroenterology, orthopedics, and rehabilitation medicine who are knowledgeable about NGLY1-CDDG. Treatment of Manifestations in Individuals with NGLY1-CDDG AC = air conditioning The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox ## Surveillance In the absence of formal surveillance guidelines, the authors recommend the following: Annual follow up by: Pediatrician or internist Physical medicine and rehabilitation medicine Ophthalmology Neurology Nutrition Follow up as recommended by: Developmental pediatrician Gastroenterologist/hepatologist Audiologist Clinical or biochemical geneticist • Annual follow up by: • Pediatrician or internist • Physical medicine and rehabilitation medicine • Ophthalmology • Neurology • Nutrition • Pediatrician or internist • Physical medicine and rehabilitation medicine • Ophthalmology • Neurology • Nutrition • Follow up as recommended by: • Developmental pediatrician • Gastroenterologist/hepatologist • Audiologist • Clinical or biochemical geneticist • Developmental pediatrician • Gastroenterologist/hepatologist • Audiologist • Clinical or biochemical geneticist • Pediatrician or internist • Physical medicine and rehabilitation medicine • Ophthalmology • Neurology • Nutrition • Developmental pediatrician • Gastroenterologist/hepatologist • Audiologist • Clinical or biochemical geneticist ## Agents/Circumstances to Avoid Hot environment should be avoided by those with hypohydrosis. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation No FDA-approved treatments for NGLY1-CDDG exist. Enzyme replacement therapy is currently being evaluated in the pre-clinical arena. Pre-clinical screens for endo-beta-N-acetylglucosaminidase (ENGase) inhibitors are underway [ Large-scale compound screens on model organisms and cell lines are being evaluated. Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics NGLY1-Related Congenital Disorder of Deglycosylation: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NGLY1-Related Congenital Disorder of Deglycosylation ( Variants listed in the table have been provided by the authors. Amino acids 26-102: peptide:N-glycanase/UBA or UBX-containing proteins (PUB) domain Amino acids 269-354: catalytic transglutaminase domain Amino acids 457-651: PAW (present in PNGase and other worm proteins) domain N-glycanase catalyzes the deglycosylation of misfolded glycoproteins as part of the endoplasmic reticulum-associated degradation (ERAD) process [ If the formation/aggregation of N-GlcNAc proteins is shown to be related to the symptoms/signs of NGLY1-CDDG, inhibition of ENGase activity may be a therapeutic target [ • Amino acids 26-102: peptide:N-glycanase/UBA or UBX-containing proteins (PUB) domain • Amino acids 269-354: catalytic transglutaminase domain • Amino acids 457-651: PAW (present in PNGase and other worm proteins) domain ## References ## Literature Cited ## Chapter Notes The Medical Genetics Branch of the National Human Genome Research Institute continues to study the natural history of patients with NGLY1-CDDG. Careful phenotyping facilitates the characterization of disease progression necessary to evaluate the efficacy of therapeutic interventions. Dr Matthew Might and Mrs Cristina Might ( 8 February 2018 (ma) Review posted live 29 November 2016 (cl) Original submission • 8 February 2018 (ma) Review posted live • 29 November 2016 (cl) Original submission ## Author Notes The Medical Genetics Branch of the National Human Genome Research Institute continues to study the natural history of patients with NGLY1-CDDG. Careful phenotyping facilitates the characterization of disease progression necessary to evaluate the efficacy of therapeutic interventions. ## Acknowledgments Dr Matthew Might and Mrs Cristina Might ( ## Revision History 8 February 2018 (ma) Review posted live 29 November 2016 (cl) Original submission • 8 February 2018 (ma) Review posted live • 29 November 2016 (cl) Original submission	[]	8/2/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nijmegen	nijmegen	[ "Nibrin", "NBN", "Nijmegen Breakage Syndrome" ]	Nijmegen Breakage Syndrome	Raymonda Varon, Ilja Demuth, Krystyna H Chrzanowska	Summary Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma). The diagnosis of NBS is established in a proband with characteristic clinical features and biallelic pathogenic variants in NBS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a heterozygote, and a 25% chance of inheriting neither of the familial	## Diagnosis Nijmegen breakage syndrome (NBS) Disproportionate microcephaly that is progressive Craniofacial features that include a sloping forehead, upward-slanted palpebral fissures, prominent nose, relatively large ears, and retrognathia Growth deficiency that is more pronounced from birth until age two years, with mild improvement thereafter Recurrent infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis Malignancies, predominantly of lymphoid origin Decline in intellectual ability, from normal or borderline-normal during early childhood to moderate intellectual disability in older individuals The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. Note: This test requires that a lymphoblastoid cell line be established. Because the process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. The diagnosis of NBS Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; More than 70% of pathogenic alleles in individuals from the US. If the common founder variant is not present in a homozygous form, sequence analysis of For an introduction to multigene panels click Molecular Genetic Testing Used in Nijmegen Breakage Syndrome See See Methods that may be used to detect the Nearly all affected individuals from Poland, the Czech Republic, and Ukraine tested to date are homozygous for the common pathogenic variant Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No large exon or multiexon deletions or duplications involving this gene have been reported to cause NBS. Immunoblotting can be used to determine if the nibrin protein is present or absent. Note: Immunoblotting requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. • Disproportionate microcephaly that is progressive • Craniofacial features that include a sloping forehead, upward-slanted palpebral fissures, prominent nose, relatively large ears, and retrognathia • Growth deficiency that is more pronounced from birth until age two years, with mild improvement thereafter • Recurrent infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis • Malignancies, predominantly of lymphoid origin • Decline in intellectual ability, from normal or borderline-normal during early childhood to moderate intellectual disability in older individuals • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. • • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. • Note: This test requires that a lymphoblastoid cell line be established. Because the process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. • If the common founder variant is not present in a homozygous form, sequence analysis of • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. • For an introduction to multigene panels click • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. ## Suggestive Findings Nijmegen breakage syndrome (NBS) Disproportionate microcephaly that is progressive Craniofacial features that include a sloping forehead, upward-slanted palpebral fissures, prominent nose, relatively large ears, and retrognathia Growth deficiency that is more pronounced from birth until age two years, with mild improvement thereafter Recurrent infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis Malignancies, predominantly of lymphoid origin Decline in intellectual ability, from normal or borderline-normal during early childhood to moderate intellectual disability in older individuals The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. Note: This test requires that a lymphoblastoid cell line be established. Because the process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. • Disproportionate microcephaly that is progressive • Craniofacial features that include a sloping forehead, upward-slanted palpebral fissures, prominent nose, relatively large ears, and retrognathia • Growth deficiency that is more pronounced from birth until age two years, with mild improvement thereafter • Recurrent infections including pneumonia, bronchitis, sinusitis, otitis media, and mastoiditis • Malignancies, predominantly of lymphoid origin • Decline in intellectual ability, from normal or borderline-normal during early childhood to moderate intellectual disability in older individuals • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. • • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. • Note: This test requires that a lymphoblastoid cell line be established. Because the process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. • The most frequent deficit was of IgG found in 62% of affected individuals and IgA deficiency in 57%. • Deficiencies of IgG subclasses are frequent even when the IgG serum concentration is normal (IgG4, IgG2, and IgG3, in decreasing order). • The most commonly reported defects in cellular immunity include reduced absolute numbers of total B cells (CD19+/CD20+), CD3+ T cells, and CD4+ T cells; these are observed in 80%-89% of affected individuals. • The in vitro proliferation of T and B lymphocytes to antigen and/or mitogenic stimuli is moderately or severely reduced in majority of affected individuals, compared to age-matched healthy controls. • Inversions and translocations involving chromosomes 7 and 14 are observed in PHA-stimulated lymphocytes in 10%-50% of metaphases. • The breakpoints most commonly involved are 7p13, 7q35, 14q11, and 14q32, which are the loci for immunoglobulin and T-cell receptor genes. ## Establishing the Diagnosis The diagnosis of NBS Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; More than 70% of pathogenic alleles in individuals from the US. If the common founder variant is not present in a homozygous form, sequence analysis of For an introduction to multigene panels click Molecular Genetic Testing Used in Nijmegen Breakage Syndrome See See Methods that may be used to detect the Nearly all affected individuals from Poland, the Czech Republic, and Ukraine tested to date are homozygous for the common pathogenic variant Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No large exon or multiexon deletions or duplications involving this gene have been reported to cause NBS. Immunoblotting can be used to determine if the nibrin protein is present or absent. Note: Immunoblotting requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. • If the common founder variant is not present in a homozygous form, sequence analysis of • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. • For an introduction to multigene panels click • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. ## Molecular Genetic Testing Molecular genetic testing approaches can include Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; More than 70% of pathogenic alleles in individuals from the US. If the common founder variant is not present in a homozygous form, sequence analysis of For an introduction to multigene panels click Molecular Genetic Testing Used in Nijmegen Breakage Syndrome See See Methods that may be used to detect the Nearly all affected individuals from Poland, the Czech Republic, and Ukraine tested to date are homozygous for the common pathogenic variant Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No large exon or multiexon deletions or duplications involving this gene have been reported to cause NBS. • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. • If the common founder variant is not present in a homozygous form, sequence analysis of • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. • For an introduction to multigene panels click • Approximately 100% of pathogenic alleles in individuals of Slavic (Poland, Czech Republic, Ukraine) ancestry; • More than 70% of pathogenic alleles in individuals from the US. ## Immunoblotting Immunoblotting can be used to determine if the nibrin protein is present or absent. Note: Immunoblotting requires that a lymphoblastoid cell line be established. Because this process is more commonly performed in a research lab than in a clinical lab, the test may not be widely available clinically. ## Clinical Characteristics Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, growth deficiency that improves with age, recurrent sinopulmonary infections, an increased risk for lymphoma, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Secondary malignancies including solid tumors have been reported in several individuals. Nijmegen Breakage Syndrome: Frequency of Select Features Growth deficiency in the first years of life results in length/height that is usually below the third centile by age two years. Thereafter, linear growth velocity tends to normalize; however, many individuals remain shorter than their peers (i.e., affected individuals do not experience catch-up growth). Some adults, both females and males, can achieve height within lower-normal ranges [ Several children have developed solid tumors, including medulloblastomas, glioma, rhabdomyosarcomas, and bilateral ovarian germ cell tumor (in a female) [ A recent study of 241 individuals with NBS showed improved long-term survival in those treated with hematopoietic stem cell transplantation (HSCT) during first malignancy remission [ No detailed studies of fertility in males with NBS have been published; however, puberty initiation and progress are comparable to healthy boys [ Irregular skin pigmentation in the form of irregular hyperpigmented or hypopigmented macules is seen in most affected individuals. In some affected individuals, progressive sarcoid-like granulomas are observed [ Congenital malformations, usually observed in single cases, include anomalies of the central nervous system (e.g., hydrocephaly, schizencephaly, arachnoid cysts), choanal atresia, cleft lip and palate, tracheal hypoplasia, preaxial or postaxial polydactyly, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia. An increased frequency of The common pathogenic variant The Nijmegen breakage syndrome (NBS) was described by Three Czech families with Seemanová syndrome [ No reliable estimates of worldwide prevalence exist, but it is likely to approximate 1:100,000 live births. NBS is most common in Eastern European / Slavic populations. Studies in Poland, the Czech Republic, and Ukraine have suggested that the carrier frequency of the common allele approaches 1:155 in these populations [ • Irregular skin pigmentation in the form of irregular hyperpigmented or hypopigmented macules is seen in most affected individuals. In some affected individuals, progressive sarcoid-like granulomas are observed [ • Congenital malformations, usually observed in single cases, include anomalies of the central nervous system (e.g., hydrocephaly, schizencephaly, arachnoid cysts), choanal atresia, cleft lip and palate, tracheal hypoplasia, preaxial or postaxial polydactyly, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia. ## Clinical Description Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, growth deficiency that improves with age, recurrent sinopulmonary infections, an increased risk for lymphoma, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Secondary malignancies including solid tumors have been reported in several individuals. Nijmegen Breakage Syndrome: Frequency of Select Features Growth deficiency in the first years of life results in length/height that is usually below the third centile by age two years. Thereafter, linear growth velocity tends to normalize; however, many individuals remain shorter than their peers (i.e., affected individuals do not experience catch-up growth). Some adults, both females and males, can achieve height within lower-normal ranges [ Several children have developed solid tumors, including medulloblastomas, glioma, rhabdomyosarcomas, and bilateral ovarian germ cell tumor (in a female) [ A recent study of 241 individuals with NBS showed improved long-term survival in those treated with hematopoietic stem cell transplantation (HSCT) during first malignancy remission [ No detailed studies of fertility in males with NBS have been published; however, puberty initiation and progress are comparable to healthy boys [ Irregular skin pigmentation in the form of irregular hyperpigmented or hypopigmented macules is seen in most affected individuals. In some affected individuals, progressive sarcoid-like granulomas are observed [ Congenital malformations, usually observed in single cases, include anomalies of the central nervous system (e.g., hydrocephaly, schizencephaly, arachnoid cysts), choanal atresia, cleft lip and palate, tracheal hypoplasia, preaxial or postaxial polydactyly, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia. An increased frequency of • Irregular skin pigmentation in the form of irregular hyperpigmented or hypopigmented macules is seen in most affected individuals. In some affected individuals, progressive sarcoid-like granulomas are observed [ • Congenital malformations, usually observed in single cases, include anomalies of the central nervous system (e.g., hydrocephaly, schizencephaly, arachnoid cysts), choanal atresia, cleft lip and palate, tracheal hypoplasia, preaxial or postaxial polydactyly, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia. ## Heterozygotes An increased frequency of ## Genotype-Phenotype Correlations The common pathogenic variant ## Nomenclature The Nijmegen breakage syndrome (NBS) was described by Three Czech families with Seemanová syndrome [ ## Prevalence No reliable estimates of worldwide prevalence exist, but it is likely to approximate 1:100,000 live births. NBS is most common in Eastern European / Slavic populations. Studies in Poland, the Czech Republic, and Ukraine have suggested that the carrier frequency of the common allele approaches 1:155 in these populations [ ## Genetically Related Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Microcephaly, growth delay, immunodeficiency, and/or bone marrow failure are common manifestations of several inherited disorders, mainly related to defective sensing, processing, and repair of double-strand DNA breaks. Recurrent infections, poor growth, and immunodeficiency can be observed in other inherited immunodeficiencies. See The early growth failure in Nijmegen breakage syndrome (NBS) may suggest other disorders of growth, such as thyroid hormone or growth hormone deficiency, or primary disorders of bone growth (e.g., skeletal dysplasias). Because malignancy may be the presenting finding in NBS, the diagnosis of NBS should be considered before radiotherapy is initiated in individuals with microcephaly who have solid tumors and are younger than age three years [ Disorders to Consider in the Differential Diagnosis of Nijmegen Breakage Syndrome ID = intellectual disability Facial features characteristic of Nijmegen breakage syndrome are a sloping forehead, retrognathia, prominent nasal bridge and nose, large ears, and upslanted palpebral fissures. Increased sensitivity of lymphocytes to alkylating agents such as mitomycin C and/or diepoxybutane is the cellular marker of Fanconi anemia and is used as a diagnostic aid. ## Management No clinical practice guidelines for Nijmegen breakage syndrome (NBS) have been published. To establish the extent of disease and needs in an individual diagnosed with NBS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Nijmegen Breakage Syndrome Eval of immunologic profile at time of diagnosis Assessment of types & frequency of infections Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells Proliferative response of peripheral blood mononuclear cells to stimuli Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) Assess for signs/symptoms of lymphoma & solid tumors. Assess family history for malignancy. Eval by gynecologist &/or endocrinologist Pelvic ultrasound to evaluate for streak gonads Plasma FSH, LH, & estrogen Community or Social work involvement for parental support; Home nursing referral. CMV = cytomegalovirus; EBV = Epstein-Barr virus; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; NBS = Nijmegen breakage syndrome Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Nijmegen Breakage Syndrome Standard treatments for bronchiectasis Treatment of pulmonary infection is based on underlying pathogen. Lymphoid malignancy Chemotherapy protocols need to be adapted to individual tolerance. Requires careful follow up by oncologist, as symptoms of lymphoid malignancies in immunodeficient persons can be misleading. There are currently no dedicated protocols of cancer treatment for persons w/NBS or recommendations of chemotherapy reduction. Notably, ↓ chemotherapy dosages were not assoc w/↓ side effects but contributed to ↑ risk of disease recurrence & poorer overall survival. Protocols should be adapted for NBS depending on treatment tolerance. Radiotherapy & radiomimetic chemotherapeutics are avoided. Consider HRT. Careful monitoring of secondary sexual characteristics & uterus development is needed. HRT = hormonal replacement therapy; HSCT = hematopoietic stem cell transplantation Recommended Surveillance for Individuals with Individuals with Nijmegen Breakage Syndrome Monitor types & frequency of infections. Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells Proliferative response of peripheral blood mononuclear cells to stimuli Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) Eval of cellular immunity & proliferative response to mitogens or antigens every 12 mos Eval of humoral immunity parameters every 6 wks until age 1 yr, then every 3-6 mos (until IVIg therapy is started) Periodic quantitative monitoring of indicators of viral infections 1x/yr or when infection is suspected Monitor for malignancy, particularly in those w/weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, &/or hepatosplenomegaly. Assessment should be considered using ultrasonography, MRI, biopsy. Monitor pubertal progression in females & males. Assess for premature ovarian insufficiency in females. CMV = cytomegalovirus; EBV = Epstein-Barr virus; HRT = hormonal replacement therapy Because the cells from individuals with NBS are as radiosensitive in vitro as those from individuals with Similarly, unnecessary exposure to ionizing radiation should be avoided; instead of radiograph or CT scan, MRI and/or ultrasound examination are strongly recommended. Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given. It is appropriate to offer molecular genetic testing for the See Search • Eval of immunologic profile at time of diagnosis • Assessment of types & frequency of infections • Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells • Proliferative response of peripheral blood mononuclear cells to stimuli • Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses • Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) • Assess for signs/symptoms of lymphoma & solid tumors. • Assess family history for malignancy. • Eval by gynecologist &/or endocrinologist • Pelvic ultrasound to evaluate for streak gonads • Plasma FSH, LH, & estrogen • Community or • Social work involvement for parental support; • Home nursing referral. • Standard treatments for bronchiectasis • Treatment of pulmonary infection is based on underlying pathogen. • Lymphoid malignancy • Chemotherapy protocols need to be adapted to individual tolerance. • Requires careful follow up by oncologist, as symptoms of lymphoid malignancies in immunodeficient persons can be misleading. • There are currently no dedicated protocols of cancer treatment for persons w/NBS or recommendations of chemotherapy reduction. • Notably, ↓ chemotherapy dosages were not assoc w/↓ side effects but contributed to ↑ risk of disease recurrence & poorer overall survival. • Protocols should be adapted for NBS depending on treatment tolerance. • Radiotherapy & radiomimetic chemotherapeutics are avoided. • Consider HRT. • Careful monitoring of secondary sexual characteristics & uterus development is needed. • Monitor types & frequency of infections. • Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells • Proliferative response of peripheral blood mononuclear cells to stimuli • Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses • Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) • Eval of cellular immunity & proliferative response to mitogens or antigens every 12 mos • Eval of humoral immunity parameters every 6 wks until age 1 yr, then every 3-6 mos (until IVIg therapy is started) • Periodic quantitative monitoring of indicators of viral infections 1x/yr or when infection is suspected • Monitor for malignancy, particularly in those w/weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, &/or hepatosplenomegaly. • Assessment should be considered using ultrasonography, MRI, biopsy. • Monitor pubertal progression in females & males. • Assess for premature ovarian insufficiency in females. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NBS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Nijmegen Breakage Syndrome Eval of immunologic profile at time of diagnosis Assessment of types & frequency of infections Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells Proliferative response of peripheral blood mononuclear cells to stimuli Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) Assess for signs/symptoms of lymphoma & solid tumors. Assess family history for malignancy. Eval by gynecologist &/or endocrinologist Pelvic ultrasound to evaluate for streak gonads Plasma FSH, LH, & estrogen Community or Social work involvement for parental support; Home nursing referral. CMV = cytomegalovirus; EBV = Epstein-Barr virus; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; NBS = Nijmegen breakage syndrome Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Eval of immunologic profile at time of diagnosis • Assessment of types & frequency of infections • Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells • Proliferative response of peripheral blood mononuclear cells to stimuli • Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses • Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) • Assess for signs/symptoms of lymphoma & solid tumors. • Assess family history for malignancy. • Eval by gynecologist &/or endocrinologist • Pelvic ultrasound to evaluate for streak gonads • Plasma FSH, LH, & estrogen • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Nijmegen Breakage Syndrome Standard treatments for bronchiectasis Treatment of pulmonary infection is based on underlying pathogen. Lymphoid malignancy Chemotherapy protocols need to be adapted to individual tolerance. Requires careful follow up by oncologist, as symptoms of lymphoid malignancies in immunodeficient persons can be misleading. There are currently no dedicated protocols of cancer treatment for persons w/NBS or recommendations of chemotherapy reduction. Notably, ↓ chemotherapy dosages were not assoc w/↓ side effects but contributed to ↑ risk of disease recurrence & poorer overall survival. Protocols should be adapted for NBS depending on treatment tolerance. Radiotherapy & radiomimetic chemotherapeutics are avoided. Consider HRT. Careful monitoring of secondary sexual characteristics & uterus development is needed. HRT = hormonal replacement therapy; HSCT = hematopoietic stem cell transplantation • Standard treatments for bronchiectasis • Treatment of pulmonary infection is based on underlying pathogen. • Lymphoid malignancy • Chemotherapy protocols need to be adapted to individual tolerance. • Requires careful follow up by oncologist, as symptoms of lymphoid malignancies in immunodeficient persons can be misleading. • There are currently no dedicated protocols of cancer treatment for persons w/NBS or recommendations of chemotherapy reduction. • Notably, ↓ chemotherapy dosages were not assoc w/↓ side effects but contributed to ↑ risk of disease recurrence & poorer overall survival. • Protocols should be adapted for NBS depending on treatment tolerance. • Radiotherapy & radiomimetic chemotherapeutics are avoided. • Consider HRT. • Careful monitoring of secondary sexual characteristics & uterus development is needed. ## Surveillance Recommended Surveillance for Individuals with Individuals with Nijmegen Breakage Syndrome Monitor types & frequency of infections. Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells Proliferative response of peripheral blood mononuclear cells to stimuli Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) Eval of cellular immunity & proliferative response to mitogens or antigens every 12 mos Eval of humoral immunity parameters every 6 wks until age 1 yr, then every 3-6 mos (until IVIg therapy is started) Periodic quantitative monitoring of indicators of viral infections 1x/yr or when infection is suspected Monitor for malignancy, particularly in those w/weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, &/or hepatosplenomegaly. Assessment should be considered using ultrasonography, MRI, biopsy. Monitor pubertal progression in females & males. Assess for premature ovarian insufficiency in females. CMV = cytomegalovirus; EBV = Epstein-Barr virus; HRT = hormonal replacement therapy • Monitor types & frequency of infections. • Absolute number of B cells, T cells, & T-cell subsets, w/special attention to naïve CD4+CD45RA cells • Proliferative response of peripheral blood mononuclear cells to stimuli • Concentration of total serum immunoglobulins (IgG, IgA, IgM) & IgG subclasses • Eval for viruses w/lymphotropic capacity (i.e., EBV, CMV) • Eval of cellular immunity & proliferative response to mitogens or antigens every 12 mos • Eval of humoral immunity parameters every 6 wks until age 1 yr, then every 3-6 mos (until IVIg therapy is started) • Periodic quantitative monitoring of indicators of viral infections 1x/yr or when infection is suspected • Monitor for malignancy, particularly in those w/weight loss, fever, weakness, enlargement of peripheral lymph nodes, dyspnea, cough, &/or hepatosplenomegaly. • Assessment should be considered using ultrasonography, MRI, biopsy. • Monitor pubertal progression in females & males. • Assess for premature ovarian insufficiency in females. ## Agents/Circumstances to Avoid Because the cells from individuals with NBS are as radiosensitive in vitro as those from individuals with Similarly, unnecessary exposure to ionizing radiation should be avoided; instead of radiograph or CT scan, MRI and/or ultrasound examination are strongly recommended. Live vaccines (e.g., live vaccines for tuberculosis, measles, mumps, rubella, and varicella) should not be given. ## Evaluation of Relatives at Risk It is appropriate to offer molecular genetic testing for the See ## Therapies Under Investigation Search ## Genetic Counseling Nijmegen breakage syndrome (NBS) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are not at risk for NBS; however, in some populations, there is clear evidence of increased cancer risk among individuals heterozygous for an If both parents are known to be heterozygous for an Heterozygotes are not at risk for NBS; however, in some populations there is clear evidence of increased cancer risk among individuals heterozygous for an Heterozygote testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes are not at risk for NBS; however, in some populations, there is clear evidence of increased cancer risk among individuals heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes are not at risk for NBS; however, in some populations there is clear evidence of increased cancer risk among individuals heterozygous for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes. ## Mode of Inheritance Nijmegen breakage syndrome (NBS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are not at risk for NBS; however, in some populations, there is clear evidence of increased cancer risk among individuals heterozygous for an If both parents are known to be heterozygous for an Heterozygotes are not at risk for NBS; however, in some populations there is clear evidence of increased cancer risk among individuals heterozygous for an • The parents of an affected child are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes are not at risk for NBS; however, in some populations, there is clear evidence of increased cancer risk among individuals heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes are not at risk for NBS; however, in some populations there is clear evidence of increased cancer risk among individuals heterozygous for an ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Nijmegen Breakage Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nijmegen Breakage Syndrome ( Most known Notable MZ = monozygotic Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Most known Notable MZ = monozygotic Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes Krystyna H Chrzanowska, MD, PhD (2017-present) Patrick Concannon, PhD; University of Florida Genetics Institute (1999-2014)Ilja Demuth, PhD (2014-present)Martin Digweed, PhD; Universitätsmedizin Berlin (2014-2017)Richard Gatti, MD; University of California Los Angeles (1999-2014)Raymonda Varon, PhD (2014-present) 30 November 2023 (sw/aa) Revision: added information about cancer surveillance for heterozygotes in 18 August 2022 (sw) Comprehensive update posted live 2 February 2017 (ma) Comprehensive update posted live 8 May 2014 (me) Comprehensive update posted live 1 March 2011 (me) Comprehensive update posted live 14 June 2005 (me) Comprehensive update posted live 14 March 2003 (me) Comprehensive update posted live 17 May 1999 (me) Review posted live 5 January 1999 (pc) Original submission • 30 November 2023 (sw/aa) Revision: added information about cancer surveillance for heterozygotes in • 18 August 2022 (sw) Comprehensive update posted live • 2 February 2017 (ma) Comprehensive update posted live • 8 May 2014 (me) Comprehensive update posted live • 1 March 2011 (me) Comprehensive update posted live • 14 June 2005 (me) Comprehensive update posted live • 14 March 2003 (me) Comprehensive update posted live • 17 May 1999 (me) Review posted live • 5 January 1999 (pc) Original submission ## Author History Krystyna H Chrzanowska, MD, PhD (2017-present) Patrick Concannon, PhD; University of Florida Genetics Institute (1999-2014)Ilja Demuth, PhD (2014-present)Martin Digweed, PhD; Universitätsmedizin Berlin (2014-2017)Richard Gatti, MD; University of California Los Angeles (1999-2014)Raymonda Varon, PhD (2014-present) ## Revision History 30 November 2023 (sw/aa) Revision: added information about cancer surveillance for heterozygotes in 18 August 2022 (sw) Comprehensive update posted live 2 February 2017 (ma) Comprehensive update posted live 8 May 2014 (me) Comprehensive update posted live 1 March 2011 (me) Comprehensive update posted live 14 June 2005 (me) Comprehensive update posted live 14 March 2003 (me) Comprehensive update posted live 17 May 1999 (me) Review posted live 5 January 1999 (pc) Original submission • 30 November 2023 (sw/aa) Revision: added information about cancer surveillance for heterozygotes in • 18 August 2022 (sw) Comprehensive update posted live • 2 February 2017 (ma) Comprehensive update posted live • 8 May 2014 (me) Comprehensive update posted live • 1 March 2011 (me) Comprehensive update posted live • 14 June 2005 (me) Comprehensive update posted live • 14 March 2003 (me) Comprehensive update posted live • 17 May 1999 (me) Review posted live • 5 January 1999 (pc) Original submission ## References ## Literature Cited	[]	17/5/1999	18/8/2022	30/11/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nkh	nkh	[ "NKH", "NKH", "Attenuated Nonketotic Hyperglycinemia (NKH)", "Severe Nonketotic Hyperglycinemia (NKH)", "Aminomethyltransferase, mitochondrial", "Glycine dehydrogenase (decarboxylating), mitochondrial", "AMT", "GLDC", "Nonketotic Hyperglycinemia" ]	Nonketotic Hyperglycinemia	Johan LK Van Hove, Curtis Coughlin, Michael Swanson, Julia B Hennermann	Summary Nonketotic hyperglycinemia (NKH) is the inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme system (GCS), which results in accumulation of large quantities of glycine in all body tissues including the brain. Based on ultimate outcome NKH is categorized into The diagnosis of NKH is established in a proband with elevated glycine in plasma and CSF, a compatible pattern on brain imaging, and either biallelic pathogenic variants in one of the genes encoding the protein subunits of the GCS identified on molecular genetic testing or deficient activity of the GCS (without deficiency of cofactors such as enzyme-bound lipoate or pyridoxal phosphate). Severe NKH. No treatment is effective in changing the natural history of developmental delays, spasticity, and intractable epilepsy, but treatment with benzoate to lower glycine improves attentiveness and facilitates seizure management. Attenuated NKH. Current treatment is reduction of plasma concentration of glycine by administration of sodium benzoate and blockade of overstimulated NMDA receptors. NKH is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygotes (i.e., carriers of one NKH-related pathogenic variant); however,	Severe NKH Attenuated NKH For synonyms and outdated names see For other genetic causes of these phenotypes see • Severe NKH • Attenuated NKH ## Diagnosis Nonketotic hyperglycinemia (NKH) due to biallelic pathogenic variants in one of the two genes ( Neonates with hypotonia, lethargy, coma, apnea, seizures with or without a burst suppression pattern on EEG Infants with lethargy, hypotonia, seizures, poor feeding, developmental delays Children with developmental delays (with expressive language more impaired than receptive language), hyperactivity with or without choreatic movements, particularly with episodic worsening of manifestations Individuals with isolated elevated levels of plasma glycine, particularly when associated with hyperactivity, developmental delays, and/or seizures, or any of the other above manifestations The combination of isolated elevation of levels of glycine in plasma and CSF (obtained simultaneously) by quantitative amino acid analysis ( Note: (1) Accurate measurement of CSF glycine requires that the CSF be completely free of contamination by blood or serum (which is not visible to the eye), as evidenced by a normal RBC (red blood cell) count and protein concentration. The presence of blood or elevated protein in the CSF invalidates the results. (2) The elevation of CSF glycine is more important than the ratio, which is only a secondary measure. (3) In CSF, the serine concentration can be low, but the threonine concentration should not be elevated. (4) The elevation of glycine levels in CSF in NKH is usually higher than that observed in disorders affecting the cofactors of the glycine cleavage enzyme system (lipoate, pyridoxal phosphate) and overlaps with attenuated NKH, but exceptions exist [ Urine organic acid profile is expected to be normal. Small elevations of multiple acylglycine esters can occasionally be noticed. CSF and Plasma Glycine Concentration (µmol/L) in Nonketotic Hyperglycinemia (NKH) From Average (range) [ The author knows of very rare cases of intermittently normal CSF glycine. Normal values vary with age. Both CSF and plasma glycine concentrations are higher in the neonatal period and decrease rapidly in the first months of life (e.g., at age >1 year, normal values for CSF glycine concentration are <12 µmol/L and for plasma glycine concentration are <350 µmol/L). Samples must be obtained simultaneously. The most consistent abnormalities are noted on diffusion-weighted imaging in the first three months of life, when the vast majority of individuals with NKH present clinically. All infants with NKH have diffusion restriction in the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum (see While the diffusion restriction in the infratentorial regions recedes after age three months, it often extends upwards to the motor cortex and a generalized diffusion restriction of the supratentorial white matter can be recognized between ages three and 14 months. Other The corpus callosum can be thin and shortened but is not absent. A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. The diagnosis of NKH Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Currently the most common testing strategy is to perform concurrent testing of all three genes ( The following considerations regarding multigene panels are offered by For an introduction to multigene panels click Molecular Genetic Testing Used in Nonketotic Hyperglycinemia (NKH) Genes are listed in alphabetic order. See See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions or duplications of Although two individuals homozygous for a The vast majority of individuals with NKH have no detectable GCS activity. Individuals with a defect in the T-protein component (encoded by Up to 5% of persons with deficient GCS activity do not have pathogenic variants in any NKH-related gene. These individuals could have pathogenic variants in genes encoding proteins involved in either GCS cofactors (lipoate and pyridoxal phosphate) or glycine transport (see Note: Although enzymatic confirmation of NKH using Epstein-Barr virus cultured lymphoblasts from peripheral blood samples was reported in six individuals with P-protein defects, others have obtained overlapping GCS activity in both controls and individuals with NKH, making this method unreliable [ • Neonates with hypotonia, lethargy, coma, apnea, seizures with or without a burst suppression pattern on EEG • Infants with lethargy, hypotonia, seizures, poor feeding, developmental delays • Children with developmental delays (with expressive language more impaired than receptive language), hyperactivity with or without choreatic movements, particularly with episodic worsening of manifestations • Individuals with isolated elevated levels of plasma glycine, particularly when associated with hyperactivity, developmental delays, and/or seizures, or any of the other above manifestations • The combination of isolated elevation of levels of glycine in plasma and CSF (obtained simultaneously) by quantitative amino acid analysis ( • Note: (1) Accurate measurement of CSF glycine requires that the CSF be completely free of contamination by blood or serum (which is not visible to the eye), as evidenced by a normal RBC (red blood cell) count and protein concentration. The presence of blood or elevated protein in the CSF invalidates the results. (2) The elevation of CSF glycine is more important than the ratio, which is only a secondary measure. (3) In CSF, the serine concentration can be low, but the threonine concentration should not be elevated. (4) The elevation of glycine levels in CSF in NKH is usually higher than that observed in disorders affecting the cofactors of the glycine cleavage enzyme system (lipoate, pyridoxal phosphate) and overlaps with attenuated NKH, but exceptions exist [ • Urine organic acid profile is expected to be normal. Small elevations of multiple acylglycine esters can occasionally be noticed. • The most consistent abnormalities are noted on diffusion-weighted imaging in the first three months of life, when the vast majority of individuals with NKH present clinically. All infants with NKH have diffusion restriction in the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum (see • While the diffusion restriction in the infratentorial regions recedes after age three months, it often extends upwards to the motor cortex and a generalized diffusion restriction of the supratentorial white matter can be recognized between ages three and 14 months. • Other • The corpus callosum can be thin and shortened but is not absent. • A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. • Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. • The corpus callosum can be thin and shortened but is not absent. • A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. • Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. • The corpus callosum can be thin and shortened but is not absent. • A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. • Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. • The vast majority of individuals with NKH have no detectable GCS activity. • Individuals with a defect in the T-protein component (encoded by • Up to 5% of persons with deficient GCS activity do not have pathogenic variants in any NKH-related gene. These individuals could have pathogenic variants in genes encoding proteins involved in either GCS cofactors (lipoate and pyridoxal phosphate) or glycine transport (see ## Suggestive Findings Nonketotic hyperglycinemia (NKH) due to biallelic pathogenic variants in one of the two genes ( Neonates with hypotonia, lethargy, coma, apnea, seizures with or without a burst suppression pattern on EEG Infants with lethargy, hypotonia, seizures, poor feeding, developmental delays Children with developmental delays (with expressive language more impaired than receptive language), hyperactivity with or without choreatic movements, particularly with episodic worsening of manifestations Individuals with isolated elevated levels of plasma glycine, particularly when associated with hyperactivity, developmental delays, and/or seizures, or any of the other above manifestations The combination of isolated elevation of levels of glycine in plasma and CSF (obtained simultaneously) by quantitative amino acid analysis ( Note: (1) Accurate measurement of CSF glycine requires that the CSF be completely free of contamination by blood or serum (which is not visible to the eye), as evidenced by a normal RBC (red blood cell) count and protein concentration. The presence of blood or elevated protein in the CSF invalidates the results. (2) The elevation of CSF glycine is more important than the ratio, which is only a secondary measure. (3) In CSF, the serine concentration can be low, but the threonine concentration should not be elevated. (4) The elevation of glycine levels in CSF in NKH is usually higher than that observed in disorders affecting the cofactors of the glycine cleavage enzyme system (lipoate, pyridoxal phosphate) and overlaps with attenuated NKH, but exceptions exist [ Urine organic acid profile is expected to be normal. Small elevations of multiple acylglycine esters can occasionally be noticed. CSF and Plasma Glycine Concentration (µmol/L) in Nonketotic Hyperglycinemia (NKH) From Average (range) [ The author knows of very rare cases of intermittently normal CSF glycine. Normal values vary with age. Both CSF and plasma glycine concentrations are higher in the neonatal period and decrease rapidly in the first months of life (e.g., at age >1 year, normal values for CSF glycine concentration are <12 µmol/L and for plasma glycine concentration are <350 µmol/L). Samples must be obtained simultaneously. The most consistent abnormalities are noted on diffusion-weighted imaging in the first three months of life, when the vast majority of individuals with NKH present clinically. All infants with NKH have diffusion restriction in the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum (see While the diffusion restriction in the infratentorial regions recedes after age three months, it often extends upwards to the motor cortex and a generalized diffusion restriction of the supratentorial white matter can be recognized between ages three and 14 months. Other The corpus callosum can be thin and shortened but is not absent. A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. • Neonates with hypotonia, lethargy, coma, apnea, seizures with or without a burst suppression pattern on EEG • Infants with lethargy, hypotonia, seizures, poor feeding, developmental delays • Children with developmental delays (with expressive language more impaired than receptive language), hyperactivity with or without choreatic movements, particularly with episodic worsening of manifestations • Individuals with isolated elevated levels of plasma glycine, particularly when associated with hyperactivity, developmental delays, and/or seizures, or any of the other above manifestations • The combination of isolated elevation of levels of glycine in plasma and CSF (obtained simultaneously) by quantitative amino acid analysis ( • Note: (1) Accurate measurement of CSF glycine requires that the CSF be completely free of contamination by blood or serum (which is not visible to the eye), as evidenced by a normal RBC (red blood cell) count and protein concentration. The presence of blood or elevated protein in the CSF invalidates the results. (2) The elevation of CSF glycine is more important than the ratio, which is only a secondary measure. (3) In CSF, the serine concentration can be low, but the threonine concentration should not be elevated. (4) The elevation of glycine levels in CSF in NKH is usually higher than that observed in disorders affecting the cofactors of the glycine cleavage enzyme system (lipoate, pyridoxal phosphate) and overlaps with attenuated NKH, but exceptions exist [ • Urine organic acid profile is expected to be normal. Small elevations of multiple acylglycine esters can occasionally be noticed. • The most consistent abnormalities are noted on diffusion-weighted imaging in the first three months of life, when the vast majority of individuals with NKH present clinically. All infants with NKH have diffusion restriction in the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum (see • While the diffusion restriction in the infratentorial regions recedes after age three months, it often extends upwards to the motor cortex and a generalized diffusion restriction of the supratentorial white matter can be recognized between ages three and 14 months. • Other • The corpus callosum can be thin and shortened but is not absent. • A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. • Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. • The corpus callosum can be thin and shortened but is not absent. • A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. • Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. • The corpus callosum can be thin and shortened but is not absent. • A small group of infants develop hydrocephalus, often with an enlarged retrocerebellar cystic region. • Atrophy is present in older individuals with severe NKH, but often not in individuals with attenuated NKH. ## Establishing the Diagnosis The diagnosis of NKH Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Currently the most common testing strategy is to perform concurrent testing of all three genes ( The following considerations regarding multigene panels are offered by For an introduction to multigene panels click Molecular Genetic Testing Used in Nonketotic Hyperglycinemia (NKH) Genes are listed in alphabetic order. See See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions or duplications of Although two individuals homozygous for a The vast majority of individuals with NKH have no detectable GCS activity. Individuals with a defect in the T-protein component (encoded by Up to 5% of persons with deficient GCS activity do not have pathogenic variants in any NKH-related gene. These individuals could have pathogenic variants in genes encoding proteins involved in either GCS cofactors (lipoate and pyridoxal phosphate) or glycine transport (see Note: Although enzymatic confirmation of NKH using Epstein-Barr virus cultured lymphoblasts from peripheral blood samples was reported in six individuals with P-protein defects, others have obtained overlapping GCS activity in both controls and individuals with NKH, making this method unreliable [ • The vast majority of individuals with NKH have no detectable GCS activity. • Individuals with a defect in the T-protein component (encoded by • Up to 5% of persons with deficient GCS activity do not have pathogenic variants in any NKH-related gene. These individuals could have pathogenic variants in genes encoding proteins involved in either GCS cofactors (lipoate and pyridoxal phosphate) or glycine transport (see ## Clinical Characteristics Nonketotic hyperglycinemia (NKH) is the inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme system (GCS), which results in accumulation of large quantities of glycine in all body tissues including the brain. NKH is categorized into severe NKH and attenuated NKH based on ultimate outcome [ The majority of children with NKH present in the neonatal period or in early infancy, with only the mildest cases presenting in late infancy or childhood. Outcomes by age of onset are as follows: Myoclonic jerks and hiccups are often a sign of epilepsy. A history of prenatal hiccups is frequently present. The initial EEG often shows a burst suppression pattern. Before age six months children with severe NKH begin to develop progressive spasticity (hyperreflexia, distal hypertonicity, and positive Babinski signs) and cortical blindness (often with poor fixation and sometimes with roving eye movements). Most have swallowing dysfunction requiring tube feeding. Increasingly difficult-to-treat seizures develop in the first year, usually requiring multiple anticonvulsants with incomplete seizure control. The EEG pattern can evolve into hypsarrhythmia and/or multifocal spikes. Many develop scoliosis or hip dislocation often requiring surgical intervention (if indicated in the overall condition) in childhood or adolescence [ Occasionally children with severe NKH have cleft palate or clubfeet [ They may develop a seizure disorder, which is often relatively easy to treat with either benzoate or dextromethorphan alone or with the addition of a single anticonvulsant [ Hyperactivity is common, often severe, and poorly responsive to interventions [ Many have choreic movements, a good prognostic sign [ They can have intermittent episodes of severe lethargy, often triggered by fever and infection (sometimes reported in the past as a "mild episodic form"). An adult experienced acute decompensation while on valproate (which is contraindicated) [ They can have episodes of severe lethargy with infections [ Individuals homozygous for A number of affected individuals have had delayed gastric emptying and poor gastrointestinal motility, leading to very severe problems including dependency on total parenteral nutrition (TPN) in a few. A few individuals had sudden severe electrolyte disturbances including profound hypokalemia causing sudden cardiac arrest. This occurrence was rare (<1%) and did not recur. A few individuals have reported dysuria with difficulty emptying the bladder. It is unclear if this is a side effect of dextromethorphan or a manifestation of the disorder. In infants with severe NKH, a retrocerebellar cyst with subsequent development of hydrocephalus occurred in 3% of cases [ Affected individuals can have recurrent and long episodes of unexplained severe crying. Note: Some atypical manifestations historically reported as NKH (e.g., cardiomyopathy or with optic atrophy) are consistent with features of variant NKH (lipoate, iron-sulfur cluster defects) (see The phenotype of severe versus attenuated NKH is consistent within families, but the subcategory of attenuated NKH and degree of developmental progress can vary. A retrospective study showed a consistent phenotype within seven families with two or more affected children [ In sibs with significant variability in developmental outcome for attenuated NKH, aggressive treatment in the first two years of life with sodium benzoate and N-methyl D-aspartate (NMDA) receptor site antagonists was associated with improved developmental outcome [ The pattern of diffusion restriction on brain MRI is not predictive of phenotype [ There are no clinical differences between individuals with biallelic pathogenic variants in Glycine cleavage enzyme system (GCS) activity predicts severe versus attenuated outcome in NKH (see Biallelic pathogenic variants associated with lack of residual GCS activity, such as exon copy number variants, frameshift variants, nonsense variants, and consensus splice site variants (-1,2 or +1,2), have no residual activity except the following Biallelic pathogenic variants with preserved residual GCS activity predict attenuated NKH, with the majority having attenuated good outcome. The presence of one variant with preserved residual GCS activity usually results in attenuated NKH, and on occasion results in severe NKH. In individuals with attenuated NKH, outcome ranges from attenuated poor to intermediate, with a few good. Note: The amount of residual activity detected in expression studies sufficient for attenuated outcome is as low as 1%. The residual function of a missense variant may be difficult to assess for the purpose of predicting genotype-phenotype correlation: Thus far, the expression of 47 missense The expression of Collectively, neurologic disorders caused by disturbance of glycine metabolism and transport are termed "glycine encephalopathy." See Note: The term "atypical NKH" is no longer used as it combined cases of attenuated NKH and variant NKH (see The birth incidence of NKH has been estimated at 1:55,000 newborns in Finland (1:12,000 in an area of Northern Finland) and 1:63,000 in British Columbia, Canada [ NKH may be underdiagnosed for several reasons: Attenuated NHK and severe NKH without apnea are clinically underappreciated (e.g., identification on exome sequencing in cases of autism [ Analysis of CSF amino acids to detect elevated CSF glycine in infants with neonatal/infantile epilepsy, a primary trigger for suspicion of NKH, is not consistently obtained; furthermore, in NKH plasma glycine levels can be normal, and elevated levels are not specific for NKH. Multigene panels for neonatal/infantile epilepsy often do not include • They can have episodes of severe lethargy with infections [ • Individuals homozygous for • A number of affected individuals have had delayed gastric emptying and poor gastrointestinal motility, leading to very severe problems including dependency on total parenteral nutrition (TPN) in a few. • A few individuals had sudden severe electrolyte disturbances including profound hypokalemia causing sudden cardiac arrest. This occurrence was rare (<1%) and did not recur. • A few individuals have reported dysuria with difficulty emptying the bladder. It is unclear if this is a side effect of dextromethorphan or a manifestation of the disorder. • In infants with severe NKH, a retrocerebellar cyst with subsequent development of hydrocephalus occurred in 3% of cases [ • Affected individuals can have recurrent and long episodes of unexplained severe crying. • Biallelic pathogenic variants associated with lack of residual GCS activity, such as exon copy number variants, frameshift variants, nonsense variants, and consensus splice site variants (-1,2 or +1,2), have no residual activity except the following • Biallelic pathogenic variants with preserved residual GCS activity predict attenuated NKH, with the majority having attenuated good outcome. • The presence of one variant with preserved residual GCS activity usually results in attenuated NKH, and on occasion results in severe NKH. In individuals with attenuated NKH, outcome ranges from attenuated poor to intermediate, with a few good. • Note: The amount of residual activity detected in expression studies sufficient for attenuated outcome is as low as 1%. • The residual function of a missense variant may be difficult to assess for the purpose of predicting genotype-phenotype correlation: • Thus far, the expression of 47 missense • The expression of • Thus far, the expression of 47 missense • The expression of • Thus far, the expression of 47 missense • The expression of • Attenuated NHK and severe NKH without apnea are clinically underappreciated (e.g., identification on exome sequencing in cases of autism [ • Analysis of CSF amino acids to detect elevated CSF glycine in infants with neonatal/infantile epilepsy, a primary trigger for suspicion of NKH, is not consistently obtained; furthermore, in NKH plasma glycine levels can be normal, and elevated levels are not specific for NKH. • Multigene panels for neonatal/infantile epilepsy often do not include ## Clinical Description Nonketotic hyperglycinemia (NKH) is the inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme system (GCS), which results in accumulation of large quantities of glycine in all body tissues including the brain. NKH is categorized into severe NKH and attenuated NKH based on ultimate outcome [ The majority of children with NKH present in the neonatal period or in early infancy, with only the mildest cases presenting in late infancy or childhood. Outcomes by age of onset are as follows: Myoclonic jerks and hiccups are often a sign of epilepsy. A history of prenatal hiccups is frequently present. The initial EEG often shows a burst suppression pattern. Before age six months children with severe NKH begin to develop progressive spasticity (hyperreflexia, distal hypertonicity, and positive Babinski signs) and cortical blindness (often with poor fixation and sometimes with roving eye movements). Most have swallowing dysfunction requiring tube feeding. Increasingly difficult-to-treat seizures develop in the first year, usually requiring multiple anticonvulsants with incomplete seizure control. The EEG pattern can evolve into hypsarrhythmia and/or multifocal spikes. Many develop scoliosis or hip dislocation often requiring surgical intervention (if indicated in the overall condition) in childhood or adolescence [ Occasionally children with severe NKH have cleft palate or clubfeet [ They may develop a seizure disorder, which is often relatively easy to treat with either benzoate or dextromethorphan alone or with the addition of a single anticonvulsant [ Hyperactivity is common, often severe, and poorly responsive to interventions [ Many have choreic movements, a good prognostic sign [ They can have intermittent episodes of severe lethargy, often triggered by fever and infection (sometimes reported in the past as a "mild episodic form"). An adult experienced acute decompensation while on valproate (which is contraindicated) [ They can have episodes of severe lethargy with infections [ Individuals homozygous for A number of affected individuals have had delayed gastric emptying and poor gastrointestinal motility, leading to very severe problems including dependency on total parenteral nutrition (TPN) in a few. A few individuals had sudden severe electrolyte disturbances including profound hypokalemia causing sudden cardiac arrest. This occurrence was rare (<1%) and did not recur. A few individuals have reported dysuria with difficulty emptying the bladder. It is unclear if this is a side effect of dextromethorphan or a manifestation of the disorder. In infants with severe NKH, a retrocerebellar cyst with subsequent development of hydrocephalus occurred in 3% of cases [ Affected individuals can have recurrent and long episodes of unexplained severe crying. Note: Some atypical manifestations historically reported as NKH (e.g., cardiomyopathy or with optic atrophy) are consistent with features of variant NKH (lipoate, iron-sulfur cluster defects) (see The phenotype of severe versus attenuated NKH is consistent within families, but the subcategory of attenuated NKH and degree of developmental progress can vary. A retrospective study showed a consistent phenotype within seven families with two or more affected children [ In sibs with significant variability in developmental outcome for attenuated NKH, aggressive treatment in the first two years of life with sodium benzoate and N-methyl D-aspartate (NMDA) receptor site antagonists was associated with improved developmental outcome [ The pattern of diffusion restriction on brain MRI is not predictive of phenotype [ • They can have episodes of severe lethargy with infections [ • Individuals homozygous for • A number of affected individuals have had delayed gastric emptying and poor gastrointestinal motility, leading to very severe problems including dependency on total parenteral nutrition (TPN) in a few. • A few individuals had sudden severe electrolyte disturbances including profound hypokalemia causing sudden cardiac arrest. This occurrence was rare (<1%) and did not recur. • A few individuals have reported dysuria with difficulty emptying the bladder. It is unclear if this is a side effect of dextromethorphan or a manifestation of the disorder. • In infants with severe NKH, a retrocerebellar cyst with subsequent development of hydrocephalus occurred in 3% of cases [ • Affected individuals can have recurrent and long episodes of unexplained severe crying. ## Presentation Myoclonic jerks and hiccups are often a sign of epilepsy. A history of prenatal hiccups is frequently present. The initial EEG often shows a burst suppression pattern. ## Outcome Before age six months children with severe NKH begin to develop progressive spasticity (hyperreflexia, distal hypertonicity, and positive Babinski signs) and cortical blindness (often with poor fixation and sometimes with roving eye movements). Most have swallowing dysfunction requiring tube feeding. Increasingly difficult-to-treat seizures develop in the first year, usually requiring multiple anticonvulsants with incomplete seizure control. The EEG pattern can evolve into hypsarrhythmia and/or multifocal spikes. Many develop scoliosis or hip dislocation often requiring surgical intervention (if indicated in the overall condition) in childhood or adolescence [ Occasionally children with severe NKH have cleft palate or clubfeet [ They may develop a seizure disorder, which is often relatively easy to treat with either benzoate or dextromethorphan alone or with the addition of a single anticonvulsant [ Hyperactivity is common, often severe, and poorly responsive to interventions [ Many have choreic movements, a good prognostic sign [ They can have intermittent episodes of severe lethargy, often triggered by fever and infection (sometimes reported in the past as a "mild episodic form"). An adult experienced acute decompensation while on valproate (which is contraindicated) [ They can have episodes of severe lethargy with infections [ Individuals homozygous for A number of affected individuals have had delayed gastric emptying and poor gastrointestinal motility, leading to very severe problems including dependency on total parenteral nutrition (TPN) in a few. A few individuals had sudden severe electrolyte disturbances including profound hypokalemia causing sudden cardiac arrest. This occurrence was rare (<1%) and did not recur. A few individuals have reported dysuria with difficulty emptying the bladder. It is unclear if this is a side effect of dextromethorphan or a manifestation of the disorder. In infants with severe NKH, a retrocerebellar cyst with subsequent development of hydrocephalus occurred in 3% of cases [ Affected individuals can have recurrent and long episodes of unexplained severe crying. Note: Some atypical manifestations historically reported as NKH (e.g., cardiomyopathy or with optic atrophy) are consistent with features of variant NKH (lipoate, iron-sulfur cluster defects) (see • They can have episodes of severe lethargy with infections [ • Individuals homozygous for • A number of affected individuals have had delayed gastric emptying and poor gastrointestinal motility, leading to very severe problems including dependency on total parenteral nutrition (TPN) in a few. • A few individuals had sudden severe electrolyte disturbances including profound hypokalemia causing sudden cardiac arrest. This occurrence was rare (<1%) and did not recur. • A few individuals have reported dysuria with difficulty emptying the bladder. It is unclear if this is a side effect of dextromethorphan or a manifestation of the disorder. • In infants with severe NKH, a retrocerebellar cyst with subsequent development of hydrocephalus occurred in 3% of cases [ • Affected individuals can have recurrent and long episodes of unexplained severe crying. ## Intrafamilial Variability The phenotype of severe versus attenuated NKH is consistent within families, but the subcategory of attenuated NKH and degree of developmental progress can vary. A retrospective study showed a consistent phenotype within seven families with two or more affected children [ In sibs with significant variability in developmental outcome for attenuated NKH, aggressive treatment in the first two years of life with sodium benzoate and N-methyl D-aspartate (NMDA) receptor site antagonists was associated with improved developmental outcome [ ## Prognostic Predictors The pattern of diffusion restriction on brain MRI is not predictive of phenotype [ ## Genotype-Phenotype Correlations There are no clinical differences between individuals with biallelic pathogenic variants in Glycine cleavage enzyme system (GCS) activity predicts severe versus attenuated outcome in NKH (see Biallelic pathogenic variants associated with lack of residual GCS activity, such as exon copy number variants, frameshift variants, nonsense variants, and consensus splice site variants (-1,2 or +1,2), have no residual activity except the following Biallelic pathogenic variants with preserved residual GCS activity predict attenuated NKH, with the majority having attenuated good outcome. The presence of one variant with preserved residual GCS activity usually results in attenuated NKH, and on occasion results in severe NKH. In individuals with attenuated NKH, outcome ranges from attenuated poor to intermediate, with a few good. Note: The amount of residual activity detected in expression studies sufficient for attenuated outcome is as low as 1%. The residual function of a missense variant may be difficult to assess for the purpose of predicting genotype-phenotype correlation: Thus far, the expression of 47 missense The expression of • Biallelic pathogenic variants associated with lack of residual GCS activity, such as exon copy number variants, frameshift variants, nonsense variants, and consensus splice site variants (-1,2 or +1,2), have no residual activity except the following • Biallelic pathogenic variants with preserved residual GCS activity predict attenuated NKH, with the majority having attenuated good outcome. • The presence of one variant with preserved residual GCS activity usually results in attenuated NKH, and on occasion results in severe NKH. In individuals with attenuated NKH, outcome ranges from attenuated poor to intermediate, with a few good. • Note: The amount of residual activity detected in expression studies sufficient for attenuated outcome is as low as 1%. • The residual function of a missense variant may be difficult to assess for the purpose of predicting genotype-phenotype correlation: • Thus far, the expression of 47 missense • The expression of • Thus far, the expression of 47 missense • The expression of • Thus far, the expression of 47 missense • The expression of ## Nomenclature Collectively, neurologic disorders caused by disturbance of glycine metabolism and transport are termed "glycine encephalopathy." See Note: The term "atypical NKH" is no longer used as it combined cases of attenuated NKH and variant NKH (see ## Prevalence The birth incidence of NKH has been estimated at 1:55,000 newborns in Finland (1:12,000 in an area of Northern Finland) and 1:63,000 in British Columbia, Canada [ NKH may be underdiagnosed for several reasons: Attenuated NHK and severe NKH without apnea are clinically underappreciated (e.g., identification on exome sequencing in cases of autism [ Analysis of CSF amino acids to detect elevated CSF glycine in infants with neonatal/infantile epilepsy, a primary trigger for suspicion of NKH, is not consistently obtained; furthermore, in NKH plasma glycine levels can be normal, and elevated levels are not specific for NKH. Multigene panels for neonatal/infantile epilepsy often do not include • Attenuated NHK and severe NKH without apnea are clinically underappreciated (e.g., identification on exome sequencing in cases of autism [ • Analysis of CSF amino acids to detect elevated CSF glycine in infants with neonatal/infantile epilepsy, a primary trigger for suspicion of NKH, is not consistently obtained; furthermore, in NKH plasma glycine levels can be normal, and elevated levels are not specific for NKH. • Multigene panels for neonatal/infantile epilepsy often do not include ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Although an association of heterozygous variants in ## Differential Diagnosis Inherited Disorders in the Differential Diagnosis of NKH ↑ plasma & CSF glycine levels Deficient GCS activity Deficient pyruvate dehydrogenase enzyme activity ↑ plasma & CSF glycine levels Deficient GCS activity ↑ CSF glycine levels Low CSF pyridoxal phosphate ↑ plasma & CSF glycine levels Combined methylmalonic aciduria & hyperhomocysteinemia ↑ CSF glycine (range: 21-33 μmol/L) Normal plasma glycine & ↑ CSF:plasma glycine ratio ↑ plasma & CSF glycine levels but normal CSF:plasma glycine ratio Abnormal urine organic acids (ketotic hyperglycinemia) AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; GCS = glycine cleavage enzyme system; IVA = isovaleric acidemia; MMA = methylmalonic aciduria; MOI = mode of inheritance; NKH = nonketotic hyperglycinemia; PA = propionic acidemia; PLPBP = pyridoxal 5'-phosphate-binding protein; PNPO = pyridoxamine 5'-phosphate oxidase; XL = X-linked "Variant NKH" refers to glycine encephalopathy with elevated glycine levels and deficient GCS activity without Impaired lipoylation or deficient lipoate due to biallelic pathogenic variants in genes encoding either lipoate synthesis (e.g., Pyridoxal phosphate is a cofactor for the glycine cleavage enzyme system. Insufficient pyridoxal phosphate results in elevated glycine levels. "Ketotic hyperglycinemia" is a term used in the past to refer to genetic disorders in which GCS activity is secondarily inhibited in particular for several organic acidurias [ Valproate treatment, which causes a secondary decrease in liver glycine cleavage enzyme system (GCS) activity and can reversibly increase the CSF glycine concentration to >60 µmol/L [Jaeken & Van Hove, unpublished observations] Hyperglycinemia of unknown cause identified on newborn screening (NBS). Several neonates have been reported to have isolated and persistently elevated serum glycine concentrations (>1,000 µmol/L) on NBS. CSF glycine concentration measured in one child was normal. Although the infants were asymptomatic, long-term follow up is not yet available. Molecular genetic testing for nonketotic hyperglycinemia did not identify causative variants in Severe liver failure can cause hyperglycinemia (>2,000 μmol/L), which can precede other manifestations of liver failure. Of note, liver failure in neonates can result from acute herpes simplex virus infection. Loading with large amounts of glycine (e.g., use of immunoglobulins in a glycine buffer or bladder irrigation with a glycine-based solution) can cause substantial hyperglycinemia. Recent reports of causative intracerebral hemorrhage [ In the presence of hemorrhage, there can be elevated CSF glycine and elevated glycine on magnetic resonance spectroscopy [ Inherited defects in renal transport of glycine: Familial iminoglycinuria. Homozygotes for a null allele in Benign hyperglycinuria. A common transient finding caused by immaturity of renal glycine reabsorption Gyral malformations or true absence of the corpus callosum are not part of NKH, but have been noted in some cases of variant NKH [ Cystic leukoencephalopathy would indicate possible variant NKH due to disorders in lipoate and/or iron-sulfur cluster metabolism. A mild increase of CSF glycine has also been reported in • ↑ plasma & CSF glycine levels • Deficient GCS activity • Deficient pyruvate dehydrogenase enzyme activity • ↑ plasma & CSF glycine levels • Deficient GCS activity • ↑ CSF glycine levels • Low CSF pyridoxal phosphate • ↑ plasma & CSF glycine levels • Combined methylmalonic aciduria & hyperhomocysteinemia • ↑ CSF glycine (range: 21-33 μmol/L) • Normal plasma glycine & ↑ CSF:plasma glycine ratio • ↑ plasma & CSF glycine levels but normal CSF:plasma glycine ratio • Abnormal urine organic acids (ketotic hyperglycinemia) • Valproate treatment, which causes a secondary decrease in liver glycine cleavage enzyme system (GCS) activity and can reversibly increase the CSF glycine concentration to >60 µmol/L [Jaeken & Van Hove, unpublished observations] • Hyperglycinemia of unknown cause identified on newborn screening (NBS). Several neonates have been reported to have isolated and persistently elevated serum glycine concentrations (>1,000 µmol/L) on NBS. CSF glycine concentration measured in one child was normal. Although the infants were asymptomatic, long-term follow up is not yet available. Molecular genetic testing for nonketotic hyperglycinemia did not identify causative variants in • Severe liver failure can cause hyperglycinemia (>2,000 μmol/L), which can precede other manifestations of liver failure. Of note, liver failure in neonates can result from acute herpes simplex virus infection. • Loading with large amounts of glycine (e.g., use of immunoglobulins in a glycine buffer or bladder irrigation with a glycine-based solution) can cause substantial hyperglycinemia. • Familial iminoglycinuria. Homozygotes for a null allele in • Benign hyperglycinuria. A common transient finding caused by immaturity of renal glycine reabsorption • Gyral malformations or true absence of the corpus callosum are not part of NKH, but have been noted in some cases of variant NKH [ • Cystic leukoencephalopathy would indicate possible variant NKH due to disorders in lipoate and/or iron-sulfur cluster metabolism. A mild increase of CSF glycine has also been reported in ## Management To establish the extent of disease and needs in an individual diagnosed with nonketotic hyperglycinemia (NKH), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. No formal management guidelines have been developed for NKH. Current treatment is focused on: For severe NKH, no treatment is effective in changing the natural history of developmental delays, spasticity, and intractable epilepsy. Specifically, glycine-lowering therapy is not effective in improving the affected individual's development, even when initiated at birth [ In contrast, for attenuated NKH current treatment consists of reduction of plasma concentration of glycine by treatment with sodium benzoate and blockade of NMDA receptors, which are overstimulated at the glycinergic site. To date two independent studies have shown that early, aggressive treatment of children with pathogenic variants associated with residual glycine cleavage enzyme system (GCS) activity who are likely to develop attenuated NKH resulted in improved neurodevelopmental outcome and reduced propensity for epilepsy [ The dose required depends on the glycine pool available. * Individuals with attenuated NKH require a lower dose (200-550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m Individuals with severe NKH require a higher dose (550-750 mg/kg/day) [ * Note: Because the glycine pool is reduced when individuals are on a ketogenic diet, sodium benzoate dose must be reduced upon initiation of this diet to avoid toxicity. Sodium benzoate should be divided into no less than three doses per day; doses are more frequent in infancy (for example, neonates typically receive six daily doses). Benzoate treatment begins with the lower dose range for the predicted disease severity; plasma glycine concentration is measured regularly. If the plasma glycine concentration is not within target range, the dose is increased by 50 mg/kg/day, and plasma glycine concentration is measured again as soon as 24 to 48 hours later. When glycine is within the target range, plasma glycine levels are measured regularly: every two weeks for infants, every month for young children, and every three months for older children. Because the liver and kidney (but not the brain) are the sites of action of sodium benzoate, it is unclear to what extent administration of sodium benzoate reduces brain or CSF glycine. It is known that treatment with sodium benzoate does not normalize CSF glycine concentration. Follow up with serial measurements of CSF glycine concentration is not required. Side effects of sodium benzoate include the following: High-dose sodium benzoate (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine; those with low carnitine levels should receive supplementation to maintain normal plasma concentrations. Dosing of sodium benzoate in excess of the individual requirement is dangerous: benzoate toxicity has high morbidity and mortality [ As benzoate is unpalatable, a saliva-resistant granulated benzoate is available in several countries for individuals not on tube feeding. When transferring individuals from regular benzoate to granulated benzoate, providers should consider that the benzoate content in the granulated form is approximately 75%. An inappropriately severe glycine-restricted diet has been associated with protein malnutrition [ Glycine is an allosteric activator of the NMDA receptor channel complex; thus, excess glycine can result in overstimulation, which has been putatively linked to seizures and developmental delays. Clinically used partial inhibitors of the NMDA receptor include dextromethorphan, ketamine, or felbamate. Pharmacogenomic differences exist in the metabolism of dextromethorphan, particularly based on CYP2D6 polymorphism. Some concomitant medications may slow the metabolism of dextromethorphan (e.g., cimetidine) and should be reviewed or not used as they may cause toxicity [ Treatment effect: Control of seizure disorders associated with a severely disturbed background such as burst suppression pattern or hypsarrhythmia is essential to allow developmental progress. Control tends to be challenging in severe NKH but is usually possible in attenuated NKH and essential for good outcome: First-line treatment for newborns and infants with myoclonic seizures is benzodiazepines, with clobazam currently the preferred first-line drug, whereas older literature mentioned clonazepam and diazepam. Variable results are reported with use of standard anti-seizure medication (ASM) in neonates. Phenytoin has limited efficacy for seizure control. The effect of phenobarbital is variable in neonates, but because the nature of the epilepsy changes in late infancy, phenobarbital is often useful in treating seizures in older affected children. Other drugs used with variable effect include levetiracetam and topiramate. Various ASMs have been used with variable success. Felbamate has been successful in some children with difficult-to-treat seizures. This treatment must be closely monitored for signs of liver or hematopoietic toxicity. Ketogenic diet has been used in some individuals with variable success. Ketogenic diet always lowers the amount of glycine substantially and the dose of sodium benzoate should be reduced accordingly to avoid benzoate toxicity [ For some older individuals with severe NKH and difficult-to-control seizures, a vagal nerve stimulator has been used with varying (sometimes very high) levels of success [ Treatment of infantile spasms and hypsarrhythmia in the context of severe NKH is difficult. Steroids rarely have an effect; vigabatrin has resulted in loss of skills and adverse outcome in individuals with attenuated NKH [ Most affected individuals need physical therapy. Scoliosis and hip dislocation, common in older children with severe NKH, are managed with standard techniques. The utility of these procedures has to be weighted in the quality of life of the individual. Individuals with severe NKH have progressive difficulty maintaining good airway management. Pulmonary review and assistance can greatly facilitate quality of life. Up to 80% of neonates with symptomatic NKH develop life-threatening bradypnea or apnea and require ventilator assistance during the first week of life. In the second to the third week of life spontaneous breathing typically resumes (even in the absence of treatment to reduce glycine levels), allowing discontinuation of ventilator assistance. Following resumption of spontaneous breathing, apnea is unlikely to recur. Following resolution of the apneic phase, some untreated infants with neonatal-onset NKH may die in the next two years, but many – if not most – live for several years. Because of the generally poor prognosis of neonatal-onset NKH, some families elect to withdraw intensive care support during the neonatal apneic phase, allowing the infant to succumb prior to recovery of spontaneous respiration. For a discussion of the ethics involved in deciding to withdraw support for neonates with apnea see Developmental assessment should be performed throughout the first years of life. Neurologic assessments in the first year can identify early development of spasticity in severely affected individuals and early development of chorea in more mildly affected individuals. Severely affected individuals should be monitored for scoliosis and hip dysplasia. Pulmonary function should be assessed, particularly in children who develop recurrent respiratory infections. Valproate is contraindicated in NKH as an anti-seizure medication. It raises blood and CSF glycine concentrations and may increase seizure frequency. It has resulted in severe lethargy, coma, severe seizures, and chorea particularly in mildly affected individuals [ Vigabatrin has resulted in rapid loss of function when used to treat West syndrome in NKH caused by deficient activity of the glycine cleavage enzyme system [ Biochemical testing to promote early diagnosis and treatment of at-risk newborn sibs is indicated. In particular, sibs at risk for attenuated NKH can benefit from early and aggressive treatment [ If the pathogenic variants in the family are known, biochemical testing can be followed with molecular genetic testing. See Pregnancy has been reported in one woman with attenuated NKH. No obvious teratogenic effect was observed and intelligence was normal [ Search • Individuals with attenuated NKH require a lower dose (200-550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m • Individuals with severe NKH require a higher dose (550-750 mg/kg/day) [ • High-dose sodium benzoate (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H • High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine; those with low carnitine levels should receive supplementation to maintain normal plasma concentrations. • Dosing of sodium benzoate in excess of the individual requirement is dangerous: benzoate toxicity has high morbidity and mortality [ • As benzoate is unpalatable, a saliva-resistant granulated benzoate is available in several countries for individuals not on tube feeding. When transferring individuals from regular benzoate to granulated benzoate, providers should consider that the benzoate content in the granulated form is approximately 75%. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with nonketotic hyperglycinemia (NKH), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. ## Treatment of Manifestations No formal management guidelines have been developed for NKH. Current treatment is focused on: For severe NKH, no treatment is effective in changing the natural history of developmental delays, spasticity, and intractable epilepsy. Specifically, glycine-lowering therapy is not effective in improving the affected individual's development, even when initiated at birth [ In contrast, for attenuated NKH current treatment consists of reduction of plasma concentration of glycine by treatment with sodium benzoate and blockade of NMDA receptors, which are overstimulated at the glycinergic site. To date two independent studies have shown that early, aggressive treatment of children with pathogenic variants associated with residual glycine cleavage enzyme system (GCS) activity who are likely to develop attenuated NKH resulted in improved neurodevelopmental outcome and reduced propensity for epilepsy [ The dose required depends on the glycine pool available. * Individuals with attenuated NKH require a lower dose (200-550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m Individuals with severe NKH require a higher dose (550-750 mg/kg/day) [ * Note: Because the glycine pool is reduced when individuals are on a ketogenic diet, sodium benzoate dose must be reduced upon initiation of this diet to avoid toxicity. Sodium benzoate should be divided into no less than three doses per day; doses are more frequent in infancy (for example, neonates typically receive six daily doses). Benzoate treatment begins with the lower dose range for the predicted disease severity; plasma glycine concentration is measured regularly. If the plasma glycine concentration is not within target range, the dose is increased by 50 mg/kg/day, and plasma glycine concentration is measured again as soon as 24 to 48 hours later. When glycine is within the target range, plasma glycine levels are measured regularly: every two weeks for infants, every month for young children, and every three months for older children. Because the liver and kidney (but not the brain) are the sites of action of sodium benzoate, it is unclear to what extent administration of sodium benzoate reduces brain or CSF glycine. It is known that treatment with sodium benzoate does not normalize CSF glycine concentration. Follow up with serial measurements of CSF glycine concentration is not required. Side effects of sodium benzoate include the following: High-dose sodium benzoate (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine; those with low carnitine levels should receive supplementation to maintain normal plasma concentrations. Dosing of sodium benzoate in excess of the individual requirement is dangerous: benzoate toxicity has high morbidity and mortality [ As benzoate is unpalatable, a saliva-resistant granulated benzoate is available in several countries for individuals not on tube feeding. When transferring individuals from regular benzoate to granulated benzoate, providers should consider that the benzoate content in the granulated form is approximately 75%. An inappropriately severe glycine-restricted diet has been associated with protein malnutrition [ Glycine is an allosteric activator of the NMDA receptor channel complex; thus, excess glycine can result in overstimulation, which has been putatively linked to seizures and developmental delays. Clinically used partial inhibitors of the NMDA receptor include dextromethorphan, ketamine, or felbamate. Pharmacogenomic differences exist in the metabolism of dextromethorphan, particularly based on CYP2D6 polymorphism. Some concomitant medications may slow the metabolism of dextromethorphan (e.g., cimetidine) and should be reviewed or not used as they may cause toxicity [ Treatment effect: Control of seizure disorders associated with a severely disturbed background such as burst suppression pattern or hypsarrhythmia is essential to allow developmental progress. Control tends to be challenging in severe NKH but is usually possible in attenuated NKH and essential for good outcome: First-line treatment for newborns and infants with myoclonic seizures is benzodiazepines, with clobazam currently the preferred first-line drug, whereas older literature mentioned clonazepam and diazepam. Variable results are reported with use of standard anti-seizure medication (ASM) in neonates. Phenytoin has limited efficacy for seizure control. The effect of phenobarbital is variable in neonates, but because the nature of the epilepsy changes in late infancy, phenobarbital is often useful in treating seizures in older affected children. Other drugs used with variable effect include levetiracetam and topiramate. Various ASMs have been used with variable success. Felbamate has been successful in some children with difficult-to-treat seizures. This treatment must be closely monitored for signs of liver or hematopoietic toxicity. Ketogenic diet has been used in some individuals with variable success. Ketogenic diet always lowers the amount of glycine substantially and the dose of sodium benzoate should be reduced accordingly to avoid benzoate toxicity [ For some older individuals with severe NKH and difficult-to-control seizures, a vagal nerve stimulator has been used with varying (sometimes very high) levels of success [ Treatment of infantile spasms and hypsarrhythmia in the context of severe NKH is difficult. Steroids rarely have an effect; vigabatrin has resulted in loss of skills and adverse outcome in individuals with attenuated NKH [ Most affected individuals need physical therapy. Scoliosis and hip dislocation, common in older children with severe NKH, are managed with standard techniques. The utility of these procedures has to be weighted in the quality of life of the individual. Individuals with severe NKH have progressive difficulty maintaining good airway management. Pulmonary review and assistance can greatly facilitate quality of life. Up to 80% of neonates with symptomatic NKH develop life-threatening bradypnea or apnea and require ventilator assistance during the first week of life. In the second to the third week of life spontaneous breathing typically resumes (even in the absence of treatment to reduce glycine levels), allowing discontinuation of ventilator assistance. Following resumption of spontaneous breathing, apnea is unlikely to recur. Following resolution of the apneic phase, some untreated infants with neonatal-onset NKH may die in the next two years, but many – if not most – live for several years. Because of the generally poor prognosis of neonatal-onset NKH, some families elect to withdraw intensive care support during the neonatal apneic phase, allowing the infant to succumb prior to recovery of spontaneous respiration. For a discussion of the ethics involved in deciding to withdraw support for neonates with apnea see • Individuals with attenuated NKH require a lower dose (200-550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m • Individuals with severe NKH require a higher dose (550-750 mg/kg/day) [ • High-dose sodium benzoate (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H • High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine; those with low carnitine levels should receive supplementation to maintain normal plasma concentrations. • Dosing of sodium benzoate in excess of the individual requirement is dangerous: benzoate toxicity has high morbidity and mortality [ • As benzoate is unpalatable, a saliva-resistant granulated benzoate is available in several countries for individuals not on tube feeding. When transferring individuals from regular benzoate to granulated benzoate, providers should consider that the benzoate content in the granulated form is approximately 75%. ## Reduction of Plasma Concentration of Glycine The dose required depends on the glycine pool available. * Individuals with attenuated NKH require a lower dose (200-550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m Individuals with severe NKH require a higher dose (550-750 mg/kg/day) [ * Note: Because the glycine pool is reduced when individuals are on a ketogenic diet, sodium benzoate dose must be reduced upon initiation of this diet to avoid toxicity. Sodium benzoate should be divided into no less than three doses per day; doses are more frequent in infancy (for example, neonates typically receive six daily doses). Benzoate treatment begins with the lower dose range for the predicted disease severity; plasma glycine concentration is measured regularly. If the plasma glycine concentration is not within target range, the dose is increased by 50 mg/kg/day, and plasma glycine concentration is measured again as soon as 24 to 48 hours later. When glycine is within the target range, plasma glycine levels are measured regularly: every two weeks for infants, every month for young children, and every three months for older children. Because the liver and kidney (but not the brain) are the sites of action of sodium benzoate, it is unclear to what extent administration of sodium benzoate reduces brain or CSF glycine. It is known that treatment with sodium benzoate does not normalize CSF glycine concentration. Follow up with serial measurements of CSF glycine concentration is not required. Side effects of sodium benzoate include the following: High-dose sodium benzoate (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine; those with low carnitine levels should receive supplementation to maintain normal plasma concentrations. Dosing of sodium benzoate in excess of the individual requirement is dangerous: benzoate toxicity has high morbidity and mortality [ As benzoate is unpalatable, a saliva-resistant granulated benzoate is available in several countries for individuals not on tube feeding. When transferring individuals from regular benzoate to granulated benzoate, providers should consider that the benzoate content in the granulated form is approximately 75%. An inappropriately severe glycine-restricted diet has been associated with protein malnutrition [ • Individuals with attenuated NKH require a lower dose (200-550 mg/kg/day). For older children and adults, consider dosing based on body surface area (e.g., for attenuated NKH start at 5.5 g/m • Individuals with severe NKH require a higher dose (550-750 mg/kg/day) [ • High-dose sodium benzoate (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H • High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine; those with low carnitine levels should receive supplementation to maintain normal plasma concentrations. • Dosing of sodium benzoate in excess of the individual requirement is dangerous: benzoate toxicity has high morbidity and mortality [ • As benzoate is unpalatable, a saliva-resistant granulated benzoate is available in several countries for individuals not on tube feeding. When transferring individuals from regular benzoate to granulated benzoate, providers should consider that the benzoate content in the granulated form is approximately 75%. ## NMDA Receptor Site Antagonists Glycine is an allosteric activator of the NMDA receptor channel complex; thus, excess glycine can result in overstimulation, which has been putatively linked to seizures and developmental delays. Clinically used partial inhibitors of the NMDA receptor include dextromethorphan, ketamine, or felbamate. Pharmacogenomic differences exist in the metabolism of dextromethorphan, particularly based on CYP2D6 polymorphism. Some concomitant medications may slow the metabolism of dextromethorphan (e.g., cimetidine) and should be reviewed or not used as they may cause toxicity [ Treatment effect: ## Symptomatic Treatment Control of seizure disorders associated with a severely disturbed background such as burst suppression pattern or hypsarrhythmia is essential to allow developmental progress. Control tends to be challenging in severe NKH but is usually possible in attenuated NKH and essential for good outcome: First-line treatment for newborns and infants with myoclonic seizures is benzodiazepines, with clobazam currently the preferred first-line drug, whereas older literature mentioned clonazepam and diazepam. Variable results are reported with use of standard anti-seizure medication (ASM) in neonates. Phenytoin has limited efficacy for seizure control. The effect of phenobarbital is variable in neonates, but because the nature of the epilepsy changes in late infancy, phenobarbital is often useful in treating seizures in older affected children. Other drugs used with variable effect include levetiracetam and topiramate. Various ASMs have been used with variable success. Felbamate has been successful in some children with difficult-to-treat seizures. This treatment must be closely monitored for signs of liver or hematopoietic toxicity. Ketogenic diet has been used in some individuals with variable success. Ketogenic diet always lowers the amount of glycine substantially and the dose of sodium benzoate should be reduced accordingly to avoid benzoate toxicity [ For some older individuals with severe NKH and difficult-to-control seizures, a vagal nerve stimulator has been used with varying (sometimes very high) levels of success [ Treatment of infantile spasms and hypsarrhythmia in the context of severe NKH is difficult. Steroids rarely have an effect; vigabatrin has resulted in loss of skills and adverse outcome in individuals with attenuated NKH [ Most affected individuals need physical therapy. Scoliosis and hip dislocation, common in older children with severe NKH, are managed with standard techniques. The utility of these procedures has to be weighted in the quality of life of the individual. Individuals with severe NKH have progressive difficulty maintaining good airway management. Pulmonary review and assistance can greatly facilitate quality of life. ## Withdrawal of Intensive Care Support Up to 80% of neonates with symptomatic NKH develop life-threatening bradypnea or apnea and require ventilator assistance during the first week of life. In the second to the third week of life spontaneous breathing typically resumes (even in the absence of treatment to reduce glycine levels), allowing discontinuation of ventilator assistance. Following resumption of spontaneous breathing, apnea is unlikely to recur. Following resolution of the apneic phase, some untreated infants with neonatal-onset NKH may die in the next two years, but many – if not most – live for several years. Because of the generally poor prognosis of neonatal-onset NKH, some families elect to withdraw intensive care support during the neonatal apneic phase, allowing the infant to succumb prior to recovery of spontaneous respiration. For a discussion of the ethics involved in deciding to withdraw support for neonates with apnea see ## Surveillance Developmental assessment should be performed throughout the first years of life. Neurologic assessments in the first year can identify early development of spasticity in severely affected individuals and early development of chorea in more mildly affected individuals. Severely affected individuals should be monitored for scoliosis and hip dysplasia. Pulmonary function should be assessed, particularly in children who develop recurrent respiratory infections. ## Agents/Circumstances to Avoid Valproate is contraindicated in NKH as an anti-seizure medication. It raises blood and CSF glycine concentrations and may increase seizure frequency. It has resulted in severe lethargy, coma, severe seizures, and chorea particularly in mildly affected individuals [ Vigabatrin has resulted in rapid loss of function when used to treat West syndrome in NKH caused by deficient activity of the glycine cleavage enzyme system [ ## Evaluation of Relatives at Risk Biochemical testing to promote early diagnosis and treatment of at-risk newborn sibs is indicated. In particular, sibs at risk for attenuated NKH can benefit from early and aggressive treatment [ If the pathogenic variants in the family are known, biochemical testing can be followed with molecular genetic testing. See ## Pregnancy Management Pregnancy has been reported in one woman with attenuated NKH. No obvious teratogenic effect was observed and intelligence was normal [ ## Therapies Under Investigation Search ## Genetic Counseling Nonketotic hyperglycinemia (NKH) is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygotes (i.e., carriers of one NKH-related pathogenic variant). Heterozygotes are asymptomatic and are not at risk of developing the disorder. If both parents are heterozygous for one pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Note: Carrier testing using biochemical methods is not reliable. See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. If only a single pathogenic variant in a causative gene is known, and if material from the proband and both parents is available, intragenic SNPs have been used to provide intragenic linkage analysis. • The parents of an affected individual are typically heterozygotes (i.e., carriers of one NKH-related pathogenic variant). • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • If both parents are heterozygous for one pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Nonketotic hyperglycinemia (NKH) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are typically heterozygotes (i.e., carriers of one NKH-related pathogenic variant). Heterozygotes are asymptomatic and are not at risk of developing the disorder. If both parents are heterozygous for one pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are typically heterozygotes (i.e., carriers of one NKH-related pathogenic variant). • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • If both parents are heterozygous for one pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Note: Carrier testing using biochemical methods is not reliable. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing If only a single pathogenic variant in a causative gene is known, and if material from the proband and both parents is available, intragenic SNPs have been used to provide intragenic linkage analysis. ## Resources United Kingdom Germany 2236 Birchbark Trail Clearwater FL 33763 • • United Kingdom • • • • • • • Germany • • • 2236 Birchbark Trail • Clearwater FL 33763 • ## Molecular Genetics Nonketotic Hyperglycinemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nonketotic Hyperglycinemia ( Nonketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by deficient activity of the glycine cleavage enzyme system (GCS) ( Laboratory Technical Considerations for Genes Causing Nonketotic Hyperglycinemia 20% of pathogenic Genes are listed alphabetically. More than 420 unique pathogenic variants were deposited in the Leiden Open Variant Database (LOVD) [ Notable Pathogenic Variants in Genes Causing Nonketotic Hyperglycinemia Variants listed in the table have been provided by the authors. GCS = glycine cleavage enzyme system Genes are listed alphabetically. Variant designation that does not conform to current naming conventions • 20% of pathogenic ## Molecular Pathogenesis Nonketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by deficient activity of the glycine cleavage enzyme system (GCS) ( Laboratory Technical Considerations for Genes Causing Nonketotic Hyperglycinemia 20% of pathogenic Genes are listed alphabetically. More than 420 unique pathogenic variants were deposited in the Leiden Open Variant Database (LOVD) [ Notable Pathogenic Variants in Genes Causing Nonketotic Hyperglycinemia Variants listed in the table have been provided by the authors. GCS = glycine cleavage enzyme system Genes are listed alphabetically. Variant designation that does not conform to current naming conventions • 20% of pathogenic ## Chapter Notes Derek A Applegarth, PhD, FCCMG; University of British Columbia (2002-2005)Curtis Coughlin II, MS, MBe (2013-present)Ada Hamosh, MD, MPH; Johns Hopkins University School of Medicine (2002-2013)Julia B Hennermann, MD, PhD (2019-present)S Lane Rutledge, MD; University of Alabama at Birmingham (2018-2019; see The authors would like to dedicate this 23 May 2019 (bp) Comprehensive update posted live 11 July 2013 (me) Comprehensive update posted live 24 November 2009 (me) Comprehensive update posted live 26 July 2005 (ah) Revision: molecular genetic testing clinically available 14 December 2004 (me) Comprehensive update posted live 16 May 2003 (cd) Revision: enzymatic prenatal testing no longer available 14 November 2002 (me) Review posted live 7 March 2002 (da) Original submission • 23 May 2019 (bp) Comprehensive update posted live • 11 July 2013 (me) Comprehensive update posted live • 24 November 2009 (me) Comprehensive update posted live • 26 July 2005 (ah) Revision: molecular genetic testing clinically available • 14 December 2004 (me) Comprehensive update posted live • 16 May 2003 (cd) Revision: enzymatic prenatal testing no longer available • 14 November 2002 (me) Review posted live • 7 March 2002 (da) Original submission ## Author History Derek A Applegarth, PhD, FCCMG; University of British Columbia (2002-2005)Curtis Coughlin II, MS, MBe (2013-present)Ada Hamosh, MD, MPH; Johns Hopkins University School of Medicine (2002-2013)Julia B Hennermann, MD, PhD (2019-present)S Lane Rutledge, MD; University of Alabama at Birmingham (2018-2019; see ## Acknowledgments The authors would like to dedicate this ## Revision History 23 May 2019 (bp) Comprehensive update posted live 11 July 2013 (me) Comprehensive update posted live 24 November 2009 (me) Comprehensive update posted live 26 July 2005 (ah) Revision: molecular genetic testing clinically available 14 December 2004 (me) Comprehensive update posted live 16 May 2003 (cd) Revision: enzymatic prenatal testing no longer available 14 November 2002 (me) Review posted live 7 March 2002 (da) Original submission • 23 May 2019 (bp) Comprehensive update posted live • 11 July 2013 (me) Comprehensive update posted live • 24 November 2009 (me) Comprehensive update posted live • 26 July 2005 (ah) Revision: molecular genetic testing clinically available • 14 December 2004 (me) Comprehensive update posted live • 16 May 2003 (cd) Revision: enzymatic prenatal testing no longer available • 14 November 2002 (me) Review posted live • 7 March 2002 (da) Original submission ## References ## Literature Cited Diffusion-weighted images of a neonate with classic NKH showing diffusion restriction: A. At the level of the posterior limb of the internal capsule; and B. In the anterior part of the brain stem, the posterior tegmental tracts, and the white matter of the cerebellum Metabolism of glycine by glycine cleavage enzyme. Glycine enters the four-protein enzyme complex at the lower left, where it is decarboxylated by the P-protein (also known as glycine decarboxylase). A defect of the P-, H-, or T-proteins of this complex causes glycine encephalopathy.	[]	14/11/2002	23/5/2019	26/7/2005	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nkx2-1-dis	nkx2-1-dis	[ "Benign Hereditary Chorea (BHC)", "Choreoathetosis, Congenital Hypothyroidism, and Neonatal Respiratory Distress Syndrome (Brain-Lung-Thyroid Syndrome)", "Homeobox protein Nkx-2.1", "NKX2-1", "NKX2-1-Related Disorders" ]		Neepa Jayant Patel, Joseph Jankovic	Summary The diagnosis of	Benign hereditary chorea (BHC) Choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (collectively also known as brain-lung-thyroid syndrome) For synonyms and outdated names see For other genetic causes of these phenotypes see • Benign hereditary chorea (BHC) • Choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome (collectively also known as brain-lung-thyroid syndrome) ## Diagnosis Infancy- or childhood-onset non-progressive chorea that may or may not be associated with: Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; Congenital hypothyroidism; Respiratory distress syndrome; OR A history of congenital hypothyroidism and: Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or Respiratory dysfunction including interstitial lung disease in children. Congenital hypothyroidism (i.e., low thyroid hormone production with elevated thyroid-stimulating hormone) Compensated hypothyroidism (i.e., low-to-normal thyroid hormone production with elevated thyroid-stimulating hormone) The diagnosis of an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click When the diagnosis of an For an introduction to comprehensive genomic testing click For an introduction to CMA click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Partial and whole-gene deletions have been reported [ Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Several large contiguous deletions have been identified in individuals with clinical features of • Infancy- or childhood-onset non-progressive chorea that may or may not be associated with: • Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; • Congenital hypothyroidism; • Respiratory distress syndrome; • OR • Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; • Congenital hypothyroidism; • Respiratory distress syndrome; • A history of congenital hypothyroidism and: • Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or • Respiratory dysfunction including interstitial lung disease in children. • Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or • Respiratory dysfunction including interstitial lung disease in children. • Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; • Congenital hypothyroidism; • Respiratory distress syndrome; • Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or • Respiratory dysfunction including interstitial lung disease in children. • Congenital hypothyroidism (i.e., low thyroid hormone production with elevated thyroid-stimulating hormone) • Compensated hypothyroidism (i.e., low-to-normal thyroid hormone production with elevated thyroid-stimulating hormone) • For an introduction to multigene panels click ## Suggestive Findings Infancy- or childhood-onset non-progressive chorea that may or may not be associated with: Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; Congenital hypothyroidism; Respiratory distress syndrome; OR A history of congenital hypothyroidism and: Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or Respiratory dysfunction including interstitial lung disease in children. Congenital hypothyroidism (i.e., low thyroid hormone production with elevated thyroid-stimulating hormone) Compensated hypothyroidism (i.e., low-to-normal thyroid hormone production with elevated thyroid-stimulating hormone) • Infancy- or childhood-onset non-progressive chorea that may or may not be associated with: • Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; • Congenital hypothyroidism; • Respiratory distress syndrome; • OR • Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; • Congenital hypothyroidism; • Respiratory distress syndrome; • A history of congenital hypothyroidism and: • Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or • Respiratory dysfunction including interstitial lung disease in children. • Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or • Respiratory dysfunction including interstitial lung disease in children. • Mild neurologic symptoms including axial hypotonia, ataxia, developmental delays, impaired mobility of upper and lower limbs; • Congenital hypothyroidism; • Respiratory distress syndrome; • Neurologic manifestations including hypotonia, neurodevelopmental delay, seizures; and/or • Respiratory dysfunction including interstitial lung disease in children. • Congenital hypothyroidism (i.e., low thyroid hormone production with elevated thyroid-stimulating hormone) • Compensated hypothyroidism (i.e., low-to-normal thyroid hormone production with elevated thyroid-stimulating hormone) ## Establishing the Diagnosis The diagnosis of an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click When the diagnosis of an For an introduction to comprehensive genomic testing click For an introduction to CMA click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Partial and whole-gene deletions have been reported [ Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Several large contiguous deletions have been identified in individuals with clinical features of • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of an For an introduction to comprehensive genomic testing click For an introduction to CMA click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Partial and whole-gene deletions have been reported [ Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Several large contiguous deletions have been identified in individuals with clinical features of ## Clinical Characteristics Based on When all three organ systems are involved, this is also known as "brain-lung-thyroid syndrome" (see The neurodevelopmental complications of congenital hypothyroidism can be prevented with thyroid hormone replacement in the neonatal period to prevent early neurodevelopmental consequences of untreated hypothyroidism (see Early infancy or within the first year of life (most common) Late childhood or adolescence Chorea progresses into the second decade, after which it remains static or may spontaneously remit [ Chorea typically involves all body regions (e.g., face, tongue, neck, trunk, limbs) and may be associated with motor and gait abnormalities, possibly secondary to the choreiform movements. The movements are jerk-like and spread randomly from one body part to another; they often worsen with stress and may disappear with sleep. Children with BHC may fall frequently [ The prevalence of chorea in Hypotonia, incoordination, and motor delays, which are common during the neonatal period / infancy but rarely reported in childhood/adulthood [ Myoclonus, dystonia, and/or ataxia [ Intention tremor [ Dysarthria [ Restless leg syndrome [ Neurocognitive changes, including learning difficulties and reduced working memory and attention [ Seizures [ In one report, two sibs initially diagnosed with ataxic dyskinetic cerebral palsy were later found to have a pathogenic variant in Single-photon emission computed tomography (SPECT) has demonstrated reduced cerebral blood flow to the basal ganglia bilaterally, and more specifically to the caudate nuclei, in three affected individuals [ Respiratory distress syndrome (RDS) with or without pulmonary hypertension is most common in the neonatal period. Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [ Pulmonary fibrosis can occur in older individuals [ The highest risk for respiratory distress is in the neonatal period. Affected infants often require mechanical ventilation [ As a result of pulmonary involvement, individuals with Thyroid dysfunction varies between individuals with Currently, newborn screening for hypothyroidism is available in most countries and includes measuring levels of thyroid-stimulating hormone with or without measuring thyroxine levels. Of note, congenital hypothyroidism can be the only manifestation of an Other features reported in single individuals or families include the following: Hypo- or oligodontia [ Urinary tract abnormalities: Vesicoureteral reflux [ Megacystis [ Endocrine abnormalities: Hypogonadotropic hypogonadism [ Growth hormone deficiency [ Short stature (without documented growth hormone deficiency) [ Webbed neck [ Cardiac abnormalities: Structural cardiac defects (ventricular or atrial septal defects) [ Patent foramen ovale [ Joint laxity [ Pes cavus [ Kyphosis [ Life expectancy in individuals with A retrospective study describing 28 individuals with 13 novel There is limited information on the long-term prognosis of pulmonary and thyroid manifestations. Progression is rare and features may improve in adulthood [ Manifestations of Missense No studies have evaluated the penetrance of Before the molecular basis was known, the disorder now known to be caused by a heterozygous pathogenic variant in Of note, More than 120 individuals with • Early infancy or within the first year of life (most common) • Late childhood or adolescence • Hypotonia, incoordination, and motor delays, which are common during the neonatal period / infancy but rarely reported in childhood/adulthood [ • Myoclonus, dystonia, and/or ataxia [ • Intention tremor [ • Dysarthria [ • Restless leg syndrome [ • Neurocognitive changes, including learning difficulties and reduced working memory and attention [ • Seizures [ • Respiratory distress syndrome (RDS) with or without pulmonary hypertension is most common in the neonatal period. • Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [ • Pulmonary fibrosis can occur in older individuals [ • Hypo- or oligodontia [ • Urinary tract abnormalities: • Vesicoureteral reflux [ • Megacystis [ • Vesicoureteral reflux [ • Megacystis [ • Endocrine abnormalities: • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Short stature (without documented growth hormone deficiency) [ • Webbed neck [ • Cardiac abnormalities: • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ • Joint laxity [ • Pes cavus [ • Kyphosis [ • Vesicoureteral reflux [ • Megacystis [ • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ ## Clinical Description Based on When all three organ systems are involved, this is also known as "brain-lung-thyroid syndrome" (see The neurodevelopmental complications of congenital hypothyroidism can be prevented with thyroid hormone replacement in the neonatal period to prevent early neurodevelopmental consequences of untreated hypothyroidism (see Early infancy or within the first year of life (most common) Late childhood or adolescence Chorea progresses into the second decade, after which it remains static or may spontaneously remit [ Chorea typically involves all body regions (e.g., face, tongue, neck, trunk, limbs) and may be associated with motor and gait abnormalities, possibly secondary to the choreiform movements. The movements are jerk-like and spread randomly from one body part to another; they often worsen with stress and may disappear with sleep. Children with BHC may fall frequently [ The prevalence of chorea in Hypotonia, incoordination, and motor delays, which are common during the neonatal period / infancy but rarely reported in childhood/adulthood [ Myoclonus, dystonia, and/or ataxia [ Intention tremor [ Dysarthria [ Restless leg syndrome [ Neurocognitive changes, including learning difficulties and reduced working memory and attention [ Seizures [ In one report, two sibs initially diagnosed with ataxic dyskinetic cerebral palsy were later found to have a pathogenic variant in Single-photon emission computed tomography (SPECT) has demonstrated reduced cerebral blood flow to the basal ganglia bilaterally, and more specifically to the caudate nuclei, in three affected individuals [ Respiratory distress syndrome (RDS) with or without pulmonary hypertension is most common in the neonatal period. Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [ Pulmonary fibrosis can occur in older individuals [ The highest risk for respiratory distress is in the neonatal period. Affected infants often require mechanical ventilation [ As a result of pulmonary involvement, individuals with Thyroid dysfunction varies between individuals with Currently, newborn screening for hypothyroidism is available in most countries and includes measuring levels of thyroid-stimulating hormone with or without measuring thyroxine levels. Of note, congenital hypothyroidism can be the only manifestation of an Other features reported in single individuals or families include the following: Hypo- or oligodontia [ Urinary tract abnormalities: Vesicoureteral reflux [ Megacystis [ Endocrine abnormalities: Hypogonadotropic hypogonadism [ Growth hormone deficiency [ Short stature (without documented growth hormone deficiency) [ Webbed neck [ Cardiac abnormalities: Structural cardiac defects (ventricular or atrial septal defects) [ Patent foramen ovale [ Joint laxity [ Pes cavus [ Kyphosis [ Life expectancy in individuals with A retrospective study describing 28 individuals with 13 novel There is limited information on the long-term prognosis of pulmonary and thyroid manifestations. Progression is rare and features may improve in adulthood [ • Early infancy or within the first year of life (most common) • Late childhood or adolescence • Hypotonia, incoordination, and motor delays, which are common during the neonatal period / infancy but rarely reported in childhood/adulthood [ • Myoclonus, dystonia, and/or ataxia [ • Intention tremor [ • Dysarthria [ • Restless leg syndrome [ • Neurocognitive changes, including learning difficulties and reduced working memory and attention [ • Seizures [ • Respiratory distress syndrome (RDS) with or without pulmonary hypertension is most common in the neonatal period. • Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [ • Pulmonary fibrosis can occur in older individuals [ • Hypo- or oligodontia [ • Urinary tract abnormalities: • Vesicoureteral reflux [ • Megacystis [ • Vesicoureteral reflux [ • Megacystis [ • Endocrine abnormalities: • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Short stature (without documented growth hormone deficiency) [ • Webbed neck [ • Cardiac abnormalities: • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ • Joint laxity [ • Pes cavus [ • Kyphosis [ • Vesicoureteral reflux [ • Megacystis [ • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ ## Neurologic Manifestations Early infancy or within the first year of life (most common) Late childhood or adolescence Chorea progresses into the second decade, after which it remains static or may spontaneously remit [ Chorea typically involves all body regions (e.g., face, tongue, neck, trunk, limbs) and may be associated with motor and gait abnormalities, possibly secondary to the choreiform movements. The movements are jerk-like and spread randomly from one body part to another; they often worsen with stress and may disappear with sleep. Children with BHC may fall frequently [ The prevalence of chorea in Hypotonia, incoordination, and motor delays, which are common during the neonatal period / infancy but rarely reported in childhood/adulthood [ Myoclonus, dystonia, and/or ataxia [ Intention tremor [ Dysarthria [ Restless leg syndrome [ Neurocognitive changes, including learning difficulties and reduced working memory and attention [ Seizures [ In one report, two sibs initially diagnosed with ataxic dyskinetic cerebral palsy were later found to have a pathogenic variant in Single-photon emission computed tomography (SPECT) has demonstrated reduced cerebral blood flow to the basal ganglia bilaterally, and more specifically to the caudate nuclei, in three affected individuals [ • Early infancy or within the first year of life (most common) • Late childhood or adolescence • Hypotonia, incoordination, and motor delays, which are common during the neonatal period / infancy but rarely reported in childhood/adulthood [ • Myoclonus, dystonia, and/or ataxia [ • Intention tremor [ • Dysarthria [ • Restless leg syndrome [ • Neurocognitive changes, including learning difficulties and reduced working memory and attention [ • Seizures [ ## Pulmonary Manifestations Respiratory distress syndrome (RDS) with or without pulmonary hypertension is most common in the neonatal period. Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [ Pulmonary fibrosis can occur in older individuals [ The highest risk for respiratory distress is in the neonatal period. Affected infants often require mechanical ventilation [ As a result of pulmonary involvement, individuals with • Respiratory distress syndrome (RDS) with or without pulmonary hypertension is most common in the neonatal period. • Neuroendocrine cell hyperplasia, a distinct form of childhood interstitial lung disease (ILD), can be present in infancy; it typically improves with age [ • Pulmonary fibrosis can occur in older individuals [ ## Thyroid Manifestations Thyroid dysfunction varies between individuals with Currently, newborn screening for hypothyroidism is available in most countries and includes measuring levels of thyroid-stimulating hormone with or without measuring thyroxine levels. Of note, congenital hypothyroidism can be the only manifestation of an ## Other Features Other features reported in single individuals or families include the following: Hypo- or oligodontia [ Urinary tract abnormalities: Vesicoureteral reflux [ Megacystis [ Endocrine abnormalities: Hypogonadotropic hypogonadism [ Growth hormone deficiency [ Short stature (without documented growth hormone deficiency) [ Webbed neck [ Cardiac abnormalities: Structural cardiac defects (ventricular or atrial septal defects) [ Patent foramen ovale [ Joint laxity [ Pes cavus [ Kyphosis [ • Hypo- or oligodontia [ • Urinary tract abnormalities: • Vesicoureteral reflux [ • Megacystis [ • Vesicoureteral reflux [ • Megacystis [ • Endocrine abnormalities: • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Short stature (without documented growth hormone deficiency) [ • Webbed neck [ • Cardiac abnormalities: • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ • Joint laxity [ • Pes cavus [ • Kyphosis [ • Vesicoureteral reflux [ • Megacystis [ • Hypogonadotropic hypogonadism [ • Growth hormone deficiency [ • Structural cardiac defects (ventricular or atrial septal defects) [ • Patent foramen ovale [ ## Prognosis and Progression Life expectancy in individuals with A retrospective study describing 28 individuals with 13 novel There is limited information on the long-term prognosis of pulmonary and thyroid manifestations. Progression is rare and features may improve in adulthood [ ## Genotype-Phenotype Correlations Manifestations of Missense ## Penetrance No studies have evaluated the penetrance of ## Nomenclature Before the molecular basis was known, the disorder now known to be caused by a heterozygous pathogenic variant in Of note, ## Prevalence More than 120 individuals with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Somatic variants in ## Differential Diagnosis The differential diagnosis of Selected Hereditary Disorders in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; RBC = red blood cell; XL = X-linked Some individuals initially diagnosed with benign hereditary chorea are later found to have another diagnosis, such as myoclonic dystonia or Huntington disease [ Mode of inheritance depends on genetic type; see Neurodegeneration with Brain Iron Accumulation, Newborn screening for congenital hypothyroidism typically includes measurement of serum thyroid-stimulating hormone (TSH) and thyroxine levels (T Mode of inheritance depends on the genetic etiology. Other hereditary disorders associated with chorea that can be considered in the differential diagnosis include: Neurometabolic disorders ( Acquired Disorders in the Differential Diagnosis of Physiologic chorea of infancy Chorea minima Idiopathic chorea Bucco-oro-lingual dyskinesias Drug & toxin-related chorea Metabolic & endocrine disorders Infection- & post-infection-related disorders Immunologic-related chorea Vascular-related chorea Tumor-related chorea Trauma-related chorea Miscellaneous causes of chorea Hypopituitarism & panhypopituitarism Iodine deficiency Maternal antibody-mediated congenital hypothyroidism Respiratory distress syndrome (hyaline membrane disease) Meconium aspiration syndrome Persistent pulmonary hypertension Pneumothorax Transient tachypnea of the newborn Polycythemia Non-pulmonary causes Neuroleptic exposure, anoxia, cerebral palsy (anoxia), carbon monoxide exposure, heavy metal poisoning Hypo- and hyperglycemia (non-ketotic), kidney failure, nutritional causes Sydenham chorea, other infectious and post-infectious encephalitis (Lyme disease, mycoplasma) Acute disseminated encephalomyelitis (ADEM), acquired immunodeficiency syndrome (AIDS) Infarction or hemorrhage, arteriovenous malformation, antiphospholipid syndrome, following cardiac surgery with hypothermia and extracorporeal circulation in children (i.e., CHAP [choreoathetosis and orofacial dyskinesia, hypotonia, and pseudobulbar signs] syndrome) Kernicterus, sarcoidosis, multiple sclerosis Screening for congenital hypothyroidism is performed by checking serum thyroid-stimulating hormone (TSH) and thyroxine levels (T The etiology of respiratory insufficiency and respiratory distress syndrome in neonates is determined by perinatal risk factors such as gestational age, method of delivery, risk of infection, and associated complications such as presence of meconium in amniotic fluid or exposure to bacterial infections in the perinatal period. Chest radiograph can aid in determining the presence of a pneumothorax and other structural abnormalities in the chest. • Neurometabolic disorders ( • • Physiologic chorea of infancy • Chorea minima • Idiopathic chorea • Bucco-oro-lingual dyskinesias • Drug & toxin-related chorea • Metabolic & endocrine disorders • Infection- & post-infection-related disorders • Immunologic-related chorea • Vascular-related chorea • Tumor-related chorea • Trauma-related chorea • Miscellaneous causes of chorea • Hypopituitarism & panhypopituitarism • Iodine deficiency • Maternal antibody-mediated congenital hypothyroidism • Respiratory distress syndrome (hyaline membrane disease) • Meconium aspiration syndrome • Persistent pulmonary hypertension • Pneumothorax • Transient tachypnea of the newborn • Polycythemia • Non-pulmonary causes ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with an Evaluate for chorea (especially benign hereditary chorea), as well as other neurologic manifestations (e.g., tone abnormalities, other abnormal movements). Brain MRI eval Evaluate & treat pulmonary dysfunction Pulmonary function tests Initial screening for pulmonary malignancy w/chest x-ray or CT scan of chest during early adolescence (age 13 yrs) Thyroid function tests (TSH, T Initial eval for thyroid malignancy by physical exam incl thyroid palpation. Thyroid ultrasound & imaging is only indicated if an abnormality is found on palpation of thyroid gland. In early childhood (age 12 mos) Evaluate for gross motor issues & gait abnormalities, which can occur in early course of disease. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; T Medical geneticist, certified genetic counselor, certified advanced genetic nurse Considered a first-line treatment for chorea. Reported to ↓ chorea in low doses. Dosage recommendation: Children: 0.5 mg/kg/day starting dose divided into 2-3 doses Adults: 37.5 mg/day starting dose divided into 2-3 doses Reported to improve chorea in some children; can be considered as second-line therapy. Has been shown to cause dramatic & substantial improvement in gait abnormalities (specifically ↓ falls); can be used as first-line therapy in children w/gait impairment. Respiratory support as needed in neonatal period Early & aggressive treatment of asthma Early & aggressive treatment of respiratory infections RSV vaccination in infancy Routine vaccinations Treatment of ILD by pulmonologist ILD = interstitial lung disease; PT = physical therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Pulmonary eval Pulmonary function tests Lung imaging (chest x-ray or chest CT scan) to screen for pulmonary malignancy Eval w/endocrinologist Thyroid function tests (T Physical exam incl palpation of thyroid to assess for thyroid cancer T Although Due to the risk of pulmonary disease in It is appropriate to clarify the genetic status of at-risk relatives prenatally or as soon as possible after birth to identify infants at high risk for congenital hypothyroidism and pulmonary disease, establish the diagnosis and initiate medical management early, and, importantly, prevent the neurodevelopmental consequences of untreated congenital hypothyroidism. In most countries, newborn screening for congenital hypothyroidism is performed; however, if this is not routine practice, it is recommended to screen at-risk newborns for congenital hypothyroidism. See There is no known increased risk during pregnancy for a woman with an Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine whether any medication she is taking for chorea is safe for the fetus. See Search • Evaluate for chorea (especially benign hereditary chorea), as well as other neurologic manifestations (e.g., tone abnormalities, other abnormal movements). • Brain MRI eval • Evaluate & treat pulmonary dysfunction • Pulmonary function tests • Initial screening for pulmonary malignancy w/chest x-ray or CT scan of chest during early adolescence (age 13 yrs) • Thyroid function tests (TSH, T • Initial eval for thyroid malignancy by physical exam incl thyroid palpation. Thyroid ultrasound & imaging is only indicated if an abnormality is found on palpation of thyroid gland. • In early childhood (age 12 mos) • Evaluate for gross motor issues & gait abnormalities, which can occur in early course of disease. • Community or • Social work involvement for parental support; • Home nursing referral. • Considered a first-line treatment for chorea. • Reported to ↓ chorea in low doses. • Dosage recommendation: • Children: 0.5 mg/kg/day starting dose divided into 2-3 doses • Adults: 37.5 mg/day starting dose divided into 2-3 doses • Children: 0.5 mg/kg/day starting dose divided into 2-3 doses • Adults: 37.5 mg/day starting dose divided into 2-3 doses • Children: 0.5 mg/kg/day starting dose divided into 2-3 doses • Adults: 37.5 mg/day starting dose divided into 2-3 doses • Reported to improve chorea in some children; can be considered as second-line therapy. • Has been shown to cause dramatic & substantial improvement in gait abnormalities (specifically ↓ falls); can be used as first-line therapy in children w/gait impairment. • Respiratory support as needed in neonatal period • Early & aggressive treatment of asthma • Early & aggressive treatment of respiratory infections • RSV vaccination in infancy • Routine vaccinations • Treatment of ILD by pulmonologist • Pulmonary eval • Pulmonary function tests • Lung imaging (chest x-ray or chest CT scan) to screen for pulmonary malignancy • Eval w/endocrinologist • Thyroid function tests (T • Physical exam incl palpation of thyroid to assess for thyroid cancer ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an Evaluate for chorea (especially benign hereditary chorea), as well as other neurologic manifestations (e.g., tone abnormalities, other abnormal movements). Brain MRI eval Evaluate & treat pulmonary dysfunction Pulmonary function tests Initial screening for pulmonary malignancy w/chest x-ray or CT scan of chest during early adolescence (age 13 yrs) Thyroid function tests (TSH, T Initial eval for thyroid malignancy by physical exam incl thyroid palpation. Thyroid ultrasound & imaging is only indicated if an abnormality is found on palpation of thyroid gland. In early childhood (age 12 mos) Evaluate for gross motor issues & gait abnormalities, which can occur in early course of disease. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; T Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Evaluate for chorea (especially benign hereditary chorea), as well as other neurologic manifestations (e.g., tone abnormalities, other abnormal movements). • Brain MRI eval • Evaluate & treat pulmonary dysfunction • Pulmonary function tests • Initial screening for pulmonary malignancy w/chest x-ray or CT scan of chest during early adolescence (age 13 yrs) • Thyroid function tests (TSH, T • Initial eval for thyroid malignancy by physical exam incl thyroid palpation. Thyroid ultrasound & imaging is only indicated if an abnormality is found on palpation of thyroid gland. • In early childhood (age 12 mos) • Evaluate for gross motor issues & gait abnormalities, which can occur in early course of disease. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Considered a first-line treatment for chorea. Reported to ↓ chorea in low doses. Dosage recommendation: Children: 0.5 mg/kg/day starting dose divided into 2-3 doses Adults: 37.5 mg/day starting dose divided into 2-3 doses Reported to improve chorea in some children; can be considered as second-line therapy. Has been shown to cause dramatic & substantial improvement in gait abnormalities (specifically ↓ falls); can be used as first-line therapy in children w/gait impairment. Respiratory support as needed in neonatal period Early & aggressive treatment of asthma Early & aggressive treatment of respiratory infections RSV vaccination in infancy Routine vaccinations Treatment of ILD by pulmonologist ILD = interstitial lung disease; PT = physical therapy • Considered a first-line treatment for chorea. • Reported to ↓ chorea in low doses. • Dosage recommendation: • Children: 0.5 mg/kg/day starting dose divided into 2-3 doses • Adults: 37.5 mg/day starting dose divided into 2-3 doses • Children: 0.5 mg/kg/day starting dose divided into 2-3 doses • Adults: 37.5 mg/day starting dose divided into 2-3 doses • Children: 0.5 mg/kg/day starting dose divided into 2-3 doses • Adults: 37.5 mg/day starting dose divided into 2-3 doses • Reported to improve chorea in some children; can be considered as second-line therapy. • Has been shown to cause dramatic & substantial improvement in gait abnormalities (specifically ↓ falls); can be used as first-line therapy in children w/gait impairment. • Respiratory support as needed in neonatal period • Early & aggressive treatment of asthma • Early & aggressive treatment of respiratory infections • RSV vaccination in infancy • Routine vaccinations • Treatment of ILD by pulmonologist ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Pulmonary eval Pulmonary function tests Lung imaging (chest x-ray or chest CT scan) to screen for pulmonary malignancy Eval w/endocrinologist Thyroid function tests (T Physical exam incl palpation of thyroid to assess for thyroid cancer T • Pulmonary eval • Pulmonary function tests • Lung imaging (chest x-ray or chest CT scan) to screen for pulmonary malignancy • Eval w/endocrinologist • Thyroid function tests (T • Physical exam incl palpation of thyroid to assess for thyroid cancer ## Agents/Circumstances to Avoid Although Due to the risk of pulmonary disease in ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk relatives prenatally or as soon as possible after birth to identify infants at high risk for congenital hypothyroidism and pulmonary disease, establish the diagnosis and initiate medical management early, and, importantly, prevent the neurodevelopmental consequences of untreated congenital hypothyroidism. In most countries, newborn screening for congenital hypothyroidism is performed; however, if this is not routine practice, it is recommended to screen at-risk newborns for congenital hypothyroidism. See ## Pregnancy Management There is no known increased risk during pregnancy for a woman with an Prior to pregnancy or early in gestation, it is recommended that a woman work with her physician to determine whether any medication she is taking for chorea is safe for the fetus. See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with an A proband with an If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with an If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with an • A proband with an • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Most individuals diagnosed with an A proband with an If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with an If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the If the parents have not been tested for the • Most individuals diagnosed with an • A proband with an • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Health Resources & Services Administration • • • • Health Resources & Services Administration • ## Molecular Genetics NKX2-1-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NKX2-1-Related Disorders ( There are several ## Chapter Notes USH University Medical Center 29 June 2023 (gm) Comprehensive update posted live 29 July 2016 (ha) Comprehensive updated posted live 20 February 2014 (me) Review posted live 9 September 2013 (np) Original submission • 29 June 2023 (gm) Comprehensive update posted live • 29 July 2016 (ha) Comprehensive updated posted live • 20 February 2014 (me) Review posted live • 9 September 2013 (np) Original submission ## Author Notes USH University Medical Center ## Revision History 29 June 2023 (gm) Comprehensive update posted live 29 July 2016 (ha) Comprehensive updated posted live 20 February 2014 (me) Review posted live 9 September 2013 (np) Original submission • 29 June 2023 (gm) Comprehensive update posted live • 29 July 2016 (ha) Comprehensive updated posted live • 20 February 2014 (me) Review posted live • 9 September 2013 (np) Original submission ## References ## Literature Cited Phenotypic spectrum of Reprinted from	[]	20/2/2014	29/6/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nkx6-2-spax	nkx6-2-spax	[ "NKX6-2-Related Spastic Ataxia with Hypomyelination", "SPAX8", "SPAX8", "NKX6-2-Related Spastic Ataxia with Hypomyelination", "Homeobox protein Nkx-6.2", "NKX6-2", "NKX6-2-Related Disorder" ]		Viorica Chelban, Namik Kaya, Fowzan Alkuraya, Henry Houlden	Summary The diagnosis of	## Diagnosis Onset between birth and age five years of either spasticity or hypotonia with rapid progression to spasticity (typically manifesting as spastic quadriplegia in those with early onset) Motor delay or developmental delay in those with a more severe phenotype Nystagmus Visual impairment manifest in severely affected children as loss of visual fixation and ocular pursuit and in older individuals as severe limitation of eye movements Hearing impairment Ataxia Dystonia particularly involving the upper limbs The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Children with the distinctive findings described in When the phenotypic and imaging findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity with hypomyelination on brain MRI, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Onset between birth and age five years of either spasticity or hypotonia with rapid progression to spasticity (typically manifesting as spastic quadriplegia in those with early onset) • Motor delay or developmental delay in those with a more severe phenotype • Nystagmus • Visual impairment manifest in severely affected children as loss of visual fixation and ocular pursuit and in older individuals as severe limitation of eye movements • Hearing impairment • Ataxia • Dystonia particularly involving the upper limbs ## Suggestive Findings Onset between birth and age five years of either spasticity or hypotonia with rapid progression to spasticity (typically manifesting as spastic quadriplegia in those with early onset) Motor delay or developmental delay in those with a more severe phenotype Nystagmus Visual impairment manifest in severely affected children as loss of visual fixation and ocular pursuit and in older individuals as severe limitation of eye movements Hearing impairment Ataxia Dystonia particularly involving the upper limbs • Onset between birth and age five years of either spasticity or hypotonia with rapid progression to spasticity (typically manifesting as spastic quadriplegia in those with early onset) • Motor delay or developmental delay in those with a more severe phenotype • Nystagmus • Visual impairment manifest in severely affected children as loss of visual fixation and ocular pursuit and in older individuals as severe limitation of eye movements • Hearing impairment • Ataxia • Dystonia particularly involving the upper limbs ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Children with the distinctive findings described in When the phenotypic and imaging findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity with hypomyelination on brain MRI, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 When the phenotypic and imaging findings suggest the diagnosis of For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity with hypomyelination on brain MRI, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics At the severe end of the spectrum is neonatal-onset nystagmus, severe spastic tetraplegia with joint contractures and scoliosis, and visual and hearing impairment, all of which rapidly progress resulting in death in early childhood. At the milder end of the spectrum is normal achievement of motor milestones in the first year of life followed by slowly progressive complex spastic ataxia with pyramidal findings (spasticity with increased muscle tone and difficulty with gait and fine motor coordination), cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia), and loss of developmental milestones. Affected individuals are born at term following uneventful pregnancy and delivery. Nystagmus is usually the first manifestation and has been reported as early as age three months. Other ocular features include loss of visual fixation and ocular pursuit, reduced upgaze, and limited voluntary eye movements [ Pyramidal syndrome, characterized by increased muscle tone in the lower extremities, hyperreflexia, and positive Babinski sign, has been present in all affected individuals reported to date. Some children with neonatal onset presented with hypotonia that progressed to spasticity within a few months [ Extrapyramidal syndrome can be associated with Cerebellar syndrome develops during later infancy and is characterized by dysarthria, titubation, and truncal and limb ataxia. Complications such as dysphagia lead to recurrent aspirations and the need for gastrostomy feedings in more advanced stages [ Walking and mobility vary. Children with neonatal onset and severe disease never achieve ambulation [ Cognitive function varies greatly. Severe developmental language and motor delay with arrested speech development was reported in children at the severe end of the spectrum [ Seizures have been reported in some individuals. The motor phenotype can vary from severe [ The following additional features have been reported: Failure to achieve head control Hearing impairment Recurrent apnea, with some children developing respiratory failure that leads to early death Congenital abnormalities including congenital heart disease and undescended testes Normal electromyogram and nerve conduction studies [ Delayed visual evoked potentials [ Absent somatosensory evoked potentials On EEG, loss of age-based background activity and absent anterior-posterior gradient of background activity and multifocal epileptic discharges [Author, personal observation] No clear genotype-phenotype correlations have been associated with biallelic Of note, biallelic pathogenic variants in the homeobox domain ( Prevalence is not known. To date, 25 affected individuals from 13 families of different ethnic backgrounds (northern European, Arab, North African, Asian) have been reported. • Failure to achieve head control • Hearing impairment • Recurrent apnea, with some children developing respiratory failure that leads to early death • Congenital abnormalities including congenital heart disease and undescended testes • Normal electromyogram and nerve conduction studies [ • Delayed visual evoked potentials [ • Delayed visual evoked potentials [ • Absent somatosensory evoked potentials • On EEG, loss of age-based background activity and absent anterior-posterior gradient of background activity and multifocal epileptic discharges [Author, personal observation] • Delayed visual evoked potentials [ ## Clinical Description At the severe end of the spectrum is neonatal-onset nystagmus, severe spastic tetraplegia with joint contractures and scoliosis, and visual and hearing impairment, all of which rapidly progress resulting in death in early childhood. At the milder end of the spectrum is normal achievement of motor milestones in the first year of life followed by slowly progressive complex spastic ataxia with pyramidal findings (spasticity with increased muscle tone and difficulty with gait and fine motor coordination), cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia), and loss of developmental milestones. Affected individuals are born at term following uneventful pregnancy and delivery. Nystagmus is usually the first manifestation and has been reported as early as age three months. Other ocular features include loss of visual fixation and ocular pursuit, reduced upgaze, and limited voluntary eye movements [ Pyramidal syndrome, characterized by increased muscle tone in the lower extremities, hyperreflexia, and positive Babinski sign, has been present in all affected individuals reported to date. Some children with neonatal onset presented with hypotonia that progressed to spasticity within a few months [ Extrapyramidal syndrome can be associated with Cerebellar syndrome develops during later infancy and is characterized by dysarthria, titubation, and truncal and limb ataxia. Complications such as dysphagia lead to recurrent aspirations and the need for gastrostomy feedings in more advanced stages [ Walking and mobility vary. Children with neonatal onset and severe disease never achieve ambulation [ Cognitive function varies greatly. Severe developmental language and motor delay with arrested speech development was reported in children at the severe end of the spectrum [ Seizures have been reported in some individuals. The motor phenotype can vary from severe [ The following additional features have been reported: Failure to achieve head control Hearing impairment Recurrent apnea, with some children developing respiratory failure that leads to early death Congenital abnormalities including congenital heart disease and undescended testes Normal electromyogram and nerve conduction studies [ Delayed visual evoked potentials [ Absent somatosensory evoked potentials On EEG, loss of age-based background activity and absent anterior-posterior gradient of background activity and multifocal epileptic discharges [Author, personal observation] • Failure to achieve head control • Hearing impairment • Recurrent apnea, with some children developing respiratory failure that leads to early death • Congenital abnormalities including congenital heart disease and undescended testes • Normal electromyogram and nerve conduction studies [ • Delayed visual evoked potentials [ • Delayed visual evoked potentials [ • Absent somatosensory evoked potentials • On EEG, loss of age-based background activity and absent anterior-posterior gradient of background activity and multifocal epileptic discharges [Author, personal observation] • Delayed visual evoked potentials [ ## Genotype-Phenotype Correlations No clear genotype-phenotype correlations have been associated with biallelic Of note, biallelic pathogenic variants in the homeobox domain ( ## Prevalence Prevalence is not known. To date, 25 affected individuals from 13 families of different ethnic backgrounds (northern European, Arab, North African, Asian) have been reported. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Hypomyelinating leukodystrophies and spastic ataxias (particularly when associated with hypomyelination) should be considered in the differential diagnosis of Movement Disorders to Consider in the Differential Diagnosis of Very similar to DD & speech delay Preservation of cognition Thinning of the corpus callosum in some No cerebellar atrophy on MRI Abnormal dentition Hypogonadotropic hypogonadism Abnormalities of basal ganglia, esp atrophy (a classic sign) Aphonia or "whispering" dysphonia may be a feature. Psychomotor retardation Seizures Severe DD Coarse facial features Hepatosplenomegaly Cardiomegaly Death usually in early childhood AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; XL = X-linked See See • Very similar to • DD & speech delay • Preservation of cognition • Thinning of the corpus callosum in some • No cerebellar atrophy on MRI • Abnormal dentition • Hypogonadotropic hypogonadism • Abnormalities of basal ganglia, esp atrophy (a classic sign) • Aphonia or "whispering" dysphonia may be a feature. • Psychomotor retardation • Seizures • Severe DD • Coarse facial features • Hepatosplenomegaly • Cardiomegaly • Death usually in early childhood ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of ↓ vision; Abnormal ocular movement. Airway Pulmonary function Secretion management Swallowing Feeding Nutritional status Motor skills Speech/language General cognitive skills Vocational skills Community or online resources (e.g., Parent to Parent) Social work involvement for parental support Home nursing referral if needed Treatment of Manifestations in Individuals with Airway & pulmonary assessment for evidence of ↓ pulmonary function or poor secretion mgmt Sleep study PT (incl stretching) to avoid contractures & falls Trial of pharmaceutical agents (e.g., baclofen or tizanidine) as recommended by rehab specialist Assess for evidence of spasticity. Consider need for positioning & mobility devices, disability parking placard. Appropriate social work involvement to connect families w/local resources, respite, & support Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies Ongoing assessment for need of palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. PT = physical therapy Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services will be reviewed annually to determine if any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox The following additional recommendations are based on the leukodystrophies consensus [ Frequent repositioning and skin care to avoid skin sores in affected individuals who are not mobile Yearly flu vaccination Vitamin D supplementation (to prevent osteoporosis) Recommended Surveillance for Individuals with See Search • ↓ vision; • Abnormal ocular movement. • Airway • Pulmonary function • Secretion management • Swallowing • Feeding • Nutritional status • Motor skills • Speech/language • General cognitive skills • Vocational skills • Community or online resources (e.g., Parent to Parent) • Social work involvement for parental support • Home nursing referral if needed • Airway & pulmonary assessment for evidence of ↓ pulmonary function or poor secretion mgmt • Sleep study • PT (incl stretching) to avoid contractures & falls • Trial of pharmaceutical agents (e.g., baclofen or tizanidine) as recommended by rehab specialist • Assess for evidence of spasticity. • Consider need for positioning & mobility devices, disability parking placard. • Appropriate social work involvement to connect families w/local resources, respite, & support • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies • Ongoing assessment for need of palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Frequent repositioning and skin care to avoid skin sores in affected individuals who are not mobile • Yearly flu vaccination • Vitamin D supplementation (to prevent osteoporosis) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of ↓ vision; Abnormal ocular movement. Airway Pulmonary function Secretion management Swallowing Feeding Nutritional status Motor skills Speech/language General cognitive skills Vocational skills Community or online resources (e.g., Parent to Parent) Social work involvement for parental support Home nursing referral if needed • ↓ vision; • Abnormal ocular movement. • Airway • Pulmonary function • Secretion management • Swallowing • Feeding • Nutritional status • Motor skills • Speech/language • General cognitive skills • Vocational skills • Community or online resources (e.g., Parent to Parent) • Social work involvement for parental support • Home nursing referral if needed ## Treatment of Manifestations Treatment of Manifestations in Individuals with Airway & pulmonary assessment for evidence of ↓ pulmonary function or poor secretion mgmt Sleep study PT (incl stretching) to avoid contractures & falls Trial of pharmaceutical agents (e.g., baclofen or tizanidine) as recommended by rehab specialist Assess for evidence of spasticity. Consider need for positioning & mobility devices, disability parking placard. Appropriate social work involvement to connect families w/local resources, respite, & support Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies Ongoing assessment for need of palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. PT = physical therapy Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services will be reviewed annually to determine if any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Airway & pulmonary assessment for evidence of ↓ pulmonary function or poor secretion mgmt • Sleep study • PT (incl stretching) to avoid contractures & falls • Trial of pharmaceutical agents (e.g., baclofen or tizanidine) as recommended by rehab specialist • Assess for evidence of spasticity. • Consider need for positioning & mobility devices, disability parking placard. • Appropriate social work involvement to connect families w/local resources, respite, & support • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies • Ongoing assessment for need of palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues Note: The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services will be reviewed annually to determine if any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Prevention of Secondary Complications The following additional recommendations are based on the leukodystrophies consensus [ Frequent repositioning and skin care to avoid skin sores in affected individuals who are not mobile Yearly flu vaccination Vitamin D supplementation (to prevent osteoporosis) • Frequent repositioning and skin care to avoid skin sores in affected individuals who are not mobile • Yearly flu vaccination • Vitamin D supplementation (to prevent osteoporosis) ## Surveillance Recommended Surveillance for Individuals with ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom United Kingdom • • • • • • United Kingdom • • • United Kingdom • • • ## Molecular Genetics NKX6-2-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NKX6-2-Related Disorder ( Variants listed in the table have been provided by the authors. ? = The predicted consequence of a frame-shifting variant changes Lys202 to Asn, but the new reading frame does not encounter a new translation termination (stop) codon. ## Chapter Notes The authors would like to thank the patients and their families for their essential help with this work. We are grateful to the Spastic Paraplegia Foundation and the UK HSP Society, the Medical Research Council (MRC UK MR/J004758/1, G0802760, G1001253), the Wellcome Trust (WT093205MA and WT104033/Z/14/Z), the Brain Research Trust (BRT), the MSA Trust, the European Union Seventh Framework Programme FP7 (NeurOmics), Ataxia UK, the British Neurological Surveillance Unit (BNSU), the National Institute for Health Research (NIHR) University College London Hospitals (UCLH), the Biomedical Research Centre (BRC), King Abdulaziz City for Science and Technology (KACST # 14-MED2007-20), and King Salman Center for Disability Research (KSCDR # 2180 004). 4 October 2018 (bp) Review posted live 7 February 2018 (vc) Original submission • 4 October 2018 (bp) Review posted live • 7 February 2018 (vc) Original submission ## Author Notes ## Acknowledgments The authors would like to thank the patients and their families for their essential help with this work. We are grateful to the Spastic Paraplegia Foundation and the UK HSP Society, the Medical Research Council (MRC UK MR/J004758/1, G0802760, G1001253), the Wellcome Trust (WT093205MA and WT104033/Z/14/Z), the Brain Research Trust (BRT), the MSA Trust, the European Union Seventh Framework Programme FP7 (NeurOmics), Ataxia UK, the British Neurological Surveillance Unit (BNSU), the National Institute for Health Research (NIHR) University College London Hospitals (UCLH), the Biomedical Research Centre (BRC), King Abdulaziz City for Science and Technology (KACST # 14-MED2007-20), and King Salman Center for Disability Research (KSCDR # 2180 004). ## Revision History 4 October 2018 (bp) Review posted live 7 February 2018 (vc) Original submission • 4 October 2018 (bp) Review posted live • 7 February 2018 (vc) Original submission ## References ## Literature Cited T Column 1. Normal to hyperintense T Column 3. Diffuse cerebellar white matter T Column 4. Predominantly diffuse pontine T	[ "S Anazi, S Maddirevula, V Salpietro, YT Asi, S Alsahli, A Alhashem, HE Shamseldin, F AlZahrani, N Patel, N Ibrahim, FM Abdulwahab, M Hashem, N Alhashmi, F Al Murshedi, A Al Kindy, A Alshaer, A Rumayyan, S Al Tala, W Kurdi, A Alsaman, A Alasmari, S Banu, T Sultan, MM Saleh, H Alkuraya, MA Salih, H Aldhalaan, T Ben-Omran, F Al Musafri, R Ali, J Suleiman, B Tabarki, AW El-Hattab, C Bupp, M Alfadhel, N Al Tassan, D Monies, ST Arold, M Abouelhoda, T Lashley, H Houlden, E Faqeih, FS Alkuraya. Expanding the genetic heterogeneity of intellectual disability.. Hum Genet. 2017;136:1419-29", "C Baldi, AM Bertoli-Avella, N Al-Sannaa, M Alfadhel, K Al-Thihli, S Alameer, AA Elmonairy, AM Al Shamsi, HA Abdelrahman, L Al-Gazali, A Shawli, F Al-Hakami, H Yavuz, KK Kandaswamy, A Rolfs, O Brandau, P Bauer. Expanding the clinical and genetic spectra of NKX6-2-related disorder.. Clin Genet. 2018;93:1087-92", "V Chelban, N Patel, J Vandrovcova, MN Zanetti, DS Lynch, M Ryten, JA Botía, O Bello, E Tribollet, S Efthymiou, I Davagnanam, FA Bashiri, NW Wood, JE Rothman, FS Alkuraya, H Houlden. Mutations in NKX6-2 cause progressive spastic ataxia and hypomyelination.. Am J Hum Genet. 2017;100:969-77", "I Dorboz, C Aiello, C Simons, RT Stone, M Niceta, M Elmaleh, M Abuawad, D Doummar, A Bruselles, NI Wolf, L Travaglini, O Boespflug-Tanguy, M Tartaglia, A Vanderver, D Rodriguez, E Bertini. Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.. Brain. 2017;140:2550-6", "WJ Gehring. Exploring the homeobox.. Gene. 1993;135:215-21", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "K Van Haren, JL Bonkowsky, G Bernard, JL Murphy, A Pizzino, G Helman, D Suhr, J Waggoner, D Hobson, A Vanderver, MC Patterson. Consensus statement on preventive and symptomatic care of leukodystrophy patients.. Mol Genet Metab. 2015;114:516-26", "YF Zhong, PW Holland. The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages.. BMC Evol Biol. 2011;11:169" ]	4/10/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
noonan	noonan	[ "Dual specificity mitogen-activated protein kinase kinase 1", "GTPase KRas", "GTPase NRas", "GTP-binding protein Rit1", "Leucine-zipper-like transcriptional regulator 1", "RAF proto-oncogene serine/threonine-protein kinase", "Ras GTPase-activating protein 2", "Ras-related protein M-Ras", "Ras-related protein R-Ras2", "Serine/threonine-protein kinase B-raf", "Son of sevenless homolog 1", "Son of sevenless homolog 2", "Tyrosine-protein phosphatase non-receptor type 11", "BRAF", "KRAS", "LZTR1", "MAP2K1", "MRAS", "NRAS", "PTPN11", "RAF1", "RASA2", "RIT1", "RRAS2", "SOS1", "SOS2", "Noonan Syndrome" ]	Noonan Syndrome	Amy E Roberts	Summary Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population. The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in In children age <5 years: if initial cardiac evaluation is normal, at least annual cardiac evaluations until age 5 years. In children age >5 years through adulthood, cardiac evaluation at least every 5 years, or as clinically indicated. Prior to any surgical procedure or in those with clinical bleeding: assessment of bleeding history, CBC with differential, and consideration of measurement of coagulation factors. For those with pathogenic NS is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant NS have a NS caused by pathogenic variants in Prenatal testing and preimplantation genetic testing are possible if the NS-related pathogenic variant(s) have been identified in an affected family member.	## Diagnosis No consensus clinical diagnostic criteria for Noonan syndrome have been published. Diagnostic scoring systems, most recently published in Noonan syndrome (NS) Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in adulthood. Key features found regardless of age include the following: Low-set, posteriorly rotated ears with fleshy helices Vivid blue or blue-green irises Widely spaced and downslanted palpebral fissures Epicanthal folds Fullness or droopiness of the upper eyelids (ptosis) Short stature for sex and family background Congenital heart defects, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy Developmental delay of variable degree Broad or webbed neck Unusual chest shape with superior pectus carinatum and inferior pectus excavatum Widely spaced nipples Cryptorchidism in males Lymphatic dysplasia of the lungs, intestines, and/or lower extremities Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and platelet aggregation testing) may show abnormalities. Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction. The molecular diagnosis of NS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of Noonan syndrome, molecular genetic testing approaches usually include the use of a multigene panel. A For an introduction to multigene panels click Note: When the diagnosis of Noonan syndrome has not been considered because an individual has atypical phenotypic features or if some but not all characteristic phenotypic features are present (e.g., a "Noonan-like" phenotype), For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Noonan Syndrome (NS) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified Recent reports have implicated additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each, including • Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in adulthood. Key features found regardless of age include the following: • Low-set, posteriorly rotated ears with fleshy helices • Vivid blue or blue-green irises • Widely spaced and downslanted palpebral fissures • Epicanthal folds • Fullness or droopiness of the upper eyelids (ptosis) • Low-set, posteriorly rotated ears with fleshy helices • Vivid blue or blue-green irises • Widely spaced and downslanted palpebral fissures • Epicanthal folds • Fullness or droopiness of the upper eyelids (ptosis) • Short stature for sex and family background • Congenital heart defects, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy • Developmental delay of variable degree • Broad or webbed neck • Unusual chest shape with superior pectus carinatum and inferior pectus excavatum • Widely spaced nipples • Cryptorchidism in males • Lymphatic dysplasia of the lungs, intestines, and/or lower extremities • Low-set, posteriorly rotated ears with fleshy helices • Vivid blue or blue-green irises • Widely spaced and downslanted palpebral fissures • Epicanthal folds • Fullness or droopiness of the upper eyelids (ptosis) • Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and platelet aggregation testing) may show abnormalities. • Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction. ## Suggestive Findings Noonan syndrome (NS) Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in adulthood. Key features found regardless of age include the following: Low-set, posteriorly rotated ears with fleshy helices Vivid blue or blue-green irises Widely spaced and downslanted palpebral fissures Epicanthal folds Fullness or droopiness of the upper eyelids (ptosis) Short stature for sex and family background Congenital heart defects, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy Developmental delay of variable degree Broad or webbed neck Unusual chest shape with superior pectus carinatum and inferior pectus excavatum Widely spaced nipples Cryptorchidism in males Lymphatic dysplasia of the lungs, intestines, and/or lower extremities Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and platelet aggregation testing) may show abnormalities. Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction. • Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in adulthood. Key features found regardless of age include the following: • Low-set, posteriorly rotated ears with fleshy helices • Vivid blue or blue-green irises • Widely spaced and downslanted palpebral fissures • Epicanthal folds • Fullness or droopiness of the upper eyelids (ptosis) • Low-set, posteriorly rotated ears with fleshy helices • Vivid blue or blue-green irises • Widely spaced and downslanted palpebral fissures • Epicanthal folds • Fullness or droopiness of the upper eyelids (ptosis) • Short stature for sex and family background • Congenital heart defects, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy • Developmental delay of variable degree • Broad or webbed neck • Unusual chest shape with superior pectus carinatum and inferior pectus excavatum • Widely spaced nipples • Cryptorchidism in males • Lymphatic dysplasia of the lungs, intestines, and/or lower extremities • Low-set, posteriorly rotated ears with fleshy helices • Vivid blue or blue-green irises • Widely spaced and downslanted palpebral fissures • Epicanthal folds • Fullness or droopiness of the upper eyelids (ptosis) • Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and platelet aggregation testing) may show abnormalities. • Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction. ## Establishing the Diagnosis The molecular diagnosis of NS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of Noonan syndrome, molecular genetic testing approaches usually include the use of a multigene panel. A For an introduction to multigene panels click Note: When the diagnosis of Noonan syndrome has not been considered because an individual has atypical phenotypic features or if some but not all characteristic phenotypic features are present (e.g., a "Noonan-like" phenotype), For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Noonan Syndrome (NS) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified Recent reports have implicated additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each, including ## Option 1 When the phenotypic findings suggest the diagnosis of Noonan syndrome, molecular genetic testing approaches usually include the use of a multigene panel. A For an introduction to multigene panels click Note: ## Option 2 When the diagnosis of Noonan syndrome has not been considered because an individual has atypical phenotypic features or if some but not all characteristic phenotypic features are present (e.g., a "Noonan-like" phenotype), For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Noonan Syndrome (NS) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified Recent reports have implicated additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each, including ## Clinical Characteristics To date, including those with a clinical and a molecular genetic diagnosis and with an estimated incidence of 1:1000-1:2500, several thousand individuals have been identified with Noonan syndrome (NS) [ Noonan Syndrome: Frequency of Select Features Defined as IQ <70 Polyhydramnios Lymphatic dysplasia including increased distended jugular lymphatic sacs, nuchal translucency, cystic hygroma, pleural effusion, and ascites Relative macrocephaly Cardiac and renal anomalies In chromosomally normal fetuses with increased nuchal translucency, it is estimated that 3%-15% have Length at birth is usually normal. Postnatal growth failure is often obvious from the first year of life [ Final adult height approaches the lower limit of normal: 161-167 cm in males and 150-155 cm in females. Growth curves have been developed from these cross-sectional retrospective data. One study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [ In many affected persons, decreased IGF-I- and IGF-binding protein 3, together with low responses to provocation, suggest impaired growth hormone release or disturbance of the growth hormone / insulin-like growth factor I axis. Mild growth hormone resistance related to a post-receptor signaling defect (which may be partially compensated for by elevated growth hormone secretion) is reported in individuals with NS and a Growth hormone (GH) therapy has been used in individuals with NS (see In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal. Short- and long-term studies of GH treatment have been published [ The increase in height standard deviation (SD) varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [ Studies have shown that children with prepubertal NS growth hormone deficiency have increased their growth rate with GH therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic GH deficiency [ Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [ Articulation deficiency is common (72%) but usually responds well to speech therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies. The average age at first words is around 15 months and simple two-word phrases emerge on average from age 31 to 32 months [ A study of the language phenotype of children and adults with NS showed that language impairments in general are more common in NS than in the general population and a majority of children (70%) receive speech and language therapy. When language issues are present, there is a higher risk for reading and spelling difficulties [ There is emerging evidence that impairment in attention and executive functioning is one of the most common neuropsychological challenges for children with NS [ Male pubertal development and subsequent fertility may be normal, delayed, or inadequate. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60%-80% of males; however, a study of male gonadal function identified Sertoli cell dysfunction both in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotropic hypogonadism [ Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years. Normal fertility is the rule. Thoracic scoliosis is reported in 13%-30% of individuals diagnosed at a mean age of nine years. Estimates of the frequency of the characteristic appearance of the chest (superior pectus carinatum and inferior pectus excavatum with a broad chest and increased inter-nipple distance) range from 28% to 95% [ Vertebral defects have also been reported. Reported upper limb anomalies include cubitus valgus, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly. Common maxillofacial features include micrognathia, high arched palate, and dental crowding [ Small studies have suggested lower bone mineral density in children and osteopenia in adults [ Multiple giant cell lesions of the jaw, joints (pigmented villonodular synovitis), and/or soft tissue have been reported in association with Café au lait spots and lentigines are described in NS more frequently than in the general population (see Noonan syndrome with multiple lentigines discussion in Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ A recent review of the literature yielded 30 cases of individuals with Noonan-like / multiple giant-cell lesion syndrome is caused by pathogenic variants in These multiple giant cell lesions are also recognized in persons with An international meeting of the American Association for Cancer Research was held to propose consensus surveillance recommendations for RASopathies and other genetic disorders associated with increased childhood cancer risk. Overall, because the cancer risk falls below 5%, routine cancer surveillance was not recommended. However, for those with There are no known phenotype correlations for Noonan Syndrome Phenotype Correlations by Gene +, ++, +++ = degree of likelihood that a given feature is present (i.e., more +s = more likely); - = a feature that is less likely to be present. Blank cells indicate that there is no known correlation between the likelihood of having a particular feature when a person has a pathogenic variant in that gene. HCM = hypertrophic cardiomyopathy; ID = intellectual disability Genes are listed in alphabetic order. Those with pathogenic variants in KRAS tend to have a greater likelihood and severity of intellectual disability [ In one study, 5/26 persons with a heterozygous pathogenic variant in Those with a pathogenic variant in The chance of having hypertrophic cardiomyopathy in persons with Noonan syndrome caused by a heterozygous pathogenic variant in Multiple nevi, lentigines, and/or café au lait spots were reported in one third of those with Hypertrophic cardiomyopathy is present in 70%-75% of persons with Including curly hair, hyperpigmentation, and wrinkled palms and soles Those with No clinically relevant genotype-phenotype correlations for Germline pathogenic variants at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [ Individuals with the An in-frame three-nucleotide An early term for NS, "male Turner syndrome," incorrectly implied that the condition would not be found in females. In 1949, Otto Ullrich reported affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term "Bonnevie-Ullrich syndrome" became popular, particularly in Europe. NS is common and reported to occur in between 1:1,000 and 1:2,500 persons. Mild expression is likely to be overlooked. • Polyhydramnios • Lymphatic dysplasia including increased distended jugular lymphatic sacs, nuchal translucency, cystic hygroma, pleural effusion, and ascites • Relative macrocephaly • Cardiac and renal anomalies • In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal. • Short- and long-term studies of GH treatment have been published [ • The increase in height standard deviation (SD) varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [ • Studies have shown that children with prepubertal NS growth hormone deficiency have increased their growth rate with GH therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic GH deficiency [ • Thoracic scoliosis is reported in 13%-30% of individuals diagnosed at a mean age of nine years. • Estimates of the frequency of the characteristic appearance of the chest (superior pectus carinatum and inferior pectus excavatum with a broad chest and increased inter-nipple distance) range from 28% to 95% [ • Vertebral defects have also been reported. • Reported upper limb anomalies include cubitus valgus, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly. • Common maxillofacial features include micrognathia, high arched palate, and dental crowding [ • Small studies have suggested lower bone mineral density in children and osteopenia in adults [ • Multiple giant cell lesions of the jaw, joints (pigmented villonodular synovitis), and/or soft tissue have been reported in association with • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ • A recent review of the literature yielded 30 cases of individuals with • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ • A recent review of the literature yielded 30 cases of individuals with • Noonan-like / multiple giant-cell lesion syndrome is caused by pathogenic variants in • These multiple giant cell lesions are also recognized in persons with • An international meeting of the American Association for Cancer Research was held to propose consensus surveillance recommendations for RASopathies and other genetic disorders associated with increased childhood cancer risk. Overall, because the cancer risk falls below 5%, routine cancer surveillance was not recommended. However, for those with • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ • A recent review of the literature yielded 30 cases of individuals with • Germline pathogenic variants at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [ • Individuals with the • An in-frame three-nucleotide ## Clinical Description To date, including those with a clinical and a molecular genetic diagnosis and with an estimated incidence of 1:1000-1:2500, several thousand individuals have been identified with Noonan syndrome (NS) [ Noonan Syndrome: Frequency of Select Features Defined as IQ <70 Polyhydramnios Lymphatic dysplasia including increased distended jugular lymphatic sacs, nuchal translucency, cystic hygroma, pleural effusion, and ascites Relative macrocephaly Cardiac and renal anomalies In chromosomally normal fetuses with increased nuchal translucency, it is estimated that 3%-15% have Length at birth is usually normal. Postnatal growth failure is often obvious from the first year of life [ Final adult height approaches the lower limit of normal: 161-167 cm in males and 150-155 cm in females. Growth curves have been developed from these cross-sectional retrospective data. One study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [ In many affected persons, decreased IGF-I- and IGF-binding protein 3, together with low responses to provocation, suggest impaired growth hormone release or disturbance of the growth hormone / insulin-like growth factor I axis. Mild growth hormone resistance related to a post-receptor signaling defect (which may be partially compensated for by elevated growth hormone secretion) is reported in individuals with NS and a Growth hormone (GH) therapy has been used in individuals with NS (see In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal. Short- and long-term studies of GH treatment have been published [ The increase in height standard deviation (SD) varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [ Studies have shown that children with prepubertal NS growth hormone deficiency have increased their growth rate with GH therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic GH deficiency [ Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [ Articulation deficiency is common (72%) but usually responds well to speech therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies. The average age at first words is around 15 months and simple two-word phrases emerge on average from age 31 to 32 months [ A study of the language phenotype of children and adults with NS showed that language impairments in general are more common in NS than in the general population and a majority of children (70%) receive speech and language therapy. When language issues are present, there is a higher risk for reading and spelling difficulties [ There is emerging evidence that impairment in attention and executive functioning is one of the most common neuropsychological challenges for children with NS [ Male pubertal development and subsequent fertility may be normal, delayed, or inadequate. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60%-80% of males; however, a study of male gonadal function identified Sertoli cell dysfunction both in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotropic hypogonadism [ Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years. Normal fertility is the rule. Thoracic scoliosis is reported in 13%-30% of individuals diagnosed at a mean age of nine years. Estimates of the frequency of the characteristic appearance of the chest (superior pectus carinatum and inferior pectus excavatum with a broad chest and increased inter-nipple distance) range from 28% to 95% [ Vertebral defects have also been reported. Reported upper limb anomalies include cubitus valgus, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly. Common maxillofacial features include micrognathia, high arched palate, and dental crowding [ Small studies have suggested lower bone mineral density in children and osteopenia in adults [ Multiple giant cell lesions of the jaw, joints (pigmented villonodular synovitis), and/or soft tissue have been reported in association with Café au lait spots and lentigines are described in NS more frequently than in the general population (see Noonan syndrome with multiple lentigines discussion in Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ A recent review of the literature yielded 30 cases of individuals with Noonan-like / multiple giant-cell lesion syndrome is caused by pathogenic variants in These multiple giant cell lesions are also recognized in persons with An international meeting of the American Association for Cancer Research was held to propose consensus surveillance recommendations for RASopathies and other genetic disorders associated with increased childhood cancer risk. Overall, because the cancer risk falls below 5%, routine cancer surveillance was not recommended. However, for those with • Polyhydramnios • Lymphatic dysplasia including increased distended jugular lymphatic sacs, nuchal translucency, cystic hygroma, pleural effusion, and ascites • Relative macrocephaly • Cardiac and renal anomalies • In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal. • Short- and long-term studies of GH treatment have been published [ • The increase in height standard deviation (SD) varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [ • Studies have shown that children with prepubertal NS growth hormone deficiency have increased their growth rate with GH therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic GH deficiency [ • Thoracic scoliosis is reported in 13%-30% of individuals diagnosed at a mean age of nine years. • Estimates of the frequency of the characteristic appearance of the chest (superior pectus carinatum and inferior pectus excavatum with a broad chest and increased inter-nipple distance) range from 28% to 95% [ • Vertebral defects have also been reported. • Reported upper limb anomalies include cubitus valgus, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly. • Common maxillofacial features include micrognathia, high arched palate, and dental crowding [ • Small studies have suggested lower bone mineral density in children and osteopenia in adults [ • Multiple giant cell lesions of the jaw, joints (pigmented villonodular synovitis), and/or soft tissue have been reported in association with • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ • A recent review of the literature yielded 30 cases of individuals with • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ • A recent review of the literature yielded 30 cases of individuals with • Noonan-like / multiple giant-cell lesion syndrome is caused by pathogenic variants in • These multiple giant cell lesions are also recognized in persons with • An international meeting of the American Association for Cancer Research was held to propose consensus surveillance recommendations for RASopathies and other genetic disorders associated with increased childhood cancer risk. Overall, because the cancer risk falls below 5%, routine cancer surveillance was not recommended. However, for those with • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [ • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [ • A recent review of the literature yielded 30 cases of individuals with ## Phenotype Correlations by Gene There are no known phenotype correlations for Noonan Syndrome Phenotype Correlations by Gene +, ++, +++ = degree of likelihood that a given feature is present (i.e., more +s = more likely); - = a feature that is less likely to be present. Blank cells indicate that there is no known correlation between the likelihood of having a particular feature when a person has a pathogenic variant in that gene. HCM = hypertrophic cardiomyopathy; ID = intellectual disability Genes are listed in alphabetic order. Those with pathogenic variants in KRAS tend to have a greater likelihood and severity of intellectual disability [ In one study, 5/26 persons with a heterozygous pathogenic variant in Those with a pathogenic variant in The chance of having hypertrophic cardiomyopathy in persons with Noonan syndrome caused by a heterozygous pathogenic variant in Multiple nevi, lentigines, and/or café au lait spots were reported in one third of those with Hypertrophic cardiomyopathy is present in 70%-75% of persons with Including curly hair, hyperpigmentation, and wrinkled palms and soles Those with ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations for Germline pathogenic variants at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [ Individuals with the An in-frame three-nucleotide • Germline pathogenic variants at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [ • Individuals with the • An in-frame three-nucleotide ## Nomenclature An early term for NS, "male Turner syndrome," incorrectly implied that the condition would not be found in females. In 1949, Otto Ullrich reported affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term "Bonnevie-Ullrich syndrome" became popular, particularly in Europe. ## Prevalence NS is common and reported to occur in between 1:1,000 and 1:2,500 persons. Mild expression is likely to be overlooked. ## Genetically Related (Allelic) Disorders The autosomal dominant allelic disorders summarized in Allelic Disorders to Consider in the Differential Diagnosis of Noonan Syndrome AD = autosomal dominant; CFC = cardiofaciocutaneous; GI = gastrointestinal; ID = intellectual disability; LEOPARD = Pathogenic variants in Heterozygous germline pathogenic variants in Heterozygous germline pathogenic variants in No phenotypes other than those discussed in this Mosaic activating pathogenic variants in • Heterozygous germline pathogenic variants in • Heterozygous germline pathogenic variants in ## Differential Diagnosis Genes of interest in the differential diagnosis of NS are summarized in Genes of Interest in the Differential Diagnosis of Noonan Syndrome AD = autosomal dominant; DD = developmental delay; GH = growth hormone; GI = gastrointestinal; ID = intellectual disability; JMML = juvenile myelomonocytic leukemia; MOI = mode of inheritance; NS = Noonan syndrome; XL = X-linked Due to the significant phenotypic overlap with classic NS, most RASopathy diagnostic gene panels include testing for the common This could be caused by chance concurrence of NS and NF1 [ B Kerr, personal observation Autosomal dominant Aarskog syndrome of unknown genetic cause (OMIM In utero exposure to alcohol or primidone • Autosomal dominant Aarskog syndrome of unknown genetic cause (OMIM • In utero exposure to alcohol or primidone ## Management Management guidelines have been developed by DYSCERNE, a European consortium [ To establish the extent of disease and needs in an individual diagnosed with Noonan syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Noonan Syndrome On NS-specific growth charts To identify those w/failure to thrive &/or short stature In infants w/poor weight gain, dysphagia Eval for malrotation if persistent unexplained vomiting Motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Assessment of gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; NS = Noonan syndrome; OT = occupational therapy; PT = physical therapy; PT/aPTT = prothrombin/activated partial thromboplastin time; vWF = von Willebrand factor Thyroid function tests may include TSH and free T4. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with Noonan Syndrome No standard dose has been established. No apparent correlation between dosage used & final height, though earlier age at initiation of GH therapy is assoc w/↑ final adult height. Short stature due to NS is an FDA-approved indication for GH treatment. No evidence supports ↑ prevalence of neoplasm, cardiac, or other comorbidities in those treated w/GH. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has also been used in an infant w/NS who had normal platelet count & prothrombin & partial thromboplastin times to control severe postoperative blood loss due to gastritis. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; DD/ID = developmental delay / intellectual disability; GH = growth hormone; HCM = hypertrophic cardiomyopathy; NS = Noonan syndrome The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment may be considered. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Recommended Surveillance for Individuals with Noonan Syndrome Measurement of growth parameters on NS-specific growth charts Eval of nutritional status in infants & toddlers CBC = complete blood count; PT/aPTT = prothrombin/activated partial thromboplastin time; vWF = von Willebrand factor; JMML = juvenile myelomonocytic leukemia; OSA = obstructive sleep apnea With referral to neurologist and consideration of head MRI to include sections through the base of the skull to assess for Chiari malformation Despite the apparent increased incidence of hematologic and solid tumor malignancies, no consensus surveillance strategies have been evaluated or recommended. Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis. See For affected women who are pregnant, consider referral to an adult congenital heart program for peripartum evaluation and management. Pregnancy is generally a time of increased coagulation, but consider a hematology referral if the pregnant woman has a history of bleeding abnormalities and/or has not undergone previous screening for coagulopathy. The MEK inhibitor trametinib was given under compassionate use to two infants with pathogenic variants in In a multicenter international retrospective analysis of 61 individuals with hypertrophic cardiomyopathy with heart failure and/or severe outflow tract obstruction due to a RASopathy (excluding those with a pathogenic Search Search CURE ID (an FDA website) for information on novel uses of existing drugs for this condition [ • On NS-specific growth charts • To identify those w/failure to thrive &/or short stature • In infants w/poor weight gain, dysphagia • Eval for malrotation if persistent unexplained vomiting • Motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Assessment of gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • No standard dose has been established. • No apparent correlation between dosage used & final height, though earlier age at initiation of GH therapy is assoc w/↑ final adult height. • Short stature due to NS is an FDA-approved indication for GH treatment. • No evidence supports ↑ prevalence of neoplasm, cardiac, or other comorbidities in those treated w/GH. • Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. • Factor VIIa has also been used in an infant w/NS who had normal platelet count & prothrombin & partial thromboplastin times to control severe postoperative blood loss due to gastritis. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment may be considered. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Measurement of growth parameters on NS-specific growth charts • Eval of nutritional status in infants & toddlers ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Noonan syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Noonan Syndrome On NS-specific growth charts To identify those w/failure to thrive &/or short stature In infants w/poor weight gain, dysphagia Eval for malrotation if persistent unexplained vomiting Motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Assessment of gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; NS = Noonan syndrome; OT = occupational therapy; PT = physical therapy; PT/aPTT = prothrombin/activated partial thromboplastin time; vWF = von Willebrand factor Thyroid function tests may include TSH and free T4. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • On NS-specific growth charts • To identify those w/failure to thrive &/or short stature • In infants w/poor weight gain, dysphagia • Eval for malrotation if persistent unexplained vomiting • Motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Assessment of gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Noonan Syndrome No standard dose has been established. No apparent correlation between dosage used & final height, though earlier age at initiation of GH therapy is assoc w/↑ final adult height. Short stature due to NS is an FDA-approved indication for GH treatment. No evidence supports ↑ prevalence of neoplasm, cardiac, or other comorbidities in those treated w/GH. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has also been used in an infant w/NS who had normal platelet count & prothrombin & partial thromboplastin times to control severe postoperative blood loss due to gastritis. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; DD/ID = developmental delay / intellectual disability; GH = growth hormone; HCM = hypertrophic cardiomyopathy; NS = Noonan syndrome The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment may be considered. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • No standard dose has been established. • No apparent correlation between dosage used & final height, though earlier age at initiation of GH therapy is assoc w/↑ final adult height. • Short stature due to NS is an FDA-approved indication for GH treatment. • No evidence supports ↑ prevalence of neoplasm, cardiac, or other comorbidities in those treated w/GH. • Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. • Factor VIIa has also been used in an infant w/NS who had normal platelet count & prothrombin & partial thromboplastin times to control severe postoperative blood loss due to gastritis. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment may be considered. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment may be considered. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment may be considered. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician, as needed. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance Recommended Surveillance for Individuals with Noonan Syndrome Measurement of growth parameters on NS-specific growth charts Eval of nutritional status in infants & toddlers CBC = complete blood count; PT/aPTT = prothrombin/activated partial thromboplastin time; vWF = von Willebrand factor; JMML = juvenile myelomonocytic leukemia; OSA = obstructive sleep apnea With referral to neurologist and consideration of head MRI to include sections through the base of the skull to assess for Chiari malformation Despite the apparent increased incidence of hematologic and solid tumor malignancies, no consensus surveillance strategies have been evaluated or recommended. • Measurement of growth parameters on NS-specific growth charts • Eval of nutritional status in infants & toddlers ## Agents/Circumstances to Avoid Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis. ## Evaluation of Relatives at Risk See ## Pregnancy Management For affected women who are pregnant, consider referral to an adult congenital heart program for peripartum evaluation and management. Pregnancy is generally a time of increased coagulation, but consider a hematology referral if the pregnant woman has a history of bleeding abnormalities and/or has not undergone previous screening for coagulopathy. ## Therapies Under Investigation The MEK inhibitor trametinib was given under compassionate use to two infants with pathogenic variants in In a multicenter international retrospective analysis of 61 individuals with hypertrophic cardiomyopathy with heart failure and/or severe outflow tract obstruction due to a RASopathy (excluding those with a pathogenic Search Search CURE ID (an FDA website) for information on novel uses of existing drugs for this condition [ ## Genetic Counseling Noonan syndrome (NS) caused by pathogenic variants in NS caused by pathogenic variants in 30%-75% of individuals diagnosed with NS have an affected parent. (Note: Because NS is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) A proband with NS may have the disorder as the result of a In simplex cases (i.e., those with no known family history), paternal origin of the If the proband is the only family member known to have NS, recommended evaluations of both parents include the following: A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS Molecular genetic testing if the NS-causing pathogenic variant in the proband is known If the proband has an NS-causing pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with NS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as the proband. If the parents are clinically unaffected and the proband has an NS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (germline mosaicism for the The parents of an affected child are presumed to be heterozygous for one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes may be asymptomatic [ If both parents are known to be heterozygous for an Heterozygotes may be asymptomatic [ Heterozygote detection for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • 30%-75% of individuals diagnosed with NS have an affected parent. (Note: Because NS is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) • A proband with NS may have the disorder as the result of a • In simplex cases (i.e., those with no known family history), paternal origin of the • If the proband is the only family member known to have NS, recommended evaluations of both parents include the following: • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known • If the proband has an NS-causing pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with NS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as the proband. • If the parents are clinically unaffected and the proband has an NS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (germline mosaicism for the • The parents of an affected child are presumed to be heterozygous for one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes may be asymptomatic [ • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes may be asymptomatic [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Noonan syndrome (NS) caused by pathogenic variants in NS caused by pathogenic variants in ## Autosomal Dominant Inheritance ‒ Risk to Family Members 30%-75% of individuals diagnosed with NS have an affected parent. (Note: Because NS is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) A proband with NS may have the disorder as the result of a In simplex cases (i.e., those with no known family history), paternal origin of the If the proband is the only family member known to have NS, recommended evaluations of both parents include the following: A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS Molecular genetic testing if the NS-causing pathogenic variant in the proband is known If the proband has an NS-causing pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with NS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as the proband. If the parents are clinically unaffected and the proband has an NS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (germline mosaicism for the • 30%-75% of individuals diagnosed with NS have an affected parent. (Note: Because NS is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.) • A proband with NS may have the disorder as the result of a • In simplex cases (i.e., those with no known family history), paternal origin of the • If the proband is the only family member known to have NS, recommended evaluations of both parents include the following: • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known • If the proband has an NS-causing pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with NS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as the proband. • If the parents are clinically unaffected and the proband has an NS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (germline mosaicism for the ## Autosomal Recessive Inheritance ‒ Risk to Family Members The parents of an affected child are presumed to be heterozygous for one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes may be asymptomatic [ If both parents are known to be heterozygous for an Heterozygotes may be asymptomatic [ Heterozygote detection for at-risk relatives requires prior identification of the • The parents of an affected child are presumed to be heterozygous for one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes may be asymptomatic [ • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes may be asymptomatic [ ## Heterozygote Detection Heterozygote detection for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing ## Resources • • • • • • • • • • • • ## Molecular Genetics Noonan Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Noonan Syndrome ( The genes implicated in Noonan syndrome are part of or interact with the Ras/MAPK pathway. This pathway is a widely important signal transduction pathway. Growth factors, cytokines, hormones, and other extracellular ligands stimulate cell differentiation, proliferation, metabolism, and survival. Adaptor proteins are recruited and form a complex that converts inactive, GDP-bound RAS to its active GTP-bound form. This leads to downstream activation of the RAF-MEK-ERK pathway via sequential phosphorylation, culminating in activated ERK entering the nucleus and altering gene transcription. Noonan syndrome pathogenic variants usually enhance signal flow through this pathway [ Noonan Syndrome: Mechanism of Disease Causation Genes from Noonan Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the author. JMML = juvenile myelomonocytic leukemia; NS = Noonan syndrome Genes from Curated from Clinvar; included variants are those classified as pathogenic or likely pathogenic with both Noonan syndrome and JMML as listed conditions for the variant [ Less likely to be associated with learning issues [ Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of Noonan syndrome may contain a somatic nucleotide variant in Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Pathogenic variants in Pathogenic variants in The spectrum of leukemogenesis associated with Somatic Somatic Recent studies have identified somatic The somatic p.Gly248Arg pathogenic variant in • Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Pathogenic variants in • Pathogenic variants in • The spectrum of leukemogenesis associated with • Somatic • Somatic • Recent studies have identified somatic • The somatic p.Gly248Arg pathogenic variant in ## Molecular Pathogenesis The genes implicated in Noonan syndrome are part of or interact with the Ras/MAPK pathway. This pathway is a widely important signal transduction pathway. Growth factors, cytokines, hormones, and other extracellular ligands stimulate cell differentiation, proliferation, metabolism, and survival. Adaptor proteins are recruited and form a complex that converts inactive, GDP-bound RAS to its active GTP-bound form. This leads to downstream activation of the RAF-MEK-ERK pathway via sequential phosphorylation, culminating in activated ERK entering the nucleus and altering gene transcription. Noonan syndrome pathogenic variants usually enhance signal flow through this pathway [ Noonan Syndrome: Mechanism of Disease Causation Genes from Noonan Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the author. JMML = juvenile myelomonocytic leukemia; NS = Noonan syndrome Genes from Curated from Clinvar; included variants are those classified as pathogenic or likely pathogenic with both Noonan syndrome and JMML as listed conditions for the variant [ Less likely to be associated with learning issues [ ## Cancer and Benign Tumors Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of Noonan syndrome may contain a somatic nucleotide variant in Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Pathogenic variants in Pathogenic variants in The spectrum of leukemogenesis associated with Somatic Somatic Recent studies have identified somatic The somatic p.Gly248Arg pathogenic variant in • Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Pathogenic variants in • Pathogenic variants in • The spectrum of leukemogenesis associated with • Somatic • Somatic • Recent studies have identified somatic • The somatic p.Gly248Arg pathogenic variant in ## Chapter Notes Amy E Roberts, MD, FACMGDepartment of Cardiology and Division of Genetics, Department of Pediatrics, Boston Children’s Hospital, Boston, MAEmail: [email protected] Website: Dr Roberts is trained in both clinical genetics and pediatrics. Her research focuses on genotype phenotype correlations and gene discovery in Noonan syndrome and other RASopathies. She is a member of the Our understanding of Noonan syndrome is deeply informed by the life's work of the late Dr Jacqueline A Noonan [ Judith E Allanson, MD; Children's Hospital of Eastern Ontario (2001-2021)Amy E Roberts, MD (2001-present) 5 June 2025 (ma) Revision: additions to 17 February 2022 (aa) Revision: 16 December 2021 (ma) Comprehensive update posted live 25 February 2016 (ha) Comprehensive update posted live 4 August 2011 (me) Comprehensive update posted live 7 October 2008 (me) Comprehensive update posted live 9 March 2006 (me) Comprehensive update posted live 17 December 2003 (me) Comprehensive update posted live 15 November 2001 (me) Review posted live 2 August 2001 (ja) Original submission • 5 June 2025 (ma) Revision: additions to • 17 February 2022 (aa) Revision: • 16 December 2021 (ma) Comprehensive update posted live • 25 February 2016 (ha) Comprehensive update posted live • 4 August 2011 (me) Comprehensive update posted live • 7 October 2008 (me) Comprehensive update posted live • 9 March 2006 (me) Comprehensive update posted live • 17 December 2003 (me) Comprehensive update posted live • 15 November 2001 (me) Review posted live • 2 August 2001 (ja) Original submission ## Author Notes Amy E Roberts, MD, FACMGDepartment of Cardiology and Division of Genetics, Department of Pediatrics, Boston Children’s Hospital, Boston, MAEmail: [email protected] Website: Dr Roberts is trained in both clinical genetics and pediatrics. Her research focuses on genotype phenotype correlations and gene discovery in Noonan syndrome and other RASopathies. She is a member of the ## Acknowledgments Our understanding of Noonan syndrome is deeply informed by the life's work of the late Dr Jacqueline A Noonan [ ## Author History Judith E Allanson, MD; Children's Hospital of Eastern Ontario (2001-2021)Amy E Roberts, MD (2001-present) ## Revision History 5 June 2025 (ma) Revision: additions to 17 February 2022 (aa) Revision: 16 December 2021 (ma) Comprehensive update posted live 25 February 2016 (ha) Comprehensive update posted live 4 August 2011 (me) Comprehensive update posted live 7 October 2008 (me) Comprehensive update posted live 9 March 2006 (me) Comprehensive update posted live 17 December 2003 (me) Comprehensive update posted live 15 November 2001 (me) Review posted live 2 August 2001 (ja) Original submission • 5 June 2025 (ma) Revision: additions to • 17 February 2022 (aa) Revision: • 16 December 2021 (ma) Comprehensive update posted live • 25 February 2016 (ha) Comprehensive update posted live • 4 August 2011 (me) Comprehensive update posted live • 7 October 2008 (me) Comprehensive update posted live • 9 March 2006 (me) Comprehensive update posted live • 17 December 2003 (me) Comprehensive update posted live • 15 November 2001 (me) Review posted live • 2 August 2001 (ja) Original submission ## References Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Available Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42. [ Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59. [ • Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Available • Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42. [ • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59. [ ## Published Guidelines / Consensus Statements Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Available Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42. [ Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59. [ • Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Available • Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42. [ • Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59. [ ## Literature Cited	[]	15/11/2001	16/12/2021	5/6/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
norrie	norrie	[ "NDP-Related Familial Exudative Vitreoretinopathy (FEVR)", "NDP-Related Coats Disease", "Norrie Disease (Classic Norrie Disease Ocular Phenotype with or without Extraocular Findings", "NDP-Related Persistent Fetal Vasculature (PFV)", "NDP-Related Advanced Retinopathy of Prematurity (ROP)", "Norrin", "NDP", "NDP-Related Retinopathies" ]		Brittni A Scruggs, Madeline Q Reding, Lisa A Schimmenti	Summary Rarely, females who are heterozygous for an The diagnosis of an	Norrie disease (classic Norrie disease ocular phenotype with or without extraocular findings) For synonyms and outdated names see For other genetic causes of these phenotypes see • Norrie disease (classic Norrie disease ocular phenotype with or without extraocular findings) ## Diagnosis An Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis Retinal detachment Cataract Infantile blindness The diagnosis of an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see When the phenotypic findings and family history suggest the diagnosis of an If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click A noncoding variant in an untranslated region outside of the exon and splice junction regions typically included in standard sequencing has been observed in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • • Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis • Retinal detachment • Cataract • Infantile blindness • Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis • Retinal detachment • Cataract • Infantile blindness • Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis • Retinal detachment • Cataract • Infantile blindness • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click ## Suggestive Findings An Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis Retinal detachment Cataract Infantile blindness • • Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis • Retinal detachment • Cataract • Infantile blindness • Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis • Retinal detachment • Cataract • Infantile blindness • Retrolental grayish-yellow fibrovascular masses composed of immature retinal cells (pseudogliomas) secondary to retinal vascular dysgenesis • Retinal detachment • Cataract • Infantile blindness ## Establishing the Diagnosis The diagnosis of an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see When the phenotypic findings and family history suggest the diagnosis of an If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click A noncoding variant in an untranslated region outside of the exon and splice junction regions typically included in standard sequencing has been observed in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click ## Option 1 When the phenotypic findings and family history suggest the diagnosis of an If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click A noncoding variant in an untranslated region outside of the exon and splice junction regions typically included in standard sequencing has been observed in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics FEVR = familial exudative vitreoretinopathy; PFV = persistent fetal vasculature; ROP = retinopathy of prematurity In rare cases In a family with an In newborns and infants, the classic finding is a grayish-yellow, glistening, elevated retrolental mass composed of immature retinal cells that is usually visible through a clear lens in both eyes. These masses are referred to as "pseudogliomas" because they resemble tumors such as retinoblastoma. There is retinal dysplasia and incomplete foveal development in all cases. Partial or complete retinal detachments are often present at birth in both eyes. If not present at birth, retinal detachments may evolve over the first few months of life. Nystagmus is common secondary to profound, bilateral vision loss [ The irides, anterior chambers, and corneal diameter may be abnormal in size and appearance as a result of anterior segment dysgenesis. The size of the globe may be normal, smaller (microphthalmia), or enlarged (buphthalmos). Intraocular pressure is often normal at birth but can become elevated (i.e., secondary glaucoma) as a result of malformations of the anterior chamber and angle resulting in impaired outflow through the trabecular meshwork. Other consequences of impaired outflow include buphthalmos, pain, and further progression of vision loss. From infancy through childhood, progressive changes typically include opacification of the lens (cataract) and cornea, atrophy or hypoplasia of the iris with adhesions forming between the lens and the iris (posterior synechiae) and between the iris and the cornea (anterior synechiae), and shallowing of the anterior chamber. Hemorrhagic necrosis of the undifferentiated retinal masses can occur. These changes are followed by corneal opacification (e.g., band keratopathy), loss of intraocular pressure (hypotony), and shrinkage of the globe (phthisis bulbi) usually within the first decade of life. In the end stage of the Norrie disease ocular phenotype, the corneas appear milky and opacified, and the globes appear small and sunken in the orbits [ The majority of affected males lose all light perception during the first year of life. In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [ Speech discrimination is relatively well preserved even when the threshold hearing loss is severe [ Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [ Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. Erectile dysfunction has been reported in 14 of 20 adults. Formerly referred to as persistent hyperplastic primary vitreous (PHPV), PFV is characterized by a fibrotic white stalk with hyaloid vessel remnants extending from the optic disc to the posterior lens capsule. If a stalk persists without surgical intervention, restricted growth of the globe through childhood can lead to further vitreoretinal traction, retinal exudation, retinal detachment, secondary glaucoma, and/or phthisis bulbi. The anterior segment, pars plana, and vitreous base are often malformed with anteriorization of retinal tissue past the ora serrata, which increases the complexity of surgical procedures. Although progression to complete retinal detachment has been described, it is not clear if such progression always occurs [ Peripheral retinal ischemia may lead to retinal or extraretinal neovascularization. Such eye findings may progress to retinal detachment either through increasing traction on the retina from progressive fibrovascular changes in the temporal retinal periphery or through exudation of serous fluid by the fragile capillaries in the abnormal peripheral retinal vasculature. Retinal detachment can be accompanied by a decrease in central visual acuity as a result of macular involvement. Stage 5 total retinal detachments may be indistinguishable from the Norrie disease ocular phenotype; however, Variable expressivity of Pathogenic variants in Clinical manifestations in heterozygous females are rare and usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. Retinal detachment, peripheral retinal avascularity, neovascularization, exudation, and high hyperopia [ Extraocular findings that include mild sensorineural hearing loss [ Phenotypic expression has also been reported in two women with an X-autosome translocation [ Intrafamilial variability may be observed among heterozygous female family members. In one family segregating an The Norrie disease ocular phenotype, especially at birth, is more severe than that of In contrast, males with non-cysteine variants (which do not affect the tertiary structure of the protein) usually have the less severe ocular findings more consistent with The term "Norrie disease" used in the literature typically refers to the classic Norrie disease ocular phenotype occurring with or without extraocular features. Outdated names for Norrie disease include Anderson-Warburg syndrome, atrophia bulborum hereditarian, Episkopi blindness, Norrie-Warburg syndrome, and pseudoglioma congenita. Persistent fetal vasculature (PFV) was formerly referred to as persistent hyperplastic primary vitreous (PHPV). No incidence or prevalence figures for In one academic institution with a large pediatric retina practice, 109 individuals with vitreoretinopathies were enrolled in a three-year prospective study. Eleven of the 109 individuals had Norrie disease has been reported in many populations, including northern and central European, American of European descent, African American, French Canadian, Hispanic, Chinese, Iranian [ • In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [ • Speech discrimination is relatively well preserved even when the threshold hearing loss is severe [ • Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [ • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Retinal detachment, peripheral retinal avascularity, neovascularization, exudation, and high hyperopia [ • Extraocular findings that include mild sensorineural hearing loss [ • In contrast, males with non-cysteine variants (which do not affect the tertiary structure of the protein) usually have the less severe ocular findings more consistent with ## Clinical Description FEVR = familial exudative vitreoretinopathy; PFV = persistent fetal vasculature; ROP = retinopathy of prematurity In rare cases In a family with an In newborns and infants, the classic finding is a grayish-yellow, glistening, elevated retrolental mass composed of immature retinal cells that is usually visible through a clear lens in both eyes. These masses are referred to as "pseudogliomas" because they resemble tumors such as retinoblastoma. There is retinal dysplasia and incomplete foveal development in all cases. Partial or complete retinal detachments are often present at birth in both eyes. If not present at birth, retinal detachments may evolve over the first few months of life. Nystagmus is common secondary to profound, bilateral vision loss [ The irides, anterior chambers, and corneal diameter may be abnormal in size and appearance as a result of anterior segment dysgenesis. The size of the globe may be normal, smaller (microphthalmia), or enlarged (buphthalmos). Intraocular pressure is often normal at birth but can become elevated (i.e., secondary glaucoma) as a result of malformations of the anterior chamber and angle resulting in impaired outflow through the trabecular meshwork. Other consequences of impaired outflow include buphthalmos, pain, and further progression of vision loss. From infancy through childhood, progressive changes typically include opacification of the lens (cataract) and cornea, atrophy or hypoplasia of the iris with adhesions forming between the lens and the iris (posterior synechiae) and between the iris and the cornea (anterior synechiae), and shallowing of the anterior chamber. Hemorrhagic necrosis of the undifferentiated retinal masses can occur. These changes are followed by corneal opacification (e.g., band keratopathy), loss of intraocular pressure (hypotony), and shrinkage of the globe (phthisis bulbi) usually within the first decade of life. In the end stage of the Norrie disease ocular phenotype, the corneas appear milky and opacified, and the globes appear small and sunken in the orbits [ The majority of affected males lose all light perception during the first year of life. In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [ Speech discrimination is relatively well preserved even when the threshold hearing loss is severe [ Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [ Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. Erectile dysfunction has been reported in 14 of 20 adults. Formerly referred to as persistent hyperplastic primary vitreous (PHPV), PFV is characterized by a fibrotic white stalk with hyaloid vessel remnants extending from the optic disc to the posterior lens capsule. If a stalk persists without surgical intervention, restricted growth of the globe through childhood can lead to further vitreoretinal traction, retinal exudation, retinal detachment, secondary glaucoma, and/or phthisis bulbi. The anterior segment, pars plana, and vitreous base are often malformed with anteriorization of retinal tissue past the ora serrata, which increases the complexity of surgical procedures. Although progression to complete retinal detachment has been described, it is not clear if such progression always occurs [ Peripheral retinal ischemia may lead to retinal or extraretinal neovascularization. Such eye findings may progress to retinal detachment either through increasing traction on the retina from progressive fibrovascular changes in the temporal retinal periphery or through exudation of serous fluid by the fragile capillaries in the abnormal peripheral retinal vasculature. Retinal detachment can be accompanied by a decrease in central visual acuity as a result of macular involvement. Stage 5 total retinal detachments may be indistinguishable from the Norrie disease ocular phenotype; however, Variable expressivity of Pathogenic variants in Clinical manifestations in heterozygous females are rare and usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. Retinal detachment, peripheral retinal avascularity, neovascularization, exudation, and high hyperopia [ Extraocular findings that include mild sensorineural hearing loss [ Phenotypic expression has also been reported in two women with an X-autosome translocation [ Intrafamilial variability may be observed among heterozygous female family members. In one family segregating an • In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [ • Speech discrimination is relatively well preserved even when the threshold hearing loss is severe [ • Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [ • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Retinal detachment, peripheral retinal avascularity, neovascularization, exudation, and high hyperopia [ • Extraocular findings that include mild sensorineural hearing loss [ ## Norrie Disease In newborns and infants, the classic finding is a grayish-yellow, glistening, elevated retrolental mass composed of immature retinal cells that is usually visible through a clear lens in both eyes. These masses are referred to as "pseudogliomas" because they resemble tumors such as retinoblastoma. There is retinal dysplasia and incomplete foveal development in all cases. Partial or complete retinal detachments are often present at birth in both eyes. If not present at birth, retinal detachments may evolve over the first few months of life. Nystagmus is common secondary to profound, bilateral vision loss [ The irides, anterior chambers, and corneal diameter may be abnormal in size and appearance as a result of anterior segment dysgenesis. The size of the globe may be normal, smaller (microphthalmia), or enlarged (buphthalmos). Intraocular pressure is often normal at birth but can become elevated (i.e., secondary glaucoma) as a result of malformations of the anterior chamber and angle resulting in impaired outflow through the trabecular meshwork. Other consequences of impaired outflow include buphthalmos, pain, and further progression of vision loss. From infancy through childhood, progressive changes typically include opacification of the lens (cataract) and cornea, atrophy or hypoplasia of the iris with adhesions forming between the lens and the iris (posterior synechiae) and between the iris and the cornea (anterior synechiae), and shallowing of the anterior chamber. Hemorrhagic necrosis of the undifferentiated retinal masses can occur. These changes are followed by corneal opacification (e.g., band keratopathy), loss of intraocular pressure (hypotony), and shrinkage of the globe (phthisis bulbi) usually within the first decade of life. In the end stage of the Norrie disease ocular phenotype, the corneas appear milky and opacified, and the globes appear small and sunken in the orbits [ The majority of affected males lose all light perception during the first year of life. In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [ Speech discrimination is relatively well preserved even when the threshold hearing loss is severe [ Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [ Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. Erectile dysfunction has been reported in 14 of 20 adults. • In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [ • Speech discrimination is relatively well preserved even when the threshold hearing loss is severe [ • Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [ • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. • Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old. • Erectile dysfunction has been reported in 14 of 20 adults. Formerly referred to as persistent hyperplastic primary vitreous (PHPV), PFV is characterized by a fibrotic white stalk with hyaloid vessel remnants extending from the optic disc to the posterior lens capsule. If a stalk persists without surgical intervention, restricted growth of the globe through childhood can lead to further vitreoretinal traction, retinal exudation, retinal detachment, secondary glaucoma, and/or phthisis bulbi. The anterior segment, pars plana, and vitreous base are often malformed with anteriorization of retinal tissue past the ora serrata, which increases the complexity of surgical procedures. Although progression to complete retinal detachment has been described, it is not clear if such progression always occurs [ Peripheral retinal ischemia may lead to retinal or extraretinal neovascularization. Such eye findings may progress to retinal detachment either through increasing traction on the retina from progressive fibrovascular changes in the temporal retinal periphery or through exudation of serous fluid by the fragile capillaries in the abnormal peripheral retinal vasculature. Retinal detachment can be accompanied by a decrease in central visual acuity as a result of macular involvement. Stage 5 total retinal detachments may be indistinguishable from the Norrie disease ocular phenotype; however, Variable expressivity of Pathogenic variants in ## Heterozygous Females Clinical manifestations in heterozygous females are rare and usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. Retinal detachment, peripheral retinal avascularity, neovascularization, exudation, and high hyperopia [ Extraocular findings that include mild sensorineural hearing loss [ Phenotypic expression has also been reported in two women with an X-autosome translocation [ Intrafamilial variability may be observed among heterozygous female family members. In one family segregating an • Retinal detachment, peripheral retinal avascularity, neovascularization, exudation, and high hyperopia [ • Extraocular findings that include mild sensorineural hearing loss [ ## Genotype-Phenotype Correlations The Norrie disease ocular phenotype, especially at birth, is more severe than that of In contrast, males with non-cysteine variants (which do not affect the tertiary structure of the protein) usually have the less severe ocular findings more consistent with • In contrast, males with non-cysteine variants (which do not affect the tertiary structure of the protein) usually have the less severe ocular findings more consistent with ## Nomenclature The term "Norrie disease" used in the literature typically refers to the classic Norrie disease ocular phenotype occurring with or without extraocular features. Outdated names for Norrie disease include Anderson-Warburg syndrome, atrophia bulborum hereditarian, Episkopi blindness, Norrie-Warburg syndrome, and pseudoglioma congenita. Persistent fetal vasculature (PFV) was formerly referred to as persistent hyperplastic primary vitreous (PHPV). ## Prevalence No incidence or prevalence figures for In one academic institution with a large pediatric retina practice, 109 individuals with vitreoretinopathies were enrolled in a three-year prospective study. Eleven of the 109 individuals had Norrie disease has been reported in many populations, including northern and central European, American of European descent, African American, French Canadian, Hispanic, Chinese, Iranian [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Deletions extending beyond Deletions including • Deletions extending beyond • Deletions including ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; diffdx = differential diagnosis; MOI = mode of inheritance; FEVR = familial exudative vitreoretinopathy; ND = Norrie disease; PFV = persistent fetal vasculature Inheritance is autosomal dominant with the exception of ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis in Individuals with Perform ultrasonography to identify retinal detachment when media opacities are present. Perform fluorescein angiography of fundus to identify areas of avascularity &/or vascular abnormalities. Assess need for intervention (e.g., surgery, laser, intravitreal injection). Brain MRI Consider EEG if seizures are a concern. Motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Screen all children (regardless of age) for sleep disturbances, as infants w/no light perception may need consultation w/sleep specialist & possible systemic treatment. For persons >12 mos: screen for behavior concerns incl ADHD, anxiety, &/or findings suggestive of ASD. Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Skin exam for evidence of peripheral vascular-related changes In adult males, history of erectile dysfunction Referral to Referral to state services for the blind or deaf-blind Ongoing coordinated care through specialized clinics Social services ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Applies for all males with the Norrie disease ocular phenotype and any person with an Medical geneticist, certified genetic counselor, certified advanced genetic nurse Pediatric ophthalmologists and pediatric vitreoretinal surgeons must individualize management based on a child's ocular development and anatomy. Early intervention, ideally at the time of diagnosis, can be vision saving. Reduction of the intraocular pressure to decrease the risk of glaucoma may require use of topical or systemic agents. A pediatric ophthalmologist should manage refractive errors and/or strabismus to optimize vision and ocular alignment. A pediatric vitreoretinal surgeon, when appropriate, should discuss risks and benefits of surgical intervention. Operating on a less developed eye, especially one with retinal dysplasia and/or other abnormalities, leaves minimal room for error. Advanced vitreoretinopathy with significant retinal dysplasia may be too severe to merit surgical intervention. The following information represents additional management recommendations, albeit generalized, for the ocular manifestations of the Individuals with Norrie disease who do not have complete retinal detachment may benefit from surgery and/or laser therapy per the following reports: Laser ablation of the avascular retina in both eyes of a two-day-old infant after planned delivery at 34 weeks' gestation (following exclusion of retinal detachment by fetal ultrasonography at 28 and 33 weeks' gestation) revealed complete attachment of the retinas in both eyes at age ten months [ Following successful prophylactic laser photocoagulation at birth at 37 weeks' gestation, Teller visual acuity testing at age 23 months revealed age-appropriate vision of 20/100 [ Thus, families may wish to consider the option of preterm genetic testing, and retinal laser treatment of an affected male immediately after birth with the intent to preserve vision. In a retrospective review of medical records in a tertiary care pediatric retinal clinical practice (1988-2008), seven of 14 male infants with the Norrie disease ocular phenotype who underwent vitrectomy by age 12 months (median 4.5 months) had documented maintenance of light perception in at least one eye [ When translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy are indicated, it is recommended that extreme caution be used to avoid intraoperative traction. When there is a total retinal detachment (Stage 5), the lens and capsule should be removed to eliminate a scaffold for anterior proliferation and to avoid iatrogenic breaks. Early simultaneous intervention in both eyes is feasible and safe for children with bilateral vitreoretinal involvement in order to avoid a second anesthesia [ In the progressive stage of the ocular findings of Norrie disease, development of increased intraocular pressure may require medications and/or surgical intervention. Rarely, enucleation is required to control pain in a blind eye caused by hypotony/phthisis. Prophylactic laser photocoagulation of avascular peripheral retina at the time of diagnosis can decrease the production of vascular endothelial growth factor (VEGF) and decrease the risk of neovascularization and vitreoretinal traction. Early careful surgical dissection of tractional tissues can potentially result in good anatomic outcomes with FEVR-associated retinal detachment. Management is similar to that for Severing transvitreal traction vectors should guide surgical management of extrafoveal retinal detachment (Stage 4A), subtotal foveal-involving retinal detachment (Stage 4B), and total retinal detachment (Stage 5). Because children born preterm have an increased prevalence of all refractive errors (especially myopia, and especially after laser treatment), these should be diagnosed and managed promptly to decrease the risk of amblyopia. Laser photocoagulation (directed to telangiectatic vessels, microaneurysms, and avascular areas of peripheral retina) may be warranted when there is significant subretinal exudation and/or hemorrhage that affects the macula. Anti-VEGF agents (e.g., bevacizumab) have been increasingly used to control the exudative process in Coats disease. Treatment involves a multidisciplinary team, typically including low-vision services, neurologists, pediatricians, developmental pediatricians, pediatric sleep specialists, mental health specialists, physiatrists, occupational and physical therapists, audiologists, and speech-language pathologists ( Treatment of Manifestations in Individuals with Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers An empiric trial of psychotropic medications may be warranted; however, no data are available for this disorder. Referral to sleep specialist may benefit persons w/profound vision impairment. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see See The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. State deaf-blind services: In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. Abnormal sleep patterns may develop in individuals with no light perception and abnormal circadian rhythmicity. Frequent early morning waking and daytime sleeping can be mitigated with strict daily schedules and medications (e.g., melatonin), often managed by a pediatric sleep specialist or developmental pediatrician [ Recommended Surveillance for Individuals with For those w/known hearing loss: per treating audiologist For those w/o known hearing loss: prior to onset of language, frequent eval; thereafter, every 6 mos ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy Given the risk of hearing loss, the following are recommended: Avoidance of exposure to loud noises Use of hearing protection in noisy environments or when using noisy equipment Minimal use of ear buds and other listening devices It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk female relatives of an affected individual. Females who are heterozygous for the familial See Search • Perform ultrasonography to identify retinal detachment when media opacities are present. • Perform fluorescein angiography of fundus to identify areas of avascularity &/or vascular abnormalities. • Assess need for intervention (e.g., surgery, laser, intravitreal injection). • Brain MRI • Consider EEG if seizures are a concern. • Motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Screen all children (regardless of age) for sleep disturbances, as infants w/no light perception may need consultation w/sleep specialist & possible systemic treatment. • For persons >12 mos: screen for behavior concerns incl ADHD, anxiety, &/or findings suggestive of ASD. • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Skin exam for evidence of peripheral vascular-related changes • In adult males, history of erectile dysfunction • Referral to • Referral to state services for the blind or deaf-blind • Ongoing coordinated care through specialized clinics • Social services • Reduction of the intraocular pressure to decrease the risk of glaucoma may require use of topical or systemic agents. • A pediatric ophthalmologist should manage refractive errors and/or strabismus to optimize vision and ocular alignment. • A pediatric vitreoretinal surgeon, when appropriate, should discuss risks and benefits of surgical intervention. Operating on a less developed eye, especially one with retinal dysplasia and/or other abnormalities, leaves minimal room for error. Advanced vitreoretinopathy with significant retinal dysplasia may be too severe to merit surgical intervention. • Laser ablation of the avascular retina in both eyes of a two-day-old infant after planned delivery at 34 weeks' gestation (following exclusion of retinal detachment by fetal ultrasonography at 28 and 33 weeks' gestation) revealed complete attachment of the retinas in both eyes at age ten months [ • Following successful prophylactic laser photocoagulation at birth at 37 weeks' gestation, Teller visual acuity testing at age 23 months revealed age-appropriate vision of 20/100 [ • Thus, families may wish to consider the option of preterm genetic testing, and retinal laser treatment of an affected male immediately after birth with the intent to preserve vision. • In a retrospective review of medical records in a tertiary care pediatric retinal clinical practice (1988-2008), seven of 14 male infants with the Norrie disease ocular phenotype who underwent vitrectomy by age 12 months (median 4.5 months) had documented maintenance of light perception in at least one eye [ • When translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy are indicated, it is recommended that extreme caution be used to avoid intraoperative traction. When there is a total retinal detachment (Stage 5), the lens and capsule should be removed to eliminate a scaffold for anterior proliferation and to avoid iatrogenic breaks. • Early simultaneous intervention in both eyes is feasible and safe for children with bilateral vitreoretinal involvement in order to avoid a second anesthesia [ • Prophylactic laser photocoagulation of avascular peripheral retina at the time of diagnosis can decrease the production of vascular endothelial growth factor (VEGF) and decrease the risk of neovascularization and vitreoretinal traction. • Early careful surgical dissection of tractional tissues can potentially result in good anatomic outcomes with FEVR-associated retinal detachment. • Management is similar to that for • Severing transvitreal traction vectors should guide surgical management of extrafoveal retinal detachment (Stage 4A), subtotal foveal-involving retinal detachment (Stage 4B), and total retinal detachment (Stage 5). • Because children born preterm have an increased prevalence of all refractive errors (especially myopia, and especially after laser treatment), these should be diagnosed and managed promptly to decrease the risk of amblyopia. • Laser photocoagulation (directed to telangiectatic vessels, microaneurysms, and avascular areas of peripheral retina) may be warranted when there is significant subretinal exudation and/or hemorrhage that affects the macula. • Anti-VEGF agents (e.g., bevacizumab) have been increasingly used to control the exudative process in Coats disease. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • An empiric trial of psychotropic medications may be warranted; however, no data are available for this disorder. • Referral to sleep specialist may benefit persons w/profound vision impairment. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • State deaf-blind services: • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • For those w/known hearing loss: per treating audiologist • For those w/o known hearing loss: prior to onset of language, frequent eval; thereafter, every 6 mos • Avoidance of exposure to loud noises • Use of hearing protection in noisy environments or when using noisy equipment • Minimal use of ear buds and other listening devices ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis in Individuals with Perform ultrasonography to identify retinal detachment when media opacities are present. Perform fluorescein angiography of fundus to identify areas of avascularity &/or vascular abnormalities. Assess need for intervention (e.g., surgery, laser, intravitreal injection). Brain MRI Consider EEG if seizures are a concern. Motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Screen all children (regardless of age) for sleep disturbances, as infants w/no light perception may need consultation w/sleep specialist & possible systemic treatment. For persons >12 mos: screen for behavior concerns incl ADHD, anxiety, &/or findings suggestive of ASD. Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Skin exam for evidence of peripheral vascular-related changes In adult males, history of erectile dysfunction Referral to Referral to state services for the blind or deaf-blind Ongoing coordinated care through specialized clinics Social services ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Applies for all males with the Norrie disease ocular phenotype and any person with an Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Perform ultrasonography to identify retinal detachment when media opacities are present. • Perform fluorescein angiography of fundus to identify areas of avascularity &/or vascular abnormalities. • Assess need for intervention (e.g., surgery, laser, intravitreal injection). • Brain MRI • Consider EEG if seizures are a concern. • Motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Screen all children (regardless of age) for sleep disturbances, as infants w/no light perception may need consultation w/sleep specialist & possible systemic treatment. • For persons >12 mos: screen for behavior concerns incl ADHD, anxiety, &/or findings suggestive of ASD. • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Skin exam for evidence of peripheral vascular-related changes • In adult males, history of erectile dysfunction • Referral to • Referral to state services for the blind or deaf-blind • Ongoing coordinated care through specialized clinics • Social services ## Treatment of Manifestations Pediatric ophthalmologists and pediatric vitreoretinal surgeons must individualize management based on a child's ocular development and anatomy. Early intervention, ideally at the time of diagnosis, can be vision saving. Reduction of the intraocular pressure to decrease the risk of glaucoma may require use of topical or systemic agents. A pediatric ophthalmologist should manage refractive errors and/or strabismus to optimize vision and ocular alignment. A pediatric vitreoretinal surgeon, when appropriate, should discuss risks and benefits of surgical intervention. Operating on a less developed eye, especially one with retinal dysplasia and/or other abnormalities, leaves minimal room for error. Advanced vitreoretinopathy with significant retinal dysplasia may be too severe to merit surgical intervention. The following information represents additional management recommendations, albeit generalized, for the ocular manifestations of the Individuals with Norrie disease who do not have complete retinal detachment may benefit from surgery and/or laser therapy per the following reports: Laser ablation of the avascular retina in both eyes of a two-day-old infant after planned delivery at 34 weeks' gestation (following exclusion of retinal detachment by fetal ultrasonography at 28 and 33 weeks' gestation) revealed complete attachment of the retinas in both eyes at age ten months [ Following successful prophylactic laser photocoagulation at birth at 37 weeks' gestation, Teller visual acuity testing at age 23 months revealed age-appropriate vision of 20/100 [ Thus, families may wish to consider the option of preterm genetic testing, and retinal laser treatment of an affected male immediately after birth with the intent to preserve vision. In a retrospective review of medical records in a tertiary care pediatric retinal clinical practice (1988-2008), seven of 14 male infants with the Norrie disease ocular phenotype who underwent vitrectomy by age 12 months (median 4.5 months) had documented maintenance of light perception in at least one eye [ When translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy are indicated, it is recommended that extreme caution be used to avoid intraoperative traction. When there is a total retinal detachment (Stage 5), the lens and capsule should be removed to eliminate a scaffold for anterior proliferation and to avoid iatrogenic breaks. Early simultaneous intervention in both eyes is feasible and safe for children with bilateral vitreoretinal involvement in order to avoid a second anesthesia [ In the progressive stage of the ocular findings of Norrie disease, development of increased intraocular pressure may require medications and/or surgical intervention. Rarely, enucleation is required to control pain in a blind eye caused by hypotony/phthisis. Prophylactic laser photocoagulation of avascular peripheral retina at the time of diagnosis can decrease the production of vascular endothelial growth factor (VEGF) and decrease the risk of neovascularization and vitreoretinal traction. Early careful surgical dissection of tractional tissues can potentially result in good anatomic outcomes with FEVR-associated retinal detachment. Management is similar to that for Severing transvitreal traction vectors should guide surgical management of extrafoveal retinal detachment (Stage 4A), subtotal foveal-involving retinal detachment (Stage 4B), and total retinal detachment (Stage 5). Because children born preterm have an increased prevalence of all refractive errors (especially myopia, and especially after laser treatment), these should be diagnosed and managed promptly to decrease the risk of amblyopia. Laser photocoagulation (directed to telangiectatic vessels, microaneurysms, and avascular areas of peripheral retina) may be warranted when there is significant subretinal exudation and/or hemorrhage that affects the macula. Anti-VEGF agents (e.g., bevacizumab) have been increasingly used to control the exudative process in Coats disease. Treatment involves a multidisciplinary team, typically including low-vision services, neurologists, pediatricians, developmental pediatricians, pediatric sleep specialists, mental health specialists, physiatrists, occupational and physical therapists, audiologists, and speech-language pathologists ( Treatment of Manifestations in Individuals with Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers An empiric trial of psychotropic medications may be warranted; however, no data are available for this disorder. Referral to sleep specialist may benefit persons w/profound vision impairment. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see See The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. State deaf-blind services: In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. Abnormal sleep patterns may develop in individuals with no light perception and abnormal circadian rhythmicity. Frequent early morning waking and daytime sleeping can be mitigated with strict daily schedules and medications (e.g., melatonin), often managed by a pediatric sleep specialist or developmental pediatrician [ • Reduction of the intraocular pressure to decrease the risk of glaucoma may require use of topical or systemic agents. • A pediatric ophthalmologist should manage refractive errors and/or strabismus to optimize vision and ocular alignment. • A pediatric vitreoretinal surgeon, when appropriate, should discuss risks and benefits of surgical intervention. Operating on a less developed eye, especially one with retinal dysplasia and/or other abnormalities, leaves minimal room for error. Advanced vitreoretinopathy with significant retinal dysplasia may be too severe to merit surgical intervention. • Laser ablation of the avascular retina in both eyes of a two-day-old infant after planned delivery at 34 weeks' gestation (following exclusion of retinal detachment by fetal ultrasonography at 28 and 33 weeks' gestation) revealed complete attachment of the retinas in both eyes at age ten months [ • Following successful prophylactic laser photocoagulation at birth at 37 weeks' gestation, Teller visual acuity testing at age 23 months revealed age-appropriate vision of 20/100 [ • Thus, families may wish to consider the option of preterm genetic testing, and retinal laser treatment of an affected male immediately after birth with the intent to preserve vision. • In a retrospective review of medical records in a tertiary care pediatric retinal clinical practice (1988-2008), seven of 14 male infants with the Norrie disease ocular phenotype who underwent vitrectomy by age 12 months (median 4.5 months) had documented maintenance of light perception in at least one eye [ • When translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy are indicated, it is recommended that extreme caution be used to avoid intraoperative traction. When there is a total retinal detachment (Stage 5), the lens and capsule should be removed to eliminate a scaffold for anterior proliferation and to avoid iatrogenic breaks. • Early simultaneous intervention in both eyes is feasible and safe for children with bilateral vitreoretinal involvement in order to avoid a second anesthesia [ • Prophylactic laser photocoagulation of avascular peripheral retina at the time of diagnosis can decrease the production of vascular endothelial growth factor (VEGF) and decrease the risk of neovascularization and vitreoretinal traction. • Early careful surgical dissection of tractional tissues can potentially result in good anatomic outcomes with FEVR-associated retinal detachment. • Management is similar to that for • Severing transvitreal traction vectors should guide surgical management of extrafoveal retinal detachment (Stage 4A), subtotal foveal-involving retinal detachment (Stage 4B), and total retinal detachment (Stage 5). • Because children born preterm have an increased prevalence of all refractive errors (especially myopia, and especially after laser treatment), these should be diagnosed and managed promptly to decrease the risk of amblyopia. • Laser photocoagulation (directed to telangiectatic vessels, microaneurysms, and avascular areas of peripheral retina) may be warranted when there is significant subretinal exudation and/or hemorrhage that affects the macula. • Anti-VEGF agents (e.g., bevacizumab) have been increasingly used to control the exudative process in Coats disease. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • An empiric trial of psychotropic medications may be warranted; however, no data are available for this disorder. • Referral to sleep specialist may benefit persons w/profound vision impairment. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • State deaf-blind services: • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. ## Ocular Manifestations Pediatric ophthalmologists and pediatric vitreoretinal surgeons must individualize management based on a child's ocular development and anatomy. Early intervention, ideally at the time of diagnosis, can be vision saving. Reduction of the intraocular pressure to decrease the risk of glaucoma may require use of topical or systemic agents. A pediatric ophthalmologist should manage refractive errors and/or strabismus to optimize vision and ocular alignment. A pediatric vitreoretinal surgeon, when appropriate, should discuss risks and benefits of surgical intervention. Operating on a less developed eye, especially one with retinal dysplasia and/or other abnormalities, leaves minimal room for error. Advanced vitreoretinopathy with significant retinal dysplasia may be too severe to merit surgical intervention. The following information represents additional management recommendations, albeit generalized, for the ocular manifestations of the Individuals with Norrie disease who do not have complete retinal detachment may benefit from surgery and/or laser therapy per the following reports: Laser ablation of the avascular retina in both eyes of a two-day-old infant after planned delivery at 34 weeks' gestation (following exclusion of retinal detachment by fetal ultrasonography at 28 and 33 weeks' gestation) revealed complete attachment of the retinas in both eyes at age ten months [ Following successful prophylactic laser photocoagulation at birth at 37 weeks' gestation, Teller visual acuity testing at age 23 months revealed age-appropriate vision of 20/100 [ Thus, families may wish to consider the option of preterm genetic testing, and retinal laser treatment of an affected male immediately after birth with the intent to preserve vision. In a retrospective review of medical records in a tertiary care pediatric retinal clinical practice (1988-2008), seven of 14 male infants with the Norrie disease ocular phenotype who underwent vitrectomy by age 12 months (median 4.5 months) had documented maintenance of light perception in at least one eye [ When translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy are indicated, it is recommended that extreme caution be used to avoid intraoperative traction. When there is a total retinal detachment (Stage 5), the lens and capsule should be removed to eliminate a scaffold for anterior proliferation and to avoid iatrogenic breaks. Early simultaneous intervention in both eyes is feasible and safe for children with bilateral vitreoretinal involvement in order to avoid a second anesthesia [ In the progressive stage of the ocular findings of Norrie disease, development of increased intraocular pressure may require medications and/or surgical intervention. Rarely, enucleation is required to control pain in a blind eye caused by hypotony/phthisis. Prophylactic laser photocoagulation of avascular peripheral retina at the time of diagnosis can decrease the production of vascular endothelial growth factor (VEGF) and decrease the risk of neovascularization and vitreoretinal traction. Early careful surgical dissection of tractional tissues can potentially result in good anatomic outcomes with FEVR-associated retinal detachment. Management is similar to that for Severing transvitreal traction vectors should guide surgical management of extrafoveal retinal detachment (Stage 4A), subtotal foveal-involving retinal detachment (Stage 4B), and total retinal detachment (Stage 5). Because children born preterm have an increased prevalence of all refractive errors (especially myopia, and especially after laser treatment), these should be diagnosed and managed promptly to decrease the risk of amblyopia. Laser photocoagulation (directed to telangiectatic vessels, microaneurysms, and avascular areas of peripheral retina) may be warranted when there is significant subretinal exudation and/or hemorrhage that affects the macula. Anti-VEGF agents (e.g., bevacizumab) have been increasingly used to control the exudative process in Coats disease. • Reduction of the intraocular pressure to decrease the risk of glaucoma may require use of topical or systemic agents. • A pediatric ophthalmologist should manage refractive errors and/or strabismus to optimize vision and ocular alignment. • A pediatric vitreoretinal surgeon, when appropriate, should discuss risks and benefits of surgical intervention. Operating on a less developed eye, especially one with retinal dysplasia and/or other abnormalities, leaves minimal room for error. Advanced vitreoretinopathy with significant retinal dysplasia may be too severe to merit surgical intervention. • Laser ablation of the avascular retina in both eyes of a two-day-old infant after planned delivery at 34 weeks' gestation (following exclusion of retinal detachment by fetal ultrasonography at 28 and 33 weeks' gestation) revealed complete attachment of the retinas in both eyes at age ten months [ • Following successful prophylactic laser photocoagulation at birth at 37 weeks' gestation, Teller visual acuity testing at age 23 months revealed age-appropriate vision of 20/100 [ • Thus, families may wish to consider the option of preterm genetic testing, and retinal laser treatment of an affected male immediately after birth with the intent to preserve vision. • In a retrospective review of medical records in a tertiary care pediatric retinal clinical practice (1988-2008), seven of 14 male infants with the Norrie disease ocular phenotype who underwent vitrectomy by age 12 months (median 4.5 months) had documented maintenance of light perception in at least one eye [ • When translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy are indicated, it is recommended that extreme caution be used to avoid intraoperative traction. When there is a total retinal detachment (Stage 5), the lens and capsule should be removed to eliminate a scaffold for anterior proliferation and to avoid iatrogenic breaks. • Early simultaneous intervention in both eyes is feasible and safe for children with bilateral vitreoretinal involvement in order to avoid a second anesthesia [ • Prophylactic laser photocoagulation of avascular peripheral retina at the time of diagnosis can decrease the production of vascular endothelial growth factor (VEGF) and decrease the risk of neovascularization and vitreoretinal traction. • Early careful surgical dissection of tractional tissues can potentially result in good anatomic outcomes with FEVR-associated retinal detachment. • Management is similar to that for • Severing transvitreal traction vectors should guide surgical management of extrafoveal retinal detachment (Stage 4A), subtotal foveal-involving retinal detachment (Stage 4B), and total retinal detachment (Stage 5). • Because children born preterm have an increased prevalence of all refractive errors (especially myopia, and especially after laser treatment), these should be diagnosed and managed promptly to decrease the risk of amblyopia. • Laser photocoagulation (directed to telangiectatic vessels, microaneurysms, and avascular areas of peripheral retina) may be warranted when there is significant subretinal exudation and/or hemorrhage that affects the macula. • Anti-VEGF agents (e.g., bevacizumab) have been increasingly used to control the exudative process in Coats disease. ## Extraocular Manifestations Treatment involves a multidisciplinary team, typically including low-vision services, neurologists, pediatricians, developmental pediatricians, pediatric sleep specialists, mental health specialists, physiatrists, occupational and physical therapists, audiologists, and speech-language pathologists ( Treatment of Manifestations in Individuals with Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers An empiric trial of psychotropic medications may be warranted; however, no data are available for this disorder. Referral to sleep specialist may benefit persons w/profound vision impairment. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see See The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. State deaf-blind services: In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. Abnormal sleep patterns may develop in individuals with no light perception and abnormal circadian rhythmicity. Frequent early morning waking and daytime sleeping can be mitigated with strict daily schedules and medications (e.g., melatonin), often managed by a pediatric sleep specialist or developmental pediatrician [ • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • An empiric trial of psychotropic medications may be warranted; however, no data are available for this disorder. • Referral to sleep specialist may benefit persons w/profound vision impairment. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • State deaf-blind services: • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues ( • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions. ## Surveillance Recommended Surveillance for Individuals with For those w/known hearing loss: per treating audiologist For those w/o known hearing loss: prior to onset of language, frequent eval; thereafter, every 6 mos ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy • For those w/known hearing loss: per treating audiologist • For those w/o known hearing loss: prior to onset of language, frequent eval; thereafter, every 6 mos ## Agents/Circumstances to Avoid Given the risk of hearing loss, the following are recommended: Avoidance of exposure to loud noises Use of hearing protection in noisy environments or when using noisy equipment Minimal use of ear buds and other listening devices • Avoidance of exposure to loud noises • Use of hearing protection in noisy environments or when using noisy equipment • Minimal use of ear buds and other listening devices ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk female relatives of an affected individual. Females who are heterozygous for the familial See ## Therapies Under Investigation Search ## Genetic Counseling The father of an affected male will not have the disorder nor will he be hemizygous for the The majority of affected males have the disorder as the result of an In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and no other affected relatives, and if the If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote; The affected male may have a The mother may have somatic/germline mosaicism. Molecular genetic testing of the mother is recommended to confirm her genetic status, allow reliable recurrence risk assessment, and clarify her risk for If the mother of the proband has an Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see If the proband represents a simplex case and if the In rare instances, females heterozygous for an Molecular genetic testing to identify female heterozygotes is most informative if the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Consideration of prompt ophthalmologic management after birth can provide the greatest opportunity for anatomic success of retinal repair [ Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • The majority of affected males have the disorder as the result of an • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and no other affected relatives, and if the • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. • Molecular genetic testing of the mother is recommended to confirm her genetic status, allow reliable recurrence risk assessment, and clarify her risk for • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see • Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. • Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see • Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see • Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. • Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see • Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. • Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the The majority of affected males have the disorder as the result of an In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and no other affected relatives, and if the If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote; The affected male may have a The mother may have somatic/germline mosaicism. Molecular genetic testing of the mother is recommended to confirm her genetic status, allow reliable recurrence risk assessment, and clarify her risk for If the mother of the proband has an Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see If the proband represents a simplex case and if the • The father of an affected male will not have the disorder nor will he be hemizygous for the • The majority of affected males have the disorder as the result of an • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and no other affected relatives, and if the • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. • Molecular genetic testing of the mother is recommended to confirm her genetic status, allow reliable recurrence risk assessment, and clarify her risk for • The mother may be a heterozygote; • The affected male may have a • The mother may have somatic/germline mosaicism. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see • Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. • Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see • Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see • Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. • Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. (Note: Intrafamilial phenotypic variability may be observed in the retinal phenotype and extraocular manifestations of the disorder; see • Females who inherit the pathogenic variant will be heterozygotes. Clinical findings in heterozygous females are rare and are usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. • Expression in heterozygous females can include retinal and extraocular features and may vary between heterozygous female family members (see ## Heterozygote Detection In rare instances, females heterozygous for an Molecular genetic testing to identify female heterozygotes is most informative if the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Consideration of prompt ophthalmologic management after birth can provide the greatest opportunity for anatomic success of retinal repair [ Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources PO Box 12476 Colchester CO1 9RB United Kingdom United Kingdom Massachusetts General Hospital 185 Cambridge Street CRP Building North, 5th Floor, Suite 5300 Boston MA 02114 • • • • PO Box 12476 • Colchester CO1 9RB • United Kingdom • • • • • • • • • • • • • • • • United Kingdom • • • Massachusetts General Hospital • 185 Cambridge Street • CRP Building North, 5th Floor, Suite 5300 • Boston MA 02114 ## Molecular Genetics NDP-Related Retinopathies: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NDP-Related Retinopathies ( Norrin is critical in central nervous system vascular development, as it is required for: Angiogenesis in the eye, ear, and brain; Maintenance of the blood-brain barrier and the blood-retinal barrier; Neuro-protective properties for retinal neurons. It has been shown that norrin protects against oxidative damage of retinal cells, and pathogenic Audiologic and animal model data suggest that the pathology resides in the cochlea (specifically, the stria vascularis) and that retrocochlear and brain auditory system function is normal [ The role of norrin in intellectual disability is unknown [ • Angiogenesis in the eye, ear, and brain; • Maintenance of the blood-brain barrier and the blood-retinal barrier; • Neuro-protective properties for retinal neurons. ## Molecular Pathogenesis Norrin is critical in central nervous system vascular development, as it is required for: Angiogenesis in the eye, ear, and brain; Maintenance of the blood-brain barrier and the blood-retinal barrier; Neuro-protective properties for retinal neurons. It has been shown that norrin protects against oxidative damage of retinal cells, and pathogenic Audiologic and animal model data suggest that the pathology resides in the cochlea (specifically, the stria vascularis) and that retrocochlear and brain auditory system function is normal [ The role of norrin in intellectual disability is unknown [ • Angiogenesis in the eye, ear, and brain; • Maintenance of the blood-brain barrier and the blood-retinal barrier; • Neuro-protective properties for retinal neurons. ## Chapter Notes Lisa A Schimmenti, MD (2022-present)Brittni A Scruggs, MD, PhD (2022-present)Madeline Q Reding, MS, MPH, CGC (2022-present)Katherine B Sims, MD; Massachusetts General Hospital (1999-2022) 23 March 2023 (aa/gm) Revision: 31 March 2022 (bp) Comprehensive update posted live 18 September 2014 (me) Comprehensive update posted live 23 July 2009 (me) Comprehensive update posted live 8 August 2006 (me) Comprehensive update posted live 14 May 2004 (me) Comprehensive update posted live 11 June 2002 (me) Comprehensive update posted live 30 July 1999 (me) Review posted live 10 February 1999 (ks) Original submission • 23 March 2023 (aa/gm) Revision: • 31 March 2022 (bp) Comprehensive update posted live • 18 September 2014 (me) Comprehensive update posted live • 23 July 2009 (me) Comprehensive update posted live • 8 August 2006 (me) Comprehensive update posted live • 14 May 2004 (me) Comprehensive update posted live • 11 June 2002 (me) Comprehensive update posted live • 30 July 1999 (me) Review posted live • 10 February 1999 (ks) Original submission ## Author History Lisa A Schimmenti, MD (2022-present)Brittni A Scruggs, MD, PhD (2022-present)Madeline Q Reding, MS, MPH, CGC (2022-present)Katherine B Sims, MD; Massachusetts General Hospital (1999-2022) ## Revision History 23 March 2023 (aa/gm) Revision: 31 March 2022 (bp) Comprehensive update posted live 18 September 2014 (me) Comprehensive update posted live 23 July 2009 (me) Comprehensive update posted live 8 August 2006 (me) Comprehensive update posted live 14 May 2004 (me) Comprehensive update posted live 11 June 2002 (me) Comprehensive update posted live 30 July 1999 (me) Review posted live 10 February 1999 (ks) Original submission • 23 March 2023 (aa/gm) Revision: • 31 March 2022 (bp) Comprehensive update posted live • 18 September 2014 (me) Comprehensive update posted live • 23 July 2009 (me) Comprehensive update posted live • 8 August 2006 (me) Comprehensive update posted live • 14 May 2004 (me) Comprehensive update posted live • 11 June 2002 (me) Comprehensive update posted live • 30 July 1999 (me) Review posted live • 10 February 1999 (ks) Original submission ## References ## Literature Cited Hearing loss by age group in a subset of affected males enrolled in the Norrie Disease Registry (n=56) [ Peripheral vascular disease by age group in a subset of affected males enrolled in the Norrie Disease Registry (n=56) [	[ "RC Allen, SR Russell, LM Streb, A Alsheikheh, EM Stone. 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Br J Ophthalmol. 2004;88:1475", "K Nikopoulos, H Venselaar, RW Collin, R Riveiro-Alvarez, FN Boonstra, JM Hooymans, A Mukhopadhyay, D Shears, M van Bers, IJ de Wijs, AJ van Essen, RH Sijmons, MA Tilanus, CE van Nouhuys, C Ayuso, LH Hoefsloot, FP Cremers. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.. Hum Mutat. 2010;31:656-66", "T Parzefall, T Lucas, M Ritter, M Ludwig, R Ramsebner, A Frohne, C Schofer, M Hengstschlager, K Frei. A novel missense NDP mutation [p.(Cys93Arg)] with a manifesting carrier in an Austrian family with Norrie disease.. Audiol Neurootol. 2014;19:203-9", "A Rattner, Y Wang, Y Zhou, J Williams, J Nathans. The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling.. Invest Ophthalmol Vis Sci. 2014;55:8614-25", "RM Redmond, JI Vaughan, M Jay, B Jay. 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Sequence analysis and transcript identification within 1.5 mB of DNA deleted together with the NDP and MAO genes in atypical Norrie disease patients presenting with a profound phenotype.. Hum Mutat 2001;17:523", "D Sudha, A Ganapathy, P Mohan, AU Mannan, S Krishna, S Neriyanuri, M Swaminathan, P Rishi, S Chidambaram, JP Arunachalam. Clinical and genetic analysis of Indian patients with NDP-related retinopathies.. Int Ophthalmol. 2018;38:1251-60", "F Talebi, F Ghanbari Mardasi, J Mohammadi Asl, A Lashgari, F. Farhadi. Identification of a novel missense mutation in the Norrie disease gene: the first molecular genetic analysis and prenatal diagnosis of Norrie disease in an Iranian family.. 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npab	npab	[ "Infantile Neurovisceral ASMD (Niemann-Pick Disease Type A; NPD-A)", "Chronic Visceral ASMD (Niemann-Pick Disease Type B; NPD-B)", "Chronic Neurovisceral ASMD (Intermediate Form; NPD-A/B)", "Sphingomyelin phosphodiesterase", "SMPD1", "Acid Sphingomyelinase Deficiency" ]	Acid Sphingomyelinase Deficiency	Melissa P Wasserstein, Edward H Schuchman	Summary The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type. As more affected individuals are treated with ERT for longer periods of time, the natural history of ASMD is likely to change. The most common presenting symptom in untreated NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Growth failure typically becomes evident by the second year of life. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. This feature may not be amenable to ERT. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children, although it is unclear if ERT will have an impact on this. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most untreated children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized in untreated individuals by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some central nervous system manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B, even when untreated. The diagnosis of ASMD is established by detection of biallelic pathogenic variants in All forms of ASMD (NPD-A, NPD-A/B, and NPD-B) are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Infantile neurovisceral ASMD (Niemann-Pick disease type A; NPD-A) Chronic neurovisceral ASMD (intermediate form; NPD-A/B) Chronic visceral ASMD (Niemann-Pick disease type B; NPD-B) ASMD = acid sphingomyelinase deficiency, which includes NPD-A, NPD-A/B, and NPD-B • Infantile neurovisceral ASMD (Niemann-Pick disease type A; NPD-A) • Chronic neurovisceral ASMD (intermediate form; NPD-A/B) • Chronic visceral ASMD (Niemann-Pick disease type B; NPD-B) ## Diagnosis Acid sphingomyelinase deficiency (ASMD) cannot be diagnosed solely on clinical grounds. NBS for ASMD is primarily based on quantification of acid sphingomyelinase activity on dried blood spots. At the time of writing, ASMD is not included on the United States Recommended Uniform Screening Panel and is performed in a limited number of states within the US. Several pilot studies have also been performed in Europe. Acid sphingomyelinase activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical and/or molecular genetic testing for confirmation. Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined. Molecular genetic testing involves sequence analysis of Referral to a metabolic or genetic disease specialist should be made immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of ASMD. A symptomatic individual who has findings associated with ASMD (infantile neurovisceral ASMD [NPD-A], chronic neurovisceral ASMD [NPD-A/B], or chronic visceral ASMD [NPD-B]) may present because of any of the following: NBS was not performed, the NBS result was false negative, and/or caregivers were not adherent to or aware of recommended treatment. In these situations, supportive – but nonspecific – clinical, radiographic, and laboratory findings to assist in diagnosis can include the following (by phenotype). Hepatosplenomegaly Developmental delay Evidence of interstitial lung disease on chest radiograph Cherry-red maculae Failure to thrive Presentation before age three years Hepatosplenomegaly Interstitial lung disease Dyslipidemia Central nervous system manifestations such as learning difficulties, ataxia, or developmental delay Thrombocytopenia Coarse facial features (present in a subset of individuals with NPD-A/B) Hepatosplenomegaly Interstitial lung disease Dyslipidemia Thrombocytopenia Growth restriction in children The diagnosis of ASMD is established in a proband with biallelic pathogenic (or likely pathogenic) variants in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Approaches include Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform Note: Targeted analysis for specific pathogenic variants can be performed first in individuals of Ashkenazi Jewish, North African, Chilean, Saudi Arabian, and Turkish ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited biochemical disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Acid Sphingomyelinase Deficiency See See Pathogenic variants included in a panel may vary by laboratory. In NPD-A, three variants ( In NPD-B, the variant Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving Note: (1) Low acid sphingomyelinase activity is required to confirm the diagnosis of ASMD. (2) The level of residual enzyme activity is not a reliable predictor of phenotype. • Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined. • Molecular genetic testing involves sequence analysis of • Hepatosplenomegaly • Developmental delay • Evidence of interstitial lung disease on chest radiograph • Cherry-red maculae • Failure to thrive • Presentation before age three years • Hepatosplenomegaly • Interstitial lung disease • Dyslipidemia • Central nervous system manifestations such as learning difficulties, ataxia, or developmental delay • Thrombocytopenia • Coarse facial features (present in a subset of individuals with NPD-A/B) • Hepatosplenomegaly • Interstitial lung disease • Dyslipidemia • Thrombocytopenia • Growth restriction in children • Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other inherited biochemical disorders, • For an introduction to comprehensive genomic testing click ## Suggestive Findings NBS for ASMD is primarily based on quantification of acid sphingomyelinase activity on dried blood spots. At the time of writing, ASMD is not included on the United States Recommended Uniform Screening Panel and is performed in a limited number of states within the US. Several pilot studies have also been performed in Europe. Acid sphingomyelinase activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical and/or molecular genetic testing for confirmation. Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined. Molecular genetic testing involves sequence analysis of Referral to a metabolic or genetic disease specialist should be made immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of ASMD. A symptomatic individual who has findings associated with ASMD (infantile neurovisceral ASMD [NPD-A], chronic neurovisceral ASMD [NPD-A/B], or chronic visceral ASMD [NPD-B]) may present because of any of the following: NBS was not performed, the NBS result was false negative, and/or caregivers were not adherent to or aware of recommended treatment. In these situations, supportive – but nonspecific – clinical, radiographic, and laboratory findings to assist in diagnosis can include the following (by phenotype). Hepatosplenomegaly Developmental delay Evidence of interstitial lung disease on chest radiograph Cherry-red maculae Failure to thrive Presentation before age three years Hepatosplenomegaly Interstitial lung disease Dyslipidemia Central nervous system manifestations such as learning difficulties, ataxia, or developmental delay Thrombocytopenia Coarse facial features (present in a subset of individuals with NPD-A/B) Hepatosplenomegaly Interstitial lung disease Dyslipidemia Thrombocytopenia Growth restriction in children • Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined. • Molecular genetic testing involves sequence analysis of • Hepatosplenomegaly • Developmental delay • Evidence of interstitial lung disease on chest radiograph • Cherry-red maculae • Failure to thrive • Presentation before age three years • Hepatosplenomegaly • Interstitial lung disease • Dyslipidemia • Central nervous system manifestations such as learning difficulties, ataxia, or developmental delay • Thrombocytopenia • Coarse facial features (present in a subset of individuals with NPD-A/B) • Hepatosplenomegaly • Interstitial lung disease • Dyslipidemia • Thrombocytopenia • Growth restriction in children ## Scenario 1 – Abnormal Newborn Screening (NBS) Result NBS for ASMD is primarily based on quantification of acid sphingomyelinase activity on dried blood spots. At the time of writing, ASMD is not included on the United States Recommended Uniform Screening Panel and is performed in a limited number of states within the US. Several pilot studies have also been performed in Europe. Acid sphingomyelinase activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical and/or molecular genetic testing for confirmation. Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined. Molecular genetic testing involves sequence analysis of Referral to a metabolic or genetic disease specialist should be made immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of ASMD. • Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined. • Molecular genetic testing involves sequence analysis of ## Scenario 2 – Symptomatic Individual A symptomatic individual who has findings associated with ASMD (infantile neurovisceral ASMD [NPD-A], chronic neurovisceral ASMD [NPD-A/B], or chronic visceral ASMD [NPD-B]) may present because of any of the following: NBS was not performed, the NBS result was false negative, and/or caregivers were not adherent to or aware of recommended treatment. In these situations, supportive – but nonspecific – clinical, radiographic, and laboratory findings to assist in diagnosis can include the following (by phenotype). Hepatosplenomegaly Developmental delay Evidence of interstitial lung disease on chest radiograph Cherry-red maculae Failure to thrive Presentation before age three years Hepatosplenomegaly Interstitial lung disease Dyslipidemia Central nervous system manifestations such as learning difficulties, ataxia, or developmental delay Thrombocytopenia Coarse facial features (present in a subset of individuals with NPD-A/B) Hepatosplenomegaly Interstitial lung disease Dyslipidemia Thrombocytopenia Growth restriction in children • Hepatosplenomegaly • Developmental delay • Evidence of interstitial lung disease on chest radiograph • Cherry-red maculae • Failure to thrive • Presentation before age three years • Hepatosplenomegaly • Interstitial lung disease • Dyslipidemia • Central nervous system manifestations such as learning difficulties, ataxia, or developmental delay • Thrombocytopenia • Coarse facial features (present in a subset of individuals with NPD-A/B) • Hepatosplenomegaly • Interstitial lung disease • Dyslipidemia • Thrombocytopenia • Growth restriction in children ## Establishing the Diagnosis The diagnosis of ASMD is established in a proband with biallelic pathogenic (or likely pathogenic) variants in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Approaches include Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform Note: Targeted analysis for specific pathogenic variants can be performed first in individuals of Ashkenazi Jewish, North African, Chilean, Saudi Arabian, and Turkish ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited biochemical disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Acid Sphingomyelinase Deficiency See See Pathogenic variants included in a panel may vary by laboratory. In NPD-A, three variants ( In NPD-B, the variant Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving Note: (1) Low acid sphingomyelinase activity is required to confirm the diagnosis of ASMD. (2) The level of residual enzyme activity is not a reliable predictor of phenotype. • Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other inherited biochemical disorders, • For an introduction to comprehensive genomic testing click ## Molecular Genetic Testing Approaches include Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform Note: Targeted analysis for specific pathogenic variants can be performed first in individuals of Ashkenazi Jewish, North African, Chilean, Saudi Arabian, and Turkish ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited biochemical disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Acid Sphingomyelinase Deficiency See See Pathogenic variants included in a panel may vary by laboratory. In NPD-A, three variants ( In NPD-B, the variant Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving • Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other inherited biochemical disorders, • For an introduction to comprehensive genomic testing click ## Other Testing Note: (1) Low acid sphingomyelinase activity is required to confirm the diagnosis of ASMD. (2) The level of residual enzyme activity is not a reliable predictor of phenotype. ## Clinical Characteristics Although the phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum, individuals with the severe early-onset infantile neurovisceral phenotype (Niemann-Pick disease type A, or NPD-A) can often be distinguished from those with the intermediate chronic neurovisceral phenotype (NPD-A/B) and chronic visceral ASMD (Niemann-Pick disease type B, or NPD-B) based on clinical presentation. Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type (see Management, Psychomotor development does not progress beyond the 12-month level for any domain and skills are lost with disease progression [ Neurologic deterioration is relentless and not significantly impacted by ERT. Most untreated children succumb before the third year. It is unclear what impact ERT may have on life expectancy due to improvements in the non-neurologic manifestations. The most common immediate cause of death is respiratory infection [Author, personal observation]. Individuals with ASMD who survive early childhood but have progressive and/or clinically significant neurologic manifestations have chronic neurovisceral ASMD (NPD-A/B). Most individuals with NPD-A/B survive into adulthood, even when untreated. The extent of visceral organ involvement is variable, similar to NPD-B. NPD-B, later in onset and milder in manifestations, is characterized in untreated individuals by hepatosplenomegaly, liver dysfunction, progressive hypersplenism, worsening atherogenic lipid profile, and gradual deterioration in pulmonary function [ Calcified pulmonary nodules can also be seen in untreated individuals and were not specifically studied in those receiving ERT. In the United States about two thirds of newly diagnosed affected individuals have a unique genotype. Although no firm genotype-phenotype correlations exist for this disease, there are some pathogenic variants for which enough data has been generated to make some conclusions. For example, the Some evidence suggests that the The The Homozygosity or compound heterozygosity for some combination of the common The estimated prevalence of ASMD is 1:250,000 [ Pathogenic variants causing the severe neurodegenerative form of ASMD (NPD-A) are more prevalent in the Ashkenazi Jewish population, in which the combined carrier frequency for the three common All forms of ASMD are pan ethnic. Genotype information on individuals with NPD-B from 29 different countries has been reported [ ## Clinical Description Although the phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum, individuals with the severe early-onset infantile neurovisceral phenotype (Niemann-Pick disease type A, or NPD-A) can often be distinguished from those with the intermediate chronic neurovisceral phenotype (NPD-A/B) and chronic visceral ASMD (Niemann-Pick disease type B, or NPD-B) based on clinical presentation. Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type (see Management, Psychomotor development does not progress beyond the 12-month level for any domain and skills are lost with disease progression [ Neurologic deterioration is relentless and not significantly impacted by ERT. Most untreated children succumb before the third year. It is unclear what impact ERT may have on life expectancy due to improvements in the non-neurologic manifestations. The most common immediate cause of death is respiratory infection [Author, personal observation]. Individuals with ASMD who survive early childhood but have progressive and/or clinically significant neurologic manifestations have chronic neurovisceral ASMD (NPD-A/B). Most individuals with NPD-A/B survive into adulthood, even when untreated. The extent of visceral organ involvement is variable, similar to NPD-B. NPD-B, later in onset and milder in manifestations, is characterized in untreated individuals by hepatosplenomegaly, liver dysfunction, progressive hypersplenism, worsening atherogenic lipid profile, and gradual deterioration in pulmonary function [ Calcified pulmonary nodules can also be seen in untreated individuals and were not specifically studied in those receiving ERT. ## Infantile Neurovisceral ASMD (NPD-A) Psychomotor development does not progress beyond the 12-month level for any domain and skills are lost with disease progression [ Neurologic deterioration is relentless and not significantly impacted by ERT. Most untreated children succumb before the third year. It is unclear what impact ERT may have on life expectancy due to improvements in the non-neurologic manifestations. The most common immediate cause of death is respiratory infection [Author, personal observation]. ## Chronic Neurovisceral ASMD (NPD-A/B) Individuals with ASMD who survive early childhood but have progressive and/or clinically significant neurologic manifestations have chronic neurovisceral ASMD (NPD-A/B). Most individuals with NPD-A/B survive into adulthood, even when untreated. The extent of visceral organ involvement is variable, similar to NPD-B. ## Chronic Visceral ASMD (NPD-B) NPD-B, later in onset and milder in manifestations, is characterized in untreated individuals by hepatosplenomegaly, liver dysfunction, progressive hypersplenism, worsening atherogenic lipid profile, and gradual deterioration in pulmonary function [ Calcified pulmonary nodules can also be seen in untreated individuals and were not specifically studied in those receiving ERT. ## Genotype-Phenotype Correlations In the United States about two thirds of newly diagnosed affected individuals have a unique genotype. Although no firm genotype-phenotype correlations exist for this disease, there are some pathogenic variants for which enough data has been generated to make some conclusions. For example, the Some evidence suggests that the The The Homozygosity or compound heterozygosity for some combination of the common ## Prevalence The estimated prevalence of ASMD is 1:250,000 [ Pathogenic variants causing the severe neurodegenerative form of ASMD (NPD-A) are more prevalent in the Ashkenazi Jewish population, in which the combined carrier frequency for the three common All forms of ASMD are pan ethnic. Genotype information on individuals with NPD-B from 29 different countries has been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders with Hepatosplenomegaly in the Differential Diagnosis of Acid Sphingomyelinase Deficiency ASMD = acid sphingomyelinase deficiency Hepatosplenomegaly can also accompany some infectious diseases (e.g., Epstein-Barr virus, cytomegalovirus). The diagnosis in infants with NPD-A is sometimes delayed during evaluation for an infectious etiology. ## Management To establish the extent of disease and needs in an individual diagnosed with acid sphingomyelinase deficiency (ASMD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Acid Sphingomyelinase Deficiency Growth assessment Gastroenterology / nutrition / feeding team eval Incl eval of aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Assess nutritional status incl appropriate caloric, calcium, & vitamin D intake. Skeletal age, often delayed, is useful for interpreting DXA scans. Knowledge about additional potential growth yrs can be reassuring to families concerned about child's stature. To assess extent of interstitial lung disease Should be done at time of diagnosis regardless of age Optional No visual consequences of cherry-red spots are known; their presence does not imply neuronopathic disease, as they are found in many adults w/NPD-B. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support Home nursing referral ALT = alanine aminotransaminase; ASMD = acid sphingomyelinase deficiency; AST = aspartate aminotransferase; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); NPD-A/B = chronic neurovisceral ASMD (intermediate form); NPD-B = chronic visceral ASMD (Niemann-Pick disease type B) Medical geneticist, certified genetic counselor, or certified advanced genetic nurse There is no cure for ASMD. Targeted Treatment of Acid Sphingomyelinase Deficiency 3 mg/kg IV infusion every 2 weeks The reported most common side effects incl cough, fever, headache, joint pain, diarrhea, & low blood pressure. Severe hypersensitivity & anaphylaxis has been observed in a minority of persons. ERT = enzyme replacement therapy; IV = intravenous Olipudase alfa ERT has been studied in those with ASMD types NPD-A/B and NPD-B and has the potential to address these issues in those with NPD-A [ During the maintenance phase, infusions may take up to 3.5 to 4 hours. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Individuals with Acid Sphingomyelinase Deficiency Regular consultation w/dietician to assure that calorie intake is adequate for growth Feeding therapy Nasogastric tube feeding or surgical placement of feeding tube should be discussed. Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy). Liver transplantation has been used successfully in liver failure due to ASMD. PT & OT to maximize function & prevent contractures Early intervention & developmental support for those w/developmental issues ASMD = acid sphingomyelinase deficiency; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); OT = occupational therapy; PT = physical therapy Some of these manifestations may be ameliorated by ERT (see Many of these treatments apply to those who are not receiving ERT or for whom ERT has not resulted in significant improvement to the manifestation or concern in question. Author, personal observation Liver function needs to be monitored in individuals receiving medications with known hepatotoxicity (e.g., statins for treatment of hypercholesterolemia). Recommendations for clinical monitoring of individuals with ASMD have been published [ Recommended Surveillance for Individuals with Acid Sphingomyelinase Deficiency Measurement of growth parameters Eval of nutritional status & safety of oral intake Assess for fatigue, abdominal pain, &/or ↑ bleeding. Platelet count Monitor developmental progress & educational needs. Evaluate OT & PT needs. ALT = alanine aminotransaminase; AST = aspartate aminotransferase; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy Individuals who have splenomegaly should avoid contact sports. Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and targeted treatment of ASMD. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, testing for the familial See For pregnant women with ASMD, prenatal care by a high-risk obstetrician is indicated to ensure appropriate monitoring of pulmonary function and hematologic status. Olipudase alfa ERT has not been studied in pregnant women, but animal studies have identified a potential impact on fetal development. Therefore, ERT is not recommended during pregnancy. See Search • Growth assessment • Gastroenterology / nutrition / feeding team eval • Incl eval of aspiration risk & nutritional status. • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Assess nutritional status incl appropriate caloric, calcium, & vitamin D intake. • Skeletal age, often delayed, is useful for interpreting DXA scans. • Knowledge about additional potential growth yrs can be reassuring to families concerned about child's stature. • To assess extent of interstitial lung disease • Should be done at time of diagnosis regardless of age • Optional • No visual consequences of cherry-red spots are known; their presence does not imply neuronopathic disease, as they are found in many adults w/NPD-B. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support • Home nursing referral • 3 mg/kg IV infusion every 2 weeks • The reported most common side effects incl cough, fever, headache, joint pain, diarrhea, & low blood pressure. • Severe hypersensitivity & anaphylaxis has been observed in a minority of persons. • Regular consultation w/dietician to assure that calorie intake is adequate for growth • Feeding therapy • Nasogastric tube feeding or surgical placement of feeding tube should be discussed. • Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy). • Liver transplantation has been used successfully in liver failure due to ASMD. • PT & OT to maximize function & prevent contractures • Early intervention & developmental support for those w/developmental issues • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assess for fatigue, abdominal pain, &/or ↑ bleeding. • Platelet count • Monitor developmental progress & educational needs. • Evaluate OT & PT needs. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with acid sphingomyelinase deficiency (ASMD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Acid Sphingomyelinase Deficiency Growth assessment Gastroenterology / nutrition / feeding team eval Incl eval of aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Assess nutritional status incl appropriate caloric, calcium, & vitamin D intake. Skeletal age, often delayed, is useful for interpreting DXA scans. Knowledge about additional potential growth yrs can be reassuring to families concerned about child's stature. To assess extent of interstitial lung disease Should be done at time of diagnosis regardless of age Optional No visual consequences of cherry-red spots are known; their presence does not imply neuronopathic disease, as they are found in many adults w/NPD-B. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support Home nursing referral ALT = alanine aminotransaminase; ASMD = acid sphingomyelinase deficiency; AST = aspartate aminotransferase; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); NPD-A/B = chronic neurovisceral ASMD (intermediate form); NPD-B = chronic visceral ASMD (Niemann-Pick disease type B) Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Growth assessment • Gastroenterology / nutrition / feeding team eval • Incl eval of aspiration risk & nutritional status. • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Assess nutritional status incl appropriate caloric, calcium, & vitamin D intake. • Skeletal age, often delayed, is useful for interpreting DXA scans. • Knowledge about additional potential growth yrs can be reassuring to families concerned about child's stature. • To assess extent of interstitial lung disease • Should be done at time of diagnosis regardless of age • Optional • No visual consequences of cherry-red spots are known; their presence does not imply neuronopathic disease, as they are found in many adults w/NPD-B. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for ASMD. Targeted Treatment of Acid Sphingomyelinase Deficiency 3 mg/kg IV infusion every 2 weeks The reported most common side effects incl cough, fever, headache, joint pain, diarrhea, & low blood pressure. Severe hypersensitivity & anaphylaxis has been observed in a minority of persons. ERT = enzyme replacement therapy; IV = intravenous Olipudase alfa ERT has been studied in those with ASMD types NPD-A/B and NPD-B and has the potential to address these issues in those with NPD-A [ During the maintenance phase, infusions may take up to 3.5 to 4 hours. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Individuals with Acid Sphingomyelinase Deficiency Regular consultation w/dietician to assure that calorie intake is adequate for growth Feeding therapy Nasogastric tube feeding or surgical placement of feeding tube should be discussed. Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy). Liver transplantation has been used successfully in liver failure due to ASMD. PT & OT to maximize function & prevent contractures Early intervention & developmental support for those w/developmental issues ASMD = acid sphingomyelinase deficiency; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); OT = occupational therapy; PT = physical therapy Some of these manifestations may be ameliorated by ERT (see Many of these treatments apply to those who are not receiving ERT or for whom ERT has not resulted in significant improvement to the manifestation or concern in question. Author, personal observation • 3 mg/kg IV infusion every 2 weeks • The reported most common side effects incl cough, fever, headache, joint pain, diarrhea, & low blood pressure. • Severe hypersensitivity & anaphylaxis has been observed in a minority of persons. • Regular consultation w/dietician to assure that calorie intake is adequate for growth • Feeding therapy • Nasogastric tube feeding or surgical placement of feeding tube should be discussed. • Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy). • Liver transplantation has been used successfully in liver failure due to ASMD. • PT & OT to maximize function & prevent contractures • Early intervention & developmental support for those w/developmental issues ## Targeted Therapies Targeted Treatment of Acid Sphingomyelinase Deficiency 3 mg/kg IV infusion every 2 weeks The reported most common side effects incl cough, fever, headache, joint pain, diarrhea, & low blood pressure. Severe hypersensitivity & anaphylaxis has been observed in a minority of persons. ERT = enzyme replacement therapy; IV = intravenous Olipudase alfa ERT has been studied in those with ASMD types NPD-A/B and NPD-B and has the potential to address these issues in those with NPD-A [ During the maintenance phase, infusions may take up to 3.5 to 4 hours. • 3 mg/kg IV infusion every 2 weeks • The reported most common side effects incl cough, fever, headache, joint pain, diarrhea, & low blood pressure. • Severe hypersensitivity & anaphylaxis has been observed in a minority of persons. ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Supportive Treatment of Manifestations in Individuals with Acid Sphingomyelinase Deficiency Regular consultation w/dietician to assure that calorie intake is adequate for growth Feeding therapy Nasogastric tube feeding or surgical placement of feeding tube should be discussed. Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy). Liver transplantation has been used successfully in liver failure due to ASMD. PT & OT to maximize function & prevent contractures Early intervention & developmental support for those w/developmental issues ASMD = acid sphingomyelinase deficiency; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); OT = occupational therapy; PT = physical therapy Some of these manifestations may be ameliorated by ERT (see Many of these treatments apply to those who are not receiving ERT or for whom ERT has not resulted in significant improvement to the manifestation or concern in question. Author, personal observation • Regular consultation w/dietician to assure that calorie intake is adequate for growth • Feeding therapy • Nasogastric tube feeding or surgical placement of feeding tube should be discussed. • Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy). • Liver transplantation has been used successfully in liver failure due to ASMD. • PT & OT to maximize function & prevent contractures • Early intervention & developmental support for those w/developmental issues ## Prevention of Secondary Complications Liver function needs to be monitored in individuals receiving medications with known hepatotoxicity (e.g., statins for treatment of hypercholesterolemia). ## Surveillance Recommendations for clinical monitoring of individuals with ASMD have been published [ Recommended Surveillance for Individuals with Acid Sphingomyelinase Deficiency Measurement of growth parameters Eval of nutritional status & safety of oral intake Assess for fatigue, abdominal pain, &/or ↑ bleeding. Platelet count Monitor developmental progress & educational needs. Evaluate OT & PT needs. ALT = alanine aminotransaminase; AST = aspartate aminotransferase; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assess for fatigue, abdominal pain, &/or ↑ bleeding. • Platelet count • Monitor developmental progress & educational needs. • Evaluate OT & PT needs. ## Agents/Circumstances to Avoid Individuals who have splenomegaly should avoid contact sports. ## Evaluation of Relatives at Risk Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and targeted treatment of ASMD. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, testing for the familial See ## Pregnancy Management For pregnant women with ASMD, prenatal care by a high-risk obstetrician is indicated to ensure appropriate monitoring of pulmonary function and hematologic status. Olipudase alfa ERT has not been studied in pregnant women, but animal studies have identified a potential impact on fetal development. Therefore, ERT is not recommended during pregnancy. See ## Therapies Under Investigation Search ## Genetic Counseling All forms of acid sphingomyelinase deficiency (ASMD), including infantile neurovisceral ASMD (Niemann-Pick disease type A, or NPD-A), chronic neurovisceral ASMD (NPD-A/B), and chronic visceral ASMD (Niemann-Pick disease type B, or NPD-B), are inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Some heterozygotes have been found to have low high-density lipoprotein (HDL) associated with ASMD. If both parents are known to be heterozygous for an Phenotypic severity is similar overall among sibs with the same biallelic pathogenic variants, although some intrafamilial clinical variability may be observed. Some heterozygotes have been found to have low HDL associated with ASMD. Individuals with NPD-A do not reproduce. The offspring of an individual with NPD-B or NPD-A/B are obligate heterozygotes (carriers) for a pathogenic variant in Molecular genetic carrier testing for at-risk relatives requires prior identification of the Note: Carrier identification by determination of acid sphingomyelinase enzyme activity is not reliable. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Some heterozygotes have been found to have low high-density lipoprotein (HDL) associated with ASMD. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Phenotypic severity is similar overall among sibs with the same biallelic pathogenic variants, although some intrafamilial clinical variability may be observed. • Some heterozygotes have been found to have low HDL associated with ASMD. • Individuals with NPD-A do not reproduce. • The offspring of an individual with NPD-B or NPD-A/B are obligate heterozygotes (carriers) for a pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance All forms of acid sphingomyelinase deficiency (ASMD), including infantile neurovisceral ASMD (Niemann-Pick disease type A, or NPD-A), chronic neurovisceral ASMD (NPD-A/B), and chronic visceral ASMD (Niemann-Pick disease type B, or NPD-B), are inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Some heterozygotes have been found to have low high-density lipoprotein (HDL) associated with ASMD. If both parents are known to be heterozygous for an Phenotypic severity is similar overall among sibs with the same biallelic pathogenic variants, although some intrafamilial clinical variability may be observed. Some heterozygotes have been found to have low HDL associated with ASMD. Individuals with NPD-A do not reproduce. The offspring of an individual with NPD-B or NPD-A/B are obligate heterozygotes (carriers) for a pathogenic variant in • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Some heterozygotes have been found to have low high-density lipoprotein (HDL) associated with ASMD. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Phenotypic severity is similar overall among sibs with the same biallelic pathogenic variants, although some intrafamilial clinical variability may be observed. • Some heterozygotes have been found to have low HDL associated with ASMD. • Individuals with NPD-A do not reproduce. • The offspring of an individual with NPD-B or NPD-A/B are obligate heterozygotes (carriers) for a pathogenic variant in ## Carrier Detection Molecular genetic carrier testing for at-risk relatives requires prior identification of the Note: Carrier identification by determination of acid sphingomyelinase enzyme activity is not reliable. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing ## Resources United Kingdom • • • • • • United Kingdom • • • • • • • • • ## Molecular Genetics Acid Sphingomyelinase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Acid Sphingomyelinase Deficiency ( Paternal imprinting of Two numbering systems to describe Notable Assoc w/intermediate phenotypes w/later-onset neuronopathic disease Appears to be relatively common in persons of Czech & Slovak descent [ Found most commonly in persons from Saudi Arabia Leads to early-onset severe form of NPD-A [ Found most commonly in persons from Saudi Arabia Leads to early-onset severe form of NPD-A [ Homozygotes have milder clinical course [ One of the most common pathogenic variants in persons w/NPD-B In persons w/NPD-B originating from Maghreb region of North Africa (i.e., Tunisia, Algeria, Morocco), accounts for almost 90% of mutated alleles On Gran Canaria Island, accounts for 100% of pathogenic alleles [ Accounts for ~20%-30% of pathogenic variants in those w/NPD-B in US NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); NPD-B = chronic visceral ASMD (Niemann-Pick disease type B) Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions • Paternal imprinting of • Two numbering systems to describe • Assoc w/intermediate phenotypes w/later-onset neuronopathic disease • Appears to be relatively common in persons of Czech & Slovak descent [ • Found most commonly in persons from Saudi Arabia • Leads to early-onset severe form of NPD-A [ • Found most commonly in persons from Saudi Arabia • Leads to early-onset severe form of NPD-A [ • Homozygotes have milder clinical course [ • One of the most common pathogenic variants in persons w/NPD-B • In persons w/NPD-B originating from Maghreb region of North Africa (i.e., Tunisia, Algeria, Morocco), accounts for almost 90% of mutated alleles • On Gran Canaria Island, accounts for 100% of pathogenic alleles [ • Accounts for ~20%-30% of pathogenic variants in those w/NPD-B in US ## Molecular Pathogenesis Paternal imprinting of Two numbering systems to describe Notable Assoc w/intermediate phenotypes w/later-onset neuronopathic disease Appears to be relatively common in persons of Czech & Slovak descent [ Found most commonly in persons from Saudi Arabia Leads to early-onset severe form of NPD-A [ Found most commonly in persons from Saudi Arabia Leads to early-onset severe form of NPD-A [ Homozygotes have milder clinical course [ One of the most common pathogenic variants in persons w/NPD-B In persons w/NPD-B originating from Maghreb region of North Africa (i.e., Tunisia, Algeria, Morocco), accounts for almost 90% of mutated alleles On Gran Canaria Island, accounts for 100% of pathogenic alleles [ Accounts for ~20%-30% of pathogenic variants in those w/NPD-B in US NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); NPD-B = chronic visceral ASMD (Niemann-Pick disease type B) Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions • Paternal imprinting of • Two numbering systems to describe • Assoc w/intermediate phenotypes w/later-onset neuronopathic disease • Appears to be relatively common in persons of Czech & Slovak descent [ • Found most commonly in persons from Saudi Arabia • Leads to early-onset severe form of NPD-A [ • Found most commonly in persons from Saudi Arabia • Leads to early-onset severe form of NPD-A [ • Homozygotes have milder clinical course [ • One of the most common pathogenic variants in persons w/NPD-B • In persons w/NPD-B originating from Maghreb region of North Africa (i.e., Tunisia, Algeria, Morocco), accounts for almost 90% of mutated alleles • On Gran Canaria Island, accounts for 100% of pathogenic alleles [ • Accounts for ~20%-30% of pathogenic variants in those w/NPD-B in US ## Chapter Notes The authors wish to acknowledge the many students and staff members who have worked with them over the years, as well as all the individuals with ASMD and their families who have contributed to these studies. Margaret M McGovern, MD, PhD; Stony Brook University School of Medicine (2006-2015)Edward H Schuchman, PhD (2006-present)Melissa P Wasserstein, MD (2015-present) 27 April 2023 (ma) Comprehensive updated posted live 25 February 2021 (sw) Comprehensive update posted live 18 June 2015 (me) Comprehensive update posted live 25 June 2009 (me) Comprehensive update posted live 7 December 2006 (me) Review posted live 8 May 2006 (mm) Original submission • 27 April 2023 (ma) Comprehensive updated posted live • 25 February 2021 (sw) Comprehensive update posted live • 18 June 2015 (me) Comprehensive update posted live • 25 June 2009 (me) Comprehensive update posted live • 7 December 2006 (me) Review posted live • 8 May 2006 (mm) Original submission ## Acknowledgments The authors wish to acknowledge the many students and staff members who have worked with them over the years, as well as all the individuals with ASMD and their families who have contributed to these studies. ## Author History Margaret M McGovern, MD, PhD; Stony Brook University School of Medicine (2006-2015)Edward H Schuchman, PhD (2006-present)Melissa P Wasserstein, MD (2015-present) ## Revision History 27 April 2023 (ma) Comprehensive updated posted live 25 February 2021 (sw) Comprehensive update posted live 18 June 2015 (me) Comprehensive update posted live 25 June 2009 (me) Comprehensive update posted live 7 December 2006 (me) Review posted live 8 May 2006 (mm) Original submission • 27 April 2023 (ma) Comprehensive updated posted live • 25 February 2021 (sw) Comprehensive update posted live • 18 June 2015 (me) Comprehensive update posted live • 25 June 2009 (me) Comprehensive update posted live • 7 December 2006 (me) Review posted live • 8 May 2006 (mm) Original submission ## Key Sections in this ## References Wasserstein M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z, Mengel E, Mistry PK, Schuchman EH, McGovern M. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Available • Wasserstein M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z, Mengel E, Mistry PK, Schuchman EH, McGovern M. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Available ## Published Guidelines / Consensus Statements Wasserstein M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z, Mengel E, Mistry PK, Schuchman EH, McGovern M. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Available • Wasserstein M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z, Mengel E, Mistry PK, Schuchman EH, McGovern M. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Available ## Literature Cited	[]	7/12/2006	27/4/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
npc	npc	[ "NPC intracellular cholesterol transporter 1", "NPC intracellular cholesterol transporter 2", "NPC1", "NPC2", "Niemann-Pick Disease Type C" ]	Niemann-Pick Disease Type C	Marc Patterson	Summary Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder whose principal manifestations are age dependent. The manifestations in the perinatal period and infancy are predominantly visceral, with hepatosplenomegaly, jaundice, and (in some instances) pulmonary infiltrates. From late infancy onward, the presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and, in some individuals, epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent that affected individuals have a progressive dementia. Older teenagers and young adults may present predominantly with apparent early-onset dementia or psychiatric manifestations; however, careful examination usually identifies typical neurologic signs. The diagnosis of NPC is established in a proband with suggestive findings and biallelic pathogenic variants in either Treatment with miglustat, approved for the management of neurologic manifestations of NPC in several countries but not the United States, has increased survival by five years from date of diagnosis or approximately ten years from onset of neurologic manifestations. NPC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of being unaffected and not a heterozygote. Once the NPC-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.	## Diagnosis No consensus clinical diagnostic criteria for Niemann-Pick disease type C (NPC) have been published. Assay of oxysterols has largely replaced skin biopsy (see Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. The diagnosis of NPC Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Niemann-Pick Disease Type C See See Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ## Suggestive Findings Assay of oxysterols has largely replaced skin biopsy (see Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Clinical Findings ## Preliminary Laboratory Findings Assay of oxysterols has largely replaced skin biopsy (see ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of NPC Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Niemann-Pick Disease Type C See See Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Niemann-Pick Disease Type C See See Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ## Clinical Characteristics Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder whose principal manifestations are age dependent. The manifestations in the perinatal period and infancy are predominantly visceral, with hepatosplenomegaly, jaundice, and (in some instances) pulmonary infiltrates. From late infancy onward, the presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and (in some individuals) epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent that affected individuals have a progressive dementia. Older teenagers and young adults may present predominantly with apparent early-onset dementia or psychiatric manifestations; however, careful examination usually identifies typical neurologic signs. Niemann-Pick Disease Type C: Comparison of Age-Related Phenotypes by Select Features VSGP = vertical supranuclear gaze palsy; (●) = sometimes present; ● = usually present The presentation of NPC in early life is nonspecific and may go unrecognized by inexperienced clinicians. On occasion, ultrasound examination in late pregnancy has detected fetal ascites; infants thus identified typically have severe neonatal liver disease with jaundice and persistent ascites. Infiltration of the lungs with foam cells may accompany neonatal liver disease or occur as a primary presenting feature (pulmonary failure secondary to impaired diffusion). Many infants succumb at this stage. Of those who survive, some are hypotonic and delayed in psychomotor development, whereas others may have complete resolution of symptoms, only to present with neurologic disease many years later. Liver and spleen are enlarged in children with symptomatic hepatic disease; however, children who survive often "grow into their organs," so that organomegaly may not be detectable later in childhood. Indeed, many individuals with NPC never have organomegaly. The absence of organomegaly never eliminates the diagnosis of NPC. Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group usually do not have vertical supranuclear gaze palsy (VSGP) at the onset but acquire this sign after a variable period, when other evidence of progressive encephalopathy supervenes. The classic presentation of NPC is in middle-to-late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical gaze, which is an early manifestation. VSGP first manifests as increased latency in initiation of vertical saccades, after which saccadic velocity gradually slows and is eventually lost. In late stages of the illness, horizontal saccades are also impaired. The physical manifestations are accompanied by insidiously progressive cognitive impairment, often mistaken at first for simple learning disability. Some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia in some instances. As the disease progresses, it becomes clear that the child is mentally deteriorating. In addition to the manifestations outlined above, many children develop dystonia, typically beginning as action dystonia in one limb and gradually spreading to involve all of the limbs and axial muscles. Speech gradually deteriorates, with a mixed dysarthria and dysphonia. Dysphagia progresses in parallel with the dysarthria, and oral feeding eventually becomes impossible. Approximately one third of individuals with NPC have partial and/or generalized seizures. Epilepsy may be refractory to medical therapy in some cases. Seizures usually improve if the child's survival is prolonged, this improvement presumably reflecting continued neuronal loss. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional (humorous) stimulus. This can be disabling in those children who experience daily multiple attacks, during which injuries may occur. Mild demyelinating peripheral neuropathy has been described in a child with otherwise typical late-infantile NPC [ Polysomnographic and biochemical studies have demonstrated disturbed sleep and variable reduction in cerebrospinal fluid hypocretin concentration in individuals with NPC, suggesting that the disease could have a specific impact on hypocretin-secreting cells of the hypothalamus [ Death from aspiration pneumonia usually occurs in the late second or third decade [ Adolescents or adults may present with neurologic disease as described in the A German report describes two individuals with adult-onset dementia associated with frontal lobe atrophy and no visceral manifestations, as is common in adult-onset disease [ Studies of magnetic resonance spectroscopy (MRS) suggested that MRS may be a more sensitive imaging technique in NPC than standard MRI [ In 2004, a report attributed tremor in an individual to presence of a heterozygous Nonetheless, the following correlations have been possible for homozygous pathogenic variants and the more common pathogenic variants in the compound heterozygous state: No individuals with Premature-termination-codon variants, variants involving the sterol-sensing domain, and In 40 unrelated individuals of Spanish descent, those who were homozygous for the All variants that correlate with the biochemical "variant" phenotype (i.e., patterns of filipin staining in cultured fibroblasts that are less intense than those typically seen in homozygotes or compound heterozygotes and overlap with those seen in heterozygotes) cluster in the cysteine-rich luminal loop [ Of the five pathogenic variants identified by The two individuals with splice site variants had juvenile-onset disease and prolonged survival. Adult-onset disease with frontal lobe atrophy has been described in association with the Neonatal or infantile onset and death in early childhood were reported in children homozygous for The older literature on NPC is bedeviled by the large number of terms used to describe individuals now known to have the disease. These include juvenile dystonic idiocy, juvenile dystonic lipidosis, juvenile NPC, neurovisceral lipidosis with vertical supranuclear gaze palsy, Neville-lake disease, sea-blue histiocytosis, lactosylceramidosis, and DAF ( The term Niemann-Pick disease type D describes a genetic isolate from Nova Scotia that is biochemically and clinically indistinguishable from NPC and that also results from biallelic pathogenic variants in The terms Niemann-Pick disease type C1 (NPC1) and Niemann-Pick disease type C2 (NPC2) are now preferred because they correspond with the associated genes ( The prevalence of NPC has been estimated at 1:150,000 in Western Europe. The incidence of NPC in France has been calculated at about 1:120,000, based on the number of postnatally diagnosed individuals in a ten-year period versus the number of births during that same time period. When prenatal cases that did not result in a live-born infant were included, a slightly higher incidence of 1:100,000 was found [ The prevalence of NPC in early life is probably underestimated, owing to its nonspecific presentations. The overall prevalence is likely higher than the calculated incidence, owing to relatively prolonged survival in those with later-onset disease, although no comprehensive data are available. Acadians in Nova Scotia and a Bedouin group in Israel represent genetic isolates with a founder effect (see • No individuals with • Premature-termination-codon variants, variants involving the sterol-sensing domain, and • In 40 unrelated individuals of Spanish descent, those who were homozygous for the • All variants that correlate with the biochemical "variant" phenotype (i.e., patterns of filipin staining in cultured fibroblasts that are less intense than those typically seen in homozygotes or compound heterozygotes and overlap with those seen in heterozygotes) cluster in the cysteine-rich luminal loop [ • Of the five pathogenic variants identified by • The two individuals with splice site variants had juvenile-onset disease and prolonged survival. • Adult-onset disease with frontal lobe atrophy has been described in association with the • Neonatal or infantile onset and death in early childhood were reported in children homozygous for ## Clinical Description Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder whose principal manifestations are age dependent. The manifestations in the perinatal period and infancy are predominantly visceral, with hepatosplenomegaly, jaundice, and (in some instances) pulmonary infiltrates. From late infancy onward, the presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and (in some individuals) epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent that affected individuals have a progressive dementia. Older teenagers and young adults may present predominantly with apparent early-onset dementia or psychiatric manifestations; however, careful examination usually identifies typical neurologic signs. Niemann-Pick Disease Type C: Comparison of Age-Related Phenotypes by Select Features VSGP = vertical supranuclear gaze palsy; (●) = sometimes present; ● = usually present The presentation of NPC in early life is nonspecific and may go unrecognized by inexperienced clinicians. On occasion, ultrasound examination in late pregnancy has detected fetal ascites; infants thus identified typically have severe neonatal liver disease with jaundice and persistent ascites. Infiltration of the lungs with foam cells may accompany neonatal liver disease or occur as a primary presenting feature (pulmonary failure secondary to impaired diffusion). Many infants succumb at this stage. Of those who survive, some are hypotonic and delayed in psychomotor development, whereas others may have complete resolution of symptoms, only to present with neurologic disease many years later. Liver and spleen are enlarged in children with symptomatic hepatic disease; however, children who survive often "grow into their organs," so that organomegaly may not be detectable later in childhood. Indeed, many individuals with NPC never have organomegaly. The absence of organomegaly never eliminates the diagnosis of NPC. Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group usually do not have vertical supranuclear gaze palsy (VSGP) at the onset but acquire this sign after a variable period, when other evidence of progressive encephalopathy supervenes. The classic presentation of NPC is in middle-to-late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical gaze, which is an early manifestation. VSGP first manifests as increased latency in initiation of vertical saccades, after which saccadic velocity gradually slows and is eventually lost. In late stages of the illness, horizontal saccades are also impaired. The physical manifestations are accompanied by insidiously progressive cognitive impairment, often mistaken at first for simple learning disability. Some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia in some instances. As the disease progresses, it becomes clear that the child is mentally deteriorating. In addition to the manifestations outlined above, many children develop dystonia, typically beginning as action dystonia in one limb and gradually spreading to involve all of the limbs and axial muscles. Speech gradually deteriorates, with a mixed dysarthria and dysphonia. Dysphagia progresses in parallel with the dysarthria, and oral feeding eventually becomes impossible. Approximately one third of individuals with NPC have partial and/or generalized seizures. Epilepsy may be refractory to medical therapy in some cases. Seizures usually improve if the child's survival is prolonged, this improvement presumably reflecting continued neuronal loss. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional (humorous) stimulus. This can be disabling in those children who experience daily multiple attacks, during which injuries may occur. Mild demyelinating peripheral neuropathy has been described in a child with otherwise typical late-infantile NPC [ Polysomnographic and biochemical studies have demonstrated disturbed sleep and variable reduction in cerebrospinal fluid hypocretin concentration in individuals with NPC, suggesting that the disease could have a specific impact on hypocretin-secreting cells of the hypothalamus [ Death from aspiration pneumonia usually occurs in the late second or third decade [ Adolescents or adults may present with neurologic disease as described in the A German report describes two individuals with adult-onset dementia associated with frontal lobe atrophy and no visceral manifestations, as is common in adult-onset disease [ Studies of magnetic resonance spectroscopy (MRS) suggested that MRS may be a more sensitive imaging technique in NPC than standard MRI [ In 2004, a report attributed tremor in an individual to presence of a heterozygous ## Neonatal and Infantile Presentations The presentation of NPC in early life is nonspecific and may go unrecognized by inexperienced clinicians. On occasion, ultrasound examination in late pregnancy has detected fetal ascites; infants thus identified typically have severe neonatal liver disease with jaundice and persistent ascites. Infiltration of the lungs with foam cells may accompany neonatal liver disease or occur as a primary presenting feature (pulmonary failure secondary to impaired diffusion). Many infants succumb at this stage. Of those who survive, some are hypotonic and delayed in psychomotor development, whereas others may have complete resolution of symptoms, only to present with neurologic disease many years later. Liver and spleen are enlarged in children with symptomatic hepatic disease; however, children who survive often "grow into their organs," so that organomegaly may not be detectable later in childhood. Indeed, many individuals with NPC never have organomegaly. The absence of organomegaly never eliminates the diagnosis of NPC. Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group usually do not have vertical supranuclear gaze palsy (VSGP) at the onset but acquire this sign after a variable period, when other evidence of progressive encephalopathy supervenes. ## Childhood Presentations The classic presentation of NPC is in middle-to-late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical gaze, which is an early manifestation. VSGP first manifests as increased latency in initiation of vertical saccades, after which saccadic velocity gradually slows and is eventually lost. In late stages of the illness, horizontal saccades are also impaired. The physical manifestations are accompanied by insidiously progressive cognitive impairment, often mistaken at first for simple learning disability. Some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia in some instances. As the disease progresses, it becomes clear that the child is mentally deteriorating. In addition to the manifestations outlined above, many children develop dystonia, typically beginning as action dystonia in one limb and gradually spreading to involve all of the limbs and axial muscles. Speech gradually deteriorates, with a mixed dysarthria and dysphonia. Dysphagia progresses in parallel with the dysarthria, and oral feeding eventually becomes impossible. Approximately one third of individuals with NPC have partial and/or generalized seizures. Epilepsy may be refractory to medical therapy in some cases. Seizures usually improve if the child's survival is prolonged, this improvement presumably reflecting continued neuronal loss. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional (humorous) stimulus. This can be disabling in those children who experience daily multiple attacks, during which injuries may occur. Mild demyelinating peripheral neuropathy has been described in a child with otherwise typical late-infantile NPC [ Polysomnographic and biochemical studies have demonstrated disturbed sleep and variable reduction in cerebrospinal fluid hypocretin concentration in individuals with NPC, suggesting that the disease could have a specific impact on hypocretin-secreting cells of the hypothalamus [ Death from aspiration pneumonia usually occurs in the late second or third decade [ ## Adolescent and Adult Presentations Adolescents or adults may present with neurologic disease as described in the A German report describes two individuals with adult-onset dementia associated with frontal lobe atrophy and no visceral manifestations, as is common in adult-onset disease [ ## Other Studies Studies of magnetic resonance spectroscopy (MRS) suggested that MRS may be a more sensitive imaging technique in NPC than standard MRI [ ## Heterozygotes In 2004, a report attributed tremor in an individual to presence of a heterozygous ## Genotype-Phenotype Correlations Nonetheless, the following correlations have been possible for homozygous pathogenic variants and the more common pathogenic variants in the compound heterozygous state: No individuals with Premature-termination-codon variants, variants involving the sterol-sensing domain, and In 40 unrelated individuals of Spanish descent, those who were homozygous for the All variants that correlate with the biochemical "variant" phenotype (i.e., patterns of filipin staining in cultured fibroblasts that are less intense than those typically seen in homozygotes or compound heterozygotes and overlap with those seen in heterozygotes) cluster in the cysteine-rich luminal loop [ Of the five pathogenic variants identified by The two individuals with splice site variants had juvenile-onset disease and prolonged survival. Adult-onset disease with frontal lobe atrophy has been described in association with the Neonatal or infantile onset and death in early childhood were reported in children homozygous for • No individuals with • Premature-termination-codon variants, variants involving the sterol-sensing domain, and • In 40 unrelated individuals of Spanish descent, those who were homozygous for the • All variants that correlate with the biochemical "variant" phenotype (i.e., patterns of filipin staining in cultured fibroblasts that are less intense than those typically seen in homozygotes or compound heterozygotes and overlap with those seen in heterozygotes) cluster in the cysteine-rich luminal loop [ • Of the five pathogenic variants identified by • The two individuals with splice site variants had juvenile-onset disease and prolonged survival. • Adult-onset disease with frontal lobe atrophy has been described in association with the • Neonatal or infantile onset and death in early childhood were reported in children homozygous for ## Nomenclature The older literature on NPC is bedeviled by the large number of terms used to describe individuals now known to have the disease. These include juvenile dystonic idiocy, juvenile dystonic lipidosis, juvenile NPC, neurovisceral lipidosis with vertical supranuclear gaze palsy, Neville-lake disease, sea-blue histiocytosis, lactosylceramidosis, and DAF ( The term Niemann-Pick disease type D describes a genetic isolate from Nova Scotia that is biochemically and clinically indistinguishable from NPC and that also results from biallelic pathogenic variants in The terms Niemann-Pick disease type C1 (NPC1) and Niemann-Pick disease type C2 (NPC2) are now preferred because they correspond with the associated genes ( ## Prevalence The prevalence of NPC has been estimated at 1:150,000 in Western Europe. The incidence of NPC in France has been calculated at about 1:120,000, based on the number of postnatally diagnosed individuals in a ten-year period versus the number of births during that same time period. When prenatal cases that did not result in a live-born infant were included, a slightly higher incidence of 1:100,000 was found [ The prevalence of NPC in early life is probably underestimated, owing to its nonspecific presentations. The overall prevalence is likely higher than the calculated incidence, owing to relatively prolonged survival in those with later-onset disease, although no comprehensive data are available. Acadians in Nova Scotia and a Bedouin group in Israel represent genetic isolates with a founder effect (see ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with biallelic variants in ## Differential Diagnosis A study from Colorado found that 27% of infants initially diagnosed with idiopathic neonatal cholestasis and 8% of all infants with cholestasis had Niemann-Pick disease type C (NPC) [ Hereditary Disorders in the Differential Diagnosis of Niemann-Pick Disease Type C – Neonatal and Infantile Presentations AR = autosomal recessive; MOI = mode of inheritance; NPD-A = Niemann-Pick disease type A Hereditary Disorders in the Differential Diagnosis of Niemann-Pick Disease Type C – Childhood Presentations AR = autosomal recessive; AD = autosomal dominant; MOI = mode of inheritance; NPD = Niemann-Pick disease See Serum potassium <3.5 mmol/L Late-onset lysosomal storage diseases Syphilis and HIV dementia Primary psychiatric illnesses • Late-onset lysosomal storage diseases • Syphilis and HIV dementia • Primary psychiatric illnesses ## Management Clinical management guidelines for Niemann-Pick C (NPC) have been published [ To establish the extent of disease and needs in an individual diagnosed with NPC, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Niemann-Pick Disease Type C MRI if not already performed Consider sleep studies if history is suggestive. Consider EEG if history is suggestive. Incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Clinical swallowing assessment in all affected persons VFSS may be useful in some. Assess need for dietary modification. Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Community or Social work involvement for parental/caregiver support; Advance care planning. MOI = mode of inheritance; PT = physical therapist; VFSS = videofluoroscopic swallowing study Medical geneticist, certified genetic counselor, or certified advanced genetic nurse No curative therapy for NPC exists. Supportive therapy by multidisciplinary specialists is summarized in Treatment with miglustat, which was approved for the management of neurologic manifestations of NPC in several countries (but not the United States), follows Treatment of Manifestations in Individuals with Niemann-Pick Disease Type C PT to maintain mobility as long as possible Structured & personalized rehab program to prolong mobility & transfer ability. Occurs in course of illness Hearing aids may be helpful. PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Based on clinical studies that supported a role of miglustat in stabilizing mice with the murine NPC, miglustat was approved for the management of neurologic manifestations of NPC in several countries [ Thus, in countries where it is an approved therapy, individuals with a confirmed diagnosis of NPC should be considered for miglustat therapy, Have advanced neurologic disease / dementia Have another life-threatening illness and an estimated life span <1 year Have only spleen/liver enlargement Are presymptomatic Note that miglustat may produce loose stools and excessive flatus; these effects may be managed with dietary modification (by reduction or removal of lactose and other sugars). Physiologic tremor may be enhanced in some individuals. Recommended Surveillance for Individuals with Niemann-Pick Disease Type C Compliance w/therapy; Side effects from therapy; Conditions that would prompt discontinuation of therapy. In children, every 6 mos until age 18 yrs, then annually if stable or asymptomatic Frequency of eval should always be guided by individual clinical circumstances. See A person identified as being near end of life may benefit from ongoing access to palliative care services incl for symptom control, respite care, & psychological/spiritual support. PT = physical therapist Avoid the following: Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medications Alcohol as well as many drugs that exacerbate ataxia It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who are symptomatic and would benefit from prompt initiation of treatment (see See Based on results of studies of hydroxypropyl beta cyclodextrin in the murine model of NPC [ Studies of intravenous and combined intravenous and intrathecal cyclodextrins are currently in progress. Studies of recombinant human heat shock protein 70 [rh HSP70] in tissue culture and animal models suggested potential benefit in NPC and other lysosomal diseases [ N-acetyl-L-leucine has shown benefit in ameliorating ataxia in NPC (and ataxia in several other disorders) in open label studies [ Treatment of certain NPC fibroblast cell lines with an HDAC inhibitor produced marked reduction of cholesterol storage [ Search • MRI if not already performed • Consider sleep studies if history is suggestive. • Consider EEG if history is suggestive. • Incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Clinical swallowing assessment in all affected persons • VFSS may be useful in some. • Assess need for dietary modification. • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental/caregiver support; • Advance care planning. • PT to maintain mobility as long as possible • Structured & personalized rehab program to prolong mobility & transfer ability. • Occurs in course of illness • Hearing aids may be helpful. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Have advanced neurologic disease / dementia • Have another life-threatening illness and an estimated life span <1 year • Have only spleen/liver enlargement • Are presymptomatic • Compliance w/therapy; • Side effects from therapy; • Conditions that would prompt discontinuation of therapy. • In children, every 6 mos until age 18 yrs, then annually if stable or asymptomatic • Frequency of eval should always be guided by individual clinical circumstances. • See • A person identified as being near end of life may benefit from ongoing access to palliative care services incl for symptom control, respite care, & psychological/spiritual support. • Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medications • Alcohol as well as many drugs that exacerbate ataxia ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NPC, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Niemann-Pick Disease Type C MRI if not already performed Consider sleep studies if history is suggestive. Consider EEG if history is suggestive. Incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Clinical swallowing assessment in all affected persons VFSS may be useful in some. Assess need for dietary modification. Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Community or Social work involvement for parental/caregiver support; Advance care planning. MOI = mode of inheritance; PT = physical therapist; VFSS = videofluoroscopic swallowing study Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • MRI if not already performed • Consider sleep studies if history is suggestive. • Consider EEG if history is suggestive. • Incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Clinical swallowing assessment in all affected persons • VFSS may be useful in some. • Assess need for dietary modification. • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental/caregiver support; • Advance care planning. ## Treatment of Manifestations No curative therapy for NPC exists. Supportive therapy by multidisciplinary specialists is summarized in Treatment with miglustat, which was approved for the management of neurologic manifestations of NPC in several countries (but not the United States), follows Treatment of Manifestations in Individuals with Niemann-Pick Disease Type C PT to maintain mobility as long as possible Structured & personalized rehab program to prolong mobility & transfer ability. Occurs in course of illness Hearing aids may be helpful. PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Based on clinical studies that supported a role of miglustat in stabilizing mice with the murine NPC, miglustat was approved for the management of neurologic manifestations of NPC in several countries [ Thus, in countries where it is an approved therapy, individuals with a confirmed diagnosis of NPC should be considered for miglustat therapy, Have advanced neurologic disease / dementia Have another life-threatening illness and an estimated life span <1 year Have only spleen/liver enlargement Are presymptomatic Note that miglustat may produce loose stools and excessive flatus; these effects may be managed with dietary modification (by reduction or removal of lactose and other sugars). Physiologic tremor may be enhanced in some individuals. • PT to maintain mobility as long as possible • Structured & personalized rehab program to prolong mobility & transfer ability. • Occurs in course of illness • Hearing aids may be helpful. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Have advanced neurologic disease / dementia • Have another life-threatening illness and an estimated life span <1 year • Have only spleen/liver enlargement • Are presymptomatic ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Treatment with Miglustat Based on clinical studies that supported a role of miglustat in stabilizing mice with the murine NPC, miglustat was approved for the management of neurologic manifestations of NPC in several countries [ Thus, in countries where it is an approved therapy, individuals with a confirmed diagnosis of NPC should be considered for miglustat therapy, Have advanced neurologic disease / dementia Have another life-threatening illness and an estimated life span <1 year Have only spleen/liver enlargement Are presymptomatic Note that miglustat may produce loose stools and excessive flatus; these effects may be managed with dietary modification (by reduction or removal of lactose and other sugars). Physiologic tremor may be enhanced in some individuals. • Have advanced neurologic disease / dementia • Have another life-threatening illness and an estimated life span <1 year • Have only spleen/liver enlargement • Are presymptomatic ## Surveillance Recommended Surveillance for Individuals with Niemann-Pick Disease Type C Compliance w/therapy; Side effects from therapy; Conditions that would prompt discontinuation of therapy. In children, every 6 mos until age 18 yrs, then annually if stable or asymptomatic Frequency of eval should always be guided by individual clinical circumstances. See A person identified as being near end of life may benefit from ongoing access to palliative care services incl for symptom control, respite care, & psychological/spiritual support. PT = physical therapist • Compliance w/therapy; • Side effects from therapy; • Conditions that would prompt discontinuation of therapy. • In children, every 6 mos until age 18 yrs, then annually if stable or asymptomatic • Frequency of eval should always be guided by individual clinical circumstances. • See • A person identified as being near end of life may benefit from ongoing access to palliative care services incl for symptom control, respite care, & psychological/spiritual support. ## Agents/Circumstances to Avoid Avoid the following: Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medications Alcohol as well as many drugs that exacerbate ataxia • Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medications • Alcohol as well as many drugs that exacerbate ataxia ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who are symptomatic and would benefit from prompt initiation of treatment (see See ## Therapies Under Investigation Based on results of studies of hydroxypropyl beta cyclodextrin in the murine model of NPC [ Studies of intravenous and combined intravenous and intrathecal cyclodextrins are currently in progress. Studies of recombinant human heat shock protein 70 [rh HSP70] in tissue culture and animal models suggested potential benefit in NPC and other lysosomal diseases [ N-acetyl-L-leucine has shown benefit in ameliorating ataxia in NPC (and ataxia in several other disorders) in open label studies [ Treatment of certain NPC fibroblast cell lines with an HDAC inhibitor produced marked reduction of cholesterol storage [ Search ## Genetic Counseling Niemann-Pick disease type C (NPC) is inherited in an autosomal recessive manner. The parents of an individual with NPC are obligate heterozygotes (i.e., presumed to be heterozygous for one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NPC-related pathogenic variant and to allow reliable recurrence risk assessment. Probable paternal germline mosaicism for an Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of being unaffected and not a heterozygote. The NPC phenotype usually runs true in families; that is, if the proband has early-onset disease, sibs who inherit biallelic pathogenic variants will have a similar clinical course. In rare cases, a proband and the proband's affected sibs have had different clinical presentations. Sibs younger than the proband may have NPC but be presymptomatic. Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Founder variants have been identified in Acadians in Nova Scotia ( Once the NPC-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an individual with NPC are obligate heterozygotes (i.e., presumed to be heterozygous for one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NPC-related pathogenic variant and to allow reliable recurrence risk assessment. • Probable paternal germline mosaicism for an • Probable paternal germline mosaicism for an • Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see • Probable paternal germline mosaicism for an • If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of being unaffected and not a heterozygote. • The NPC phenotype usually runs true in families; that is, if the proband has early-onset disease, sibs who inherit biallelic pathogenic variants will have a similar clinical course. In rare cases, a proband and the proband's affected sibs have had different clinical presentations. • Sibs younger than the proband may have NPC but be presymptomatic. • Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • Founder variants have been identified in Acadians in Nova Scotia ( ## Mode of Inheritance Niemann-Pick disease type C (NPC) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an individual with NPC are obligate heterozygotes (i.e., presumed to be heterozygous for one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NPC-related pathogenic variant and to allow reliable recurrence risk assessment. Probable paternal germline mosaicism for an Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of being unaffected and not a heterozygote. The NPC phenotype usually runs true in families; that is, if the proband has early-onset disease, sibs who inherit biallelic pathogenic variants will have a similar clinical course. In rare cases, a proband and the proband's affected sibs have had different clinical presentations. Sibs younger than the proband may have NPC but be presymptomatic. Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see • The parents of an individual with NPC are obligate heterozygotes (i.e., presumed to be heterozygous for one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NPC-related pathogenic variant and to allow reliable recurrence risk assessment. • Probable paternal germline mosaicism for an • Probable paternal germline mosaicism for an • Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see • Probable paternal germline mosaicism for an • If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of being unaffected and not a heterozygote. • The NPC phenotype usually runs true in families; that is, if the proband has early-onset disease, sibs who inherit biallelic pathogenic variants will have a similar clinical course. In rare cases, a proband and the proband's affected sibs have had different clinical presentations. • Sibs younger than the proband may have NPC but be presymptomatic. • Heterozygotes may manifest clinical and biochemical abnormalities, although most appear to be asymptomatic (see ## Heterozygote Detection ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Founder variants have been identified in Acadians in Nova Scotia ( • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • Founder variants have been identified in Acadians in Nova Scotia ( ## Prenatal Testing and Preimplantation Genetic Testing Once the NPC-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Canada • • • • • • • • • • • • United Kingdom • • • Canada • • • • • ## Molecular Genetics Niemann-Pick Disease Type C: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Niemann-Pick Disease Type C ( Pathogenic variants have been described throughout Niemann-Pick Disease Type C: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the author. ## Molecular Pathogenesis Pathogenic variants have been described throughout Niemann-Pick Disease Type C: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the author. ## Chapter Notes At the time of submission in October 2020, the author's work was supported by the Peggy Furth Fund at Mayo Clinic, and research grants from NINDS, Amicus, Cerecor, Glycomine, Idorsia, Orphazyme, and Shire-Takeda. The author currently serves as Chair of the Scientific Advisory Committee of the International Niemann-Pick Disease Registry. He also serves as a consultant for IntraBio and Orphazyme, and holds stock in IntraBio. 10 December 2020 (bp) Comprehensive update posted live 18 July 2013 (me) Comprehensive update posted live 22 July 2008 (me) Comprehensive update posted live 13 February 2006 (me) Comprehensive update posted live 18 December 2003 (me) Comprehensive update posted live 26 January 2000 (me) Review posted live 20 October 1999 (mp) Original submission • 10 December 2020 (bp) Comprehensive update posted live • 18 July 2013 (me) Comprehensive update posted live • 22 July 2008 (me) Comprehensive update posted live • 13 February 2006 (me) Comprehensive update posted live • 18 December 2003 (me) Comprehensive update posted live • 26 January 2000 (me) Review posted live • 20 October 1999 (mp) Original submission ## Author Notes At the time of submission in October 2020, the author's work was supported by the Peggy Furth Fund at Mayo Clinic, and research grants from NINDS, Amicus, Cerecor, Glycomine, Idorsia, Orphazyme, and Shire-Takeda. The author currently serves as Chair of the Scientific Advisory Committee of the International Niemann-Pick Disease Registry. He also serves as a consultant for IntraBio and Orphazyme, and holds stock in IntraBio. ## Revision History 10 December 2020 (bp) Comprehensive update posted live 18 July 2013 (me) Comprehensive update posted live 22 July 2008 (me) Comprehensive update posted live 13 February 2006 (me) Comprehensive update posted live 18 December 2003 (me) Comprehensive update posted live 26 January 2000 (me) Review posted live 20 October 1999 (mp) Original submission • 10 December 2020 (bp) Comprehensive update posted live • 18 July 2013 (me) Comprehensive update posted live • 22 July 2008 (me) Comprehensive update posted live • 13 February 2006 (me) Comprehensive update posted live • 18 December 2003 (me) Comprehensive update posted live • 26 January 2000 (me) Review posted live • 20 October 1999 (mp) Original submission ## References ## Literature Cited	[]	26/1/2000	10/12/2020	29/8/2019	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nr2f1-ndd	nr2f1-ndd	[ "Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS)", "Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS)", "COUP transcription factor 1", "NR2F1", "NR2F1-Related Neurodevelopmental Disorder" ]		Christian Schaaf, Patrick Yu-Wai-Man, Ilia Valentin	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Developmental delay (i.e., delay in milestone acquisition in at least one domain) and/or intellectual disability Hypotonia Speech difficulties Vision impairment, including: Optic atrophy (OA), optic nerve hypoplasia Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors Behavioral findings including: Autism spectrum disorder or autistic features Attention-deficit/hyperactivity disorder Obsessive-compulsive behavior and/or repetitive behaviors Feeding difficulties (oromotor dysfunction, mouth stuffing) Seizures including infantile spasms Hearing impairment Other common findings: Alacrima Love of music Good long-term memory High pain tolerance Sleep disturbances Touch sensitivity Abnormalities of the corpus callosum (particularly thinning of the corpus callosum) Hypoplasia of the optic nerves and optic chiasms Other nonspecific findings (See The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Developmental delay (i.e., delay in milestone acquisition in at least one domain) and/or intellectual disability • Hypotonia • Speech difficulties • Vision impairment, including: • Optic atrophy (OA), optic nerve hypoplasia • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors • Optic atrophy (OA), optic nerve hypoplasia • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors • Behavioral findings including: • Autism spectrum disorder or autistic features • Attention-deficit/hyperactivity disorder • Obsessive-compulsive behavior and/or repetitive behaviors • Autism spectrum disorder or autistic features • Attention-deficit/hyperactivity disorder • Obsessive-compulsive behavior and/or repetitive behaviors • Feeding difficulties (oromotor dysfunction, mouth stuffing) • Seizures including infantile spasms • Hearing impairment • Other common findings: • Alacrima • Love of music • Good long-term memory • High pain tolerance • Sleep disturbances • Touch sensitivity • Alacrima • Love of music • Good long-term memory • High pain tolerance • Sleep disturbances • Touch sensitivity • Optic atrophy (OA), optic nerve hypoplasia • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors • Autism spectrum disorder or autistic features • Attention-deficit/hyperactivity disorder • Obsessive-compulsive behavior and/or repetitive behaviors • Alacrima • Love of music • Good long-term memory • High pain tolerance • Sleep disturbances • Touch sensitivity • Abnormalities of the corpus callosum (particularly thinning of the corpus callosum) • Hypoplasia of the optic nerves and optic chiasms • Other nonspecific findings (See • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Developmental delay (i.e., delay in milestone acquisition in at least one domain) and/or intellectual disability Hypotonia Speech difficulties Vision impairment, including: Optic atrophy (OA), optic nerve hypoplasia Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors Behavioral findings including: Autism spectrum disorder or autistic features Attention-deficit/hyperactivity disorder Obsessive-compulsive behavior and/or repetitive behaviors Feeding difficulties (oromotor dysfunction, mouth stuffing) Seizures including infantile spasms Hearing impairment Other common findings: Alacrima Love of music Good long-term memory High pain tolerance Sleep disturbances Touch sensitivity Abnormalities of the corpus callosum (particularly thinning of the corpus callosum) Hypoplasia of the optic nerves and optic chiasms Other nonspecific findings (See • Developmental delay (i.e., delay in milestone acquisition in at least one domain) and/or intellectual disability • Hypotonia • Speech difficulties • Vision impairment, including: • Optic atrophy (OA), optic nerve hypoplasia • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors • Optic atrophy (OA), optic nerve hypoplasia • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors • Behavioral findings including: • Autism spectrum disorder or autistic features • Attention-deficit/hyperactivity disorder • Obsessive-compulsive behavior and/or repetitive behaviors • Autism spectrum disorder or autistic features • Attention-deficit/hyperactivity disorder • Obsessive-compulsive behavior and/or repetitive behaviors • Feeding difficulties (oromotor dysfunction, mouth stuffing) • Seizures including infantile spasms • Hearing impairment • Other common findings: • Alacrima • Love of music • Good long-term memory • High pain tolerance • Sleep disturbances • Touch sensitivity • Alacrima • Love of music • Good long-term memory • High pain tolerance • Sleep disturbances • Touch sensitivity • Optic atrophy (OA), optic nerve hypoplasia • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [ • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors • Autism spectrum disorder or autistic features • Attention-deficit/hyperactivity disorder • Obsessive-compulsive behavior and/or repetitive behaviors • Alacrima • Love of music • Good long-term memory • High pain tolerance • Sleep disturbances • Touch sensitivity • Abnormalities of the corpus callosum (particularly thinning of the corpus callosum) • Hypoplasia of the optic nerves and optic chiasms • Other nonspecific findings (See ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, 92 individuals have been described with a pathogenic variant in Select Features of Adapted and modified from Based on published reports to date: Children are able to sit independently at an average age of 14 months, crawl at 16 months, and walk at 33 months [ Children are able to speak their first words at an average age of 32 months and combine words by the age of 47 months [ Some affected individuals have more significant delays, including severe language/speech delays (e.g., they are nonverbal), and others are not able to walk independently [ Visual acuity is relatively preserved with a mean logMAR of 0.64 (20/90 Snellen equivalent). Fundus examination revealed optic atrophy in 77% of individuals and small and/or tilted hypoplastic optic nerves in 46% of individuals. Most individuals have a refractive error (91%) with a predominance of hyperopia (68%). Strabismus (77%) and nystagmus (45%) are common features. Cerebral visual impairment is present in 55% of children. Electroencephalography may reveal abnormalities, often predominantly in the occipital brain regions [ No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific. Information on life expectancy in individuals with Preliminary genotype-phenotype correlations based on published reports to date suggest that compared to individuals with pathogenic variants in other domains of In addition, individuals with heterozygous whole-gene deletions and other variants causing functional haploinsufficiency have a milder phenotype than those with heterozygous missense variants in the DNA-binding domain [ The title of this • Children are able to sit independently at an average age of 14 months, crawl at 16 months, and walk at 33 months [ • Children are able to speak their first words at an average age of 32 months and combine words by the age of 47 months [ • Some affected individuals have more significant delays, including severe language/speech delays (e.g., they are nonverbal), and others are not able to walk independently [ • Visual acuity is relatively preserved with a mean logMAR of 0.64 (20/90 Snellen equivalent). Fundus examination revealed optic atrophy in 77% of individuals and small and/or tilted hypoplastic optic nerves in 46% of individuals. • Most individuals have a refractive error (91%) with a predominance of hyperopia (68%). • Strabismus (77%) and nystagmus (45%) are common features. • Cerebral visual impairment is present in 55% of children. • No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific. ## Clinical Description To date, 92 individuals have been described with a pathogenic variant in Select Features of Adapted and modified from Based on published reports to date: Children are able to sit independently at an average age of 14 months, crawl at 16 months, and walk at 33 months [ Children are able to speak their first words at an average age of 32 months and combine words by the age of 47 months [ Some affected individuals have more significant delays, including severe language/speech delays (e.g., they are nonverbal), and others are not able to walk independently [ Visual acuity is relatively preserved with a mean logMAR of 0.64 (20/90 Snellen equivalent). Fundus examination revealed optic atrophy in 77% of individuals and small and/or tilted hypoplastic optic nerves in 46% of individuals. Most individuals have a refractive error (91%) with a predominance of hyperopia (68%). Strabismus (77%) and nystagmus (45%) are common features. Cerebral visual impairment is present in 55% of children. Electroencephalography may reveal abnormalities, often predominantly in the occipital brain regions [ No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific. Information on life expectancy in individuals with • Children are able to sit independently at an average age of 14 months, crawl at 16 months, and walk at 33 months [ • Children are able to speak their first words at an average age of 32 months and combine words by the age of 47 months [ • Some affected individuals have more significant delays, including severe language/speech delays (e.g., they are nonverbal), and others are not able to walk independently [ • Visual acuity is relatively preserved with a mean logMAR of 0.64 (20/90 Snellen equivalent). Fundus examination revealed optic atrophy in 77% of individuals and small and/or tilted hypoplastic optic nerves in 46% of individuals. • Most individuals have a refractive error (91%) with a predominance of hyperopia (68%). • Strabismus (77%) and nystagmus (45%) are common features. • Cerebral visual impairment is present in 55% of children. • No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific. ## Genotype-Phenotype Correlations Preliminary genotype-phenotype correlations based on published reports to date suggest that compared to individuals with pathogenic variants in other domains of In addition, individuals with heterozygous whole-gene deletions and other variants causing functional haploinsufficiency have a milder phenotype than those with heterozygous missense variants in the DNA-binding domain [ ## Nomenclature The title of this ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders with Ophthalmologic Features in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; CVI = cerebral visual impairment; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To assess for ↓ visual acuity, refractive errors, & abnormal ocular movement (incl strabismus & nystagmus) Eval for optic nerve abnormalities (optic atrophy & optic nerve hypoplasia) & CVI, which may require subspecialty referral Infants may have problems w/poor latch/suck. Older children may have trouble chewing & swallowing, incl mouth overstuffing &/or food pocketing. To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. Use of ADI Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADI Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Supportive treatment typically relies on multidisciplinary specialists in the fields of neurology, speech-language pathology, ophthalmology (including low-vision services), gastroenterology, nutrition, occupational therapy, physical therapy, audiology, clinical genetics, and genetic counseling (see Treatment of Manifestations in Individuals with Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Children: through early intervention programs &/or school district Adults: referral to low-vision clinic &/or community vision services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; CVI = cerebral visual impairment; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. See Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Ophthalmologic assessment to evaluate visual function Low-vision services to assess changes in visual acuity & personal needs ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy See Search • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To assess for ↓ visual acuity, refractive errors, & abnormal ocular movement (incl strabismus & nystagmus) • Eval for optic nerve abnormalities (optic atrophy & optic nerve hypoplasia) & CVI, which may require subspecialty referral • Infants may have problems w/poor latch/suck. • Older children may have trouble chewing & swallowing, incl mouth overstuffing &/or food pocketing. • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. • Use of ADI • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Children: through early intervention programs &/or school district • Adults: referral to low-vision clinic &/or community vision services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Ophthalmologic assessment to evaluate visual function • Low-vision services to assess changes in visual acuity & personal needs ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To assess for ↓ visual acuity, refractive errors, & abnormal ocular movement (incl strabismus & nystagmus) Eval for optic nerve abnormalities (optic atrophy & optic nerve hypoplasia) & CVI, which may require subspecialty referral Infants may have problems w/poor latch/suck. Older children may have trouble chewing & swallowing, incl mouth overstuffing &/or food pocketing. To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. Use of ADI Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADI Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To assess for ↓ visual acuity, refractive errors, & abnormal ocular movement (incl strabismus & nystagmus) • Eval for optic nerve abnormalities (optic atrophy & optic nerve hypoplasia) & CVI, which may require subspecialty referral • Infants may have problems w/poor latch/suck. • Older children may have trouble chewing & swallowing, incl mouth overstuffing &/or food pocketing. • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. • Use of ADI • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Supportive treatment typically relies on multidisciplinary specialists in the fields of neurology, speech-language pathology, ophthalmology (including low-vision services), gastroenterology, nutrition, occupational therapy, physical therapy, audiology, clinical genetics, and genetic counseling (see Treatment of Manifestations in Individuals with Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Children: through early intervention programs &/or school district Adults: referral to low-vision clinic &/or community vision services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; CVI = cerebral visual impairment; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Children: through early intervention programs &/or school district • Adults: referral to low-vision clinic &/or community vision services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Social / Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance See Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Ophthalmologic assessment to evaluate visual function Low-vision services to assess changes in visual acuity & personal needs ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Ophthalmologic assessment to evaluate visual function • Low-vision services to assess changes in visual acuity & personal needs ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Note: Vertical transmission of a contiguous gene deletion encompassing All probands reported to date with an intragenic Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for an If a parent of the proband is known to have the If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • All probands reported to date with an intragenic • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for an • If a parent of the proband is known to have the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance Note: Vertical transmission of a contiguous gene deletion encompassing ## Risk to Family Members All probands reported to date with an intragenic Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for an If a parent of the proband is known to have the If the • All probands reported to date with an intragenic • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for an • If a parent of the proband is known to have the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics NR2F1-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NR2F1-Related Neurodevelopmental Disorder ( ## Molecular Pathogenesis ## Chapter Notes 8 December 2022 (bp) Review posted live 17 August 2022 (cs) Original submission • 8 December 2022 (bp) Review posted live • 17 August 2022 (cs) Original submission ## Revision History 8 December 2022 (bp) Review posted live 17 August 2022 (cs) Original submission • 8 December 2022 (bp) Review posted live • 17 August 2022 (cs) Original submission ## References ## Literature Cited	[]	8/12/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nsdhl-dis	nsdhl-dis	[ "CHILD (Congenital Hemidysplasia with Ichthyosiform Nevus and Limb Defects) Syndrome", "CK Syndrome", "Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating", "NSDHL", "NSDHL-Related Disorders" ]		Mazen Kurban, Jinia El Feghaly, Lamiaa Hamie	Summary CHILD syndrome is characterized by unilateral distribution of ichthyosiform skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Onychodystrophy and periungual hyperkeratosis are common. Heart, lung, and kidney malformations can also occur. CK syndrome is characterized by mild-to-severe cognitive impairment and behavior problems (aggression, attention-deficit/hyperactivity disorder [ADHD], and irritability). All reported affected males have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported. The diagnosis of CHILD syndrome is established in a female proband with a heterozygous In CK syndrome, developmental and educational support; behavior modification and/or drug therapy to control aggression and help with manifestations of ADHD; anti-seizure medication to control seizures; standard treatments for orthopedic and ocular manifestations; support transition to adult care; and social work and family support as needed. In CK syndrome, monitor for developmental and educational progress, behavioral issues, changes in seizures, and development of scoliosis and/or kyphosis annually or as needed. Follow-up ophthalmology examination per ophthalmologist. Once the	CHILD ( CK syndrome For synonyms and outdated names see • CHILD ( • CK syndrome ## Diagnosis For the purposes of this No consensus clinical diagnostic criteria for An Unilateral distribution of ichthyosiform nevus Limb defects ipsilateral to the skin lesions Punctate calcifications of cartilaginous structures Central nervous system (CNS) anomalies Visceral malformations (heart, lung, and/or renal anomalies) CNS findings, including mild-to-severe intellectual disability, microcephaly, seizures, cerebral cortical malformations (polymicrogyria), and spasticity Characteristic craniofacial features, such as microcephaly, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high-arched palate, crowded dentition, and micrognathia Thin body habitus with normal height Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click When the diagnosis of an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, only one of three Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Large intragenic deletion/duplications have not been reported in individuals with CK syndrome. One individual with a contiguous gene duplication (not included in these calculations) has been reported (see When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxysterols and slightly decreased levels of cholesterol [ In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxysterols [ Serum concentrations of methylsterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome. Two ketosterols were detected in one female with CHILD syndrome [ • Unilateral distribution of ichthyosiform nevus • Limb defects ipsilateral to the skin lesions • Punctate calcifications of cartilaginous structures • Central nervous system (CNS) anomalies • Visceral malformations (heart, lung, and/or renal anomalies) • CNS findings, including mild-to-severe intellectual disability, microcephaly, seizures, cerebral cortical malformations (polymicrogyria), and spasticity • Characteristic craniofacial features, such as microcephaly, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high-arched palate, crowded dentition, and micrognathia • Thin body habitus with normal height • For an introduction to multigene panels click • When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxysterols and slightly decreased levels of cholesterol [ • In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxysterols [ • Serum concentrations of methylsterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome. Two ketosterols were detected in one female with CHILD syndrome [ ## Suggestive Findings An Unilateral distribution of ichthyosiform nevus Limb defects ipsilateral to the skin lesions Punctate calcifications of cartilaginous structures Central nervous system (CNS) anomalies Visceral malformations (heart, lung, and/or renal anomalies) CNS findings, including mild-to-severe intellectual disability, microcephaly, seizures, cerebral cortical malformations (polymicrogyria), and spasticity Characteristic craniofacial features, such as microcephaly, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high-arched palate, crowded dentition, and micrognathia Thin body habitus with normal height • Unilateral distribution of ichthyosiform nevus • Limb defects ipsilateral to the skin lesions • Punctate calcifications of cartilaginous structures • Central nervous system (CNS) anomalies • Visceral malformations (heart, lung, and/or renal anomalies) • CNS findings, including mild-to-severe intellectual disability, microcephaly, seizures, cerebral cortical malformations (polymicrogyria), and spasticity • Characteristic craniofacial features, such as microcephaly, plagiocephaly, almond-shaped and upslanted palpebral fissures, prominent nasal bridge, high-arched palate, crowded dentition, and micrognathia • Thin body habitus with normal height ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click When the diagnosis of an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, only one of three Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Large intragenic deletion/duplications have not been reported in individuals with CK syndrome. One individual with a contiguous gene duplication (not included in these calculations) has been reported (see When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxysterols and slightly decreased levels of cholesterol [ In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxysterols [ Serum concentrations of methylsterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome. Two ketosterols were detected in one female with CHILD syndrome [ • For an introduction to multigene panels click • When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxysterols and slightly decreased levels of cholesterol [ • In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxysterols [ • Serum concentrations of methylsterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome. Two ketosterols were detected in one female with CHILD syndrome [ ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ To date, only one of three Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Large intragenic deletion/duplications have not been reported in individuals with CK syndrome. One individual with a contiguous gene duplication (not included in these calculations) has been reported (see When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxysterols and slightly decreased levels of cholesterol [ In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxysterols [ Serum concentrations of methylsterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome. Two ketosterols were detected in one female with CHILD syndrome [ • When cultured in cholesterol-depleted medium, lymphoblastoid cells of individuals with CHILD syndrome and CK syndrome have increased levels of methyl- and carboxysterols and slightly decreased levels of cholesterol [ • In individuals with CHILD syndrome, sterol analysis of skin flakes collected from an affected area show elevated levels of methyl- and carboxysterols [ • Serum concentrations of methylsterol and cholesterol are almost always normal in individuals with CHILD syndrome and CK syndrome. Two ketosterols were detected in one female with CHILD syndrome [ ## Clinical Characteristics CHILD syndrome is characterized by unilateral ichthyosiform skin lesions typically with sharp midline demarcation with ipsilateral limb defects, onychodystrophy, and periungual hyperkeratosis (see Histologically, the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates (foamy histiocytes) within the dermal papillae [ Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [ Intellect is usually normal. CK syndrome is characterized by intellectual disability, behavior issues, seizures, characteristic facial features, thin habitus, and ocular manifestations in males. To date, 25 affected males from three unrelated families have been reported [ Penetrance appears to be complete in CHILD syndrome is also known as unilateral congenital ichthyosiform erythroderma (CIE) and is a syndromic form of ichthyosis. The prevalence of CHILD syndrome is unknown; more than 60 individuals have been reported to date. The prevalence of CK syndrome is unknown; it is thought to be rare. To date, 25 affected males from three unrelated families have been reported [ • Histologically, the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates (foamy histiocytes) within the dermal papillae [ • Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [ • Intellect is usually normal. ## Clinical Description CHILD syndrome is characterized by unilateral ichthyosiform skin lesions typically with sharp midline demarcation with ipsilateral limb defects, onychodystrophy, and periungual hyperkeratosis (see Histologically, the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates (foamy histiocytes) within the dermal papillae [ Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [ Intellect is usually normal. CK syndrome is characterized by intellectual disability, behavior issues, seizures, characteristic facial features, thin habitus, and ocular manifestations in males. To date, 25 affected males from three unrelated families have been reported [ • Histologically, the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates (foamy histiocytes) within the dermal papillae [ • Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [ • Intellect is usually normal. ## CHILD Syndrome CHILD syndrome is characterized by unilateral ichthyosiform skin lesions typically with sharp midline demarcation with ipsilateral limb defects, onychodystrophy, and periungual hyperkeratosis (see Histologically, the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates (foamy histiocytes) within the dermal papillae [ Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [ Intellect is usually normal. • Histologically, the skin lesions exhibit hyperkeratosis, parakeratosis, and acanthosis as well as inflammatory and lipid-laden infiltrates (foamy histiocytes) within the dermal papillae [ • Occasionally, heterozygous females present with comparatively minor skin lesions such as Blaschko-linear inflammatory scaly lesions, patchy alopecia, or nail changes. In some affected females, an ichthyosiform nevus (CHILD nevus) can be present without any additional manifestations of CHILD syndrome [ • Intellect is usually normal. ## CK Syndrome CK syndrome is characterized by intellectual disability, behavior issues, seizures, characteristic facial features, thin habitus, and ocular manifestations in males. To date, 25 affected males from three unrelated families have been reported [ ## Genotype-Phenotype Correlations ## Penetrance Penetrance appears to be complete in ## Nomenclature CHILD syndrome is also known as unilateral congenital ichthyosiform erythroderma (CIE) and is a syndromic form of ichthyosis. ## Prevalence The prevalence of CHILD syndrome is unknown; more than 60 individuals have been reported to date. The prevalence of CK syndrome is unknown; it is thought to be rare. To date, 25 affected males from three unrelated families have been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this A ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of CHILD Syndrome ≥95% of affected persons are female. Linear or blotchy scaly ichthyosiform plaques in newborns; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) & scarring Asymmetric limb shortening, kyphoscoliosis, & chondrodysplasia punctata (epiphyseal stippling) Absence of strict midline demarcation & lack of unilaterality seen in CHILD syndrome Skin findings fade over time. Most persons have follicular atrophoderma by age 2 yrs. Ocular anomalies are prominent (develop early in life). Skin lesions (epidermal nevi) can be flat, verrucous, inflammatory or non-inflammatory, scaly or non-scaly; they typically follow lines of Blaschko & many grow over time. In Schimmelpenning-Feuerstein-Mims syndrome face &/or scalp are typically involved. Extensive epidermal nevi (various subtypes); unilateral or bilateral Cerebral anomalies & neurologic symptoms Coloboma of iris, choroid, or eyelids Conjunctival lipodermoid Overgrowth & other vascular lesions seen in some ENSs Embryonic lethality in many males Skin lesions present as erythema & then blisters at birth (vesicular stage), progress to wart-like rash (verrucous stage), swirling macular hyperpigmentation following lines of Blaschko (hyperpigmented stage), & then linear hypopigmentation (hypopigmented stage). Cutaneous lesions evolve through multiple stages. Hypodontia Onychogryphosis Ocular findings (mostly retinal; peripheral neovascularization in eyes) Seizures ID ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Not known to be inherited. Postzygotic somatic mosaic pathogenic variants in The evolution of the four skin stages in incontinentia pigmenti may or may not occur in all individuals. The X-linked inheritance, intellectual disability, and asthenic habitus of CK syndrome overlap with several disorders (see Genes of Interest in the Differential Diagnosis of CK Syndrome ID Generalized tonic-clonic seizures Scoliosis Progressive gait disturbance Pes planus ID; severe speech delay Microcephaly Narrow face; slanted palpebral fissures Short stature Infantile hypotonia; development of hypertonia in adolescence to early adulthood ID Marfanoid appearance; thin fingers & toes Tall, narrow face; prominent nasal bridge; high, narrow palate; micrognathia; low-set, posteriorly rotated ears Large head circumference Short philtrum Hypernasal speech Generalized hypotonia; abnormalities of corpus callosum Pectus excavatum ID Seizures Microcephaly Hypotonia Congenital heart malformation Pigmentary retinopathy Megaloblastic anemia Poor weight gain, feeding difficulties, vomiting, lethargy ID Microcephaly Short stature Heart defects Cleft palate Microphthalmia ID Marfanoid habitus Craniosynostosis Cardiovascular & abdominal wall defects Minimal subcutaneous fat ID Microcephaly Epilepsy Truncal ataxia Absent or limited speech Ophthalmoplegia ID Asthenic build High-arched palate Kyphoscoliosis Prominent lower lip Osteoporosis Hypotonia Unsteady gait Hypernasal speech in some affected males (may also be dysarthric, coarse, or absent) Thin habitus; long face & digits ID Joint hypermobility Absence of other dysmorphic features AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked • ≥95% of affected persons are female. • Linear or blotchy scaly ichthyosiform plaques in newborns; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) & scarring • Asymmetric limb shortening, kyphoscoliosis, & chondrodysplasia punctata (epiphyseal stippling) • Absence of strict midline demarcation & lack of unilaterality seen in CHILD syndrome • Skin findings fade over time. • Most persons have follicular atrophoderma by age 2 yrs. • Ocular anomalies are prominent (develop early in life). • Skin lesions (epidermal nevi) can be flat, verrucous, inflammatory or non-inflammatory, scaly or non-scaly; they typically follow lines of Blaschko & many grow over time. • In Schimmelpenning-Feuerstein-Mims syndrome face &/or scalp are typically involved. • Extensive epidermal nevi (various subtypes); unilateral or bilateral • Cerebral anomalies & neurologic symptoms • Coloboma of iris, choroid, or eyelids • Conjunctival lipodermoid • Overgrowth & other vascular lesions seen in some ENSs • Embryonic lethality in many males • Skin lesions present as erythema & then blisters at birth (vesicular stage), progress to wart-like rash (verrucous stage), swirling macular hyperpigmentation following lines of Blaschko (hyperpigmented stage), & then linear hypopigmentation (hypopigmented stage). • Cutaneous lesions evolve through multiple stages. • Hypodontia • Onychogryphosis • Ocular findings (mostly retinal; peripheral neovascularization in eyes) • Seizures • ID • ID • Generalized tonic-clonic seizures • Scoliosis • Progressive gait disturbance • Pes planus • ID; severe speech delay • Microcephaly • Narrow face; slanted palpebral fissures • Short stature • Infantile hypotonia; development of hypertonia in adolescence to early adulthood • ID • Marfanoid appearance; thin fingers & toes • Tall, narrow face; prominent nasal bridge; high, narrow palate; micrognathia; low-set, posteriorly rotated ears • Large head circumference • Short philtrum • Hypernasal speech • Generalized hypotonia; abnormalities of corpus callosum • Pectus excavatum • ID • Seizures • Microcephaly • Hypotonia • Congenital heart malformation • Pigmentary retinopathy • Megaloblastic anemia • Poor weight gain, feeding difficulties, vomiting, lethargy • ID • Microcephaly • Short stature • Heart defects • Cleft palate • Microphthalmia • ID • Marfanoid habitus • Craniosynostosis • Cardiovascular & abdominal wall defects • Minimal subcutaneous fat • ID • Microcephaly • Epilepsy • Truncal ataxia • Absent or limited speech • Ophthalmoplegia • ID • Asthenic build • High-arched palate • Kyphoscoliosis • Prominent lower lip • Osteoporosis • Hypotonia • Unsteady gait • Hypernasal speech in some affected males (may also be dysarthric, coarse, or absent) • Thin habitus; long face & digits • ID • Joint hypermobility • Absence of other dysmorphic features ## Management No clinical practice guidelines for CHILD Syndrome: Recommended Evaluations Following Initial Diagnosis Radiographs as needed of extremities & spine Clinical assessment for joint contractures & scoliosis Referral to orthopedist as needed Referral to neurologist EEG Brain MRI/CT To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse CK Syndrome: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Referral to neurologist EEG Brain MRI/CT Spine radiographs as needed Referral to orthopedist as needed ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see CHILD Syndrome: Treatment of Manifestations Lovastatin 2% / cholesterol 2% led to complete healing in a few persons. Simvastatin 2% ointment led to remarkable improvement in 1 person. Simvastatin 5% in a petroleum base led to clearance after 4 wks. Combined simvastatin 2% & cholesterol corrected the cutaneous phenotype of 1 person. Simvastatin was ↑ from 2.5% to 5% to enhance effectiveness of treatment. The addition of glycolic acid to cholesterol & lovastatin creams improved penetrance of therapy into thick skin scales, thus improving treatment. Grafting skin obtained from contralateral unaffected region was successful in 1 person. Removal by dermabrasion was reported; however, it recurred w/in 8 mos. Lactic acid 12% creams or lotions for itching Urea creams for dry skin CK Syndrome: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary between countries. IEP services: An IEP provides specially designed instruction and related services to eligible children. IEP services will be reviewed annually to determine the need for adjustments. Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in CHILD Syndrome: Recommended Surveillance CK Syndrome: Recommended Surveillance ADHD = attention-deficit/hyperactivity disorder See Search • Radiographs as needed of extremities & spine • Clinical assessment for joint contractures & scoliosis • Referral to orthopedist as needed • Referral to neurologist • EEG • Brain MRI/CT • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Referral to neurologist • EEG • Brain MRI/CT • Spine radiographs as needed • Referral to orthopedist as needed • Lovastatin 2% / cholesterol 2% led to complete healing in a few persons. • Simvastatin 2% ointment led to remarkable improvement in 1 person. • Simvastatin 5% in a petroleum base led to clearance after 4 wks. • Combined simvastatin 2% & cholesterol corrected the cutaneous phenotype of 1 person. • Simvastatin was ↑ from 2.5% to 5% to enhance effectiveness of treatment. • The addition of glycolic acid to cholesterol & lovastatin creams improved penetrance of therapy into thick skin scales, thus improving treatment. • Grafting skin obtained from contralateral unaffected region was successful in 1 person. • Removal by dermabrasion was reported; however, it recurred w/in 8 mos. • Lactic acid 12% creams or lotions for itching • Urea creams for dry skin • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Evaluations Following Initial Diagnosis CHILD Syndrome: Recommended Evaluations Following Initial Diagnosis Radiographs as needed of extremities & spine Clinical assessment for joint contractures & scoliosis Referral to orthopedist as needed Referral to neurologist EEG Brain MRI/CT To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse CK Syndrome: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Referral to neurologist EEG Brain MRI/CT Spine radiographs as needed Referral to orthopedist as needed ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance • Radiographs as needed of extremities & spine • Clinical assessment for joint contractures & scoliosis • Referral to orthopedist as needed • Referral to neurologist • EEG • Brain MRI/CT • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Referral to neurologist • EEG • Brain MRI/CT • Spine radiographs as needed • Referral to orthopedist as needed ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see CHILD Syndrome: Treatment of Manifestations Lovastatin 2% / cholesterol 2% led to complete healing in a few persons. Simvastatin 2% ointment led to remarkable improvement in 1 person. Simvastatin 5% in a petroleum base led to clearance after 4 wks. Combined simvastatin 2% & cholesterol corrected the cutaneous phenotype of 1 person. Simvastatin was ↑ from 2.5% to 5% to enhance effectiveness of treatment. The addition of glycolic acid to cholesterol & lovastatin creams improved penetrance of therapy into thick skin scales, thus improving treatment. Grafting skin obtained from contralateral unaffected region was successful in 1 person. Removal by dermabrasion was reported; however, it recurred w/in 8 mos. Lactic acid 12% creams or lotions for itching Urea creams for dry skin CK Syndrome: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary between countries. IEP services: An IEP provides specially designed instruction and related services to eligible children. IEP services will be reviewed annually to determine the need for adjustments. Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Lovastatin 2% / cholesterol 2% led to complete healing in a few persons. • Simvastatin 2% ointment led to remarkable improvement in 1 person. • Simvastatin 5% in a petroleum base led to clearance after 4 wks. • Combined simvastatin 2% & cholesterol corrected the cutaneous phenotype of 1 person. • Simvastatin was ↑ from 2.5% to 5% to enhance effectiveness of treatment. • The addition of glycolic acid to cholesterol & lovastatin creams improved penetrance of therapy into thick skin scales, thus improving treatment. • Grafting skin obtained from contralateral unaffected region was successful in 1 person. • Removal by dermabrasion was reported; however, it recurred w/in 8 mos. • Lactic acid 12% creams or lotions for itching • Urea creams for dry skin • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary between countries. IEP services: An IEP provides specially designed instruction and related services to eligible children. IEP services will be reviewed annually to determine the need for adjustments. Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to eligible children. • IEP services will be reviewed annually to determine the need for adjustments. • Special education law mandates integrating children participating in an IEP into the least restrictive educational environment feasible, with inclusion in general education when suitable. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in CHILD Syndrome: Recommended Surveillance CK Syndrome: Recommended Surveillance ADHD = attention-deficit/hyperactivity disorder ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling CHILD syndrome (associated with CK syndrome (associated with hypomorphic A female proband may have inherited the Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Although CHILD syndrome-associated If a male proband has CHILD syndrome as the result of mosaicism for a postzygotic An affected male fetus may have inherited the Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. If the mother of the proband has an 33% heterozygous (typically) affected females; 33% unaffected females who have not inherited the 33% unaffected males who have not inherited the If the proband represents a simplex case (i.e., a single affected family member) and if pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal gonadal mosaicism. Theoretically, if the father of a female proband has gonadal mosaicism for an The risk to the offspring of a female with CHILD syndrome must take into consideration the presumed lethality to affected males during gestation. At conception, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, since male conceptuses with an Of note, a female proband with comparatively minor skin lesions (e.g., an ichthyosiform nevus without any additional manifestations of CHILD syndrome) is at risk of having a daughter with typical CHILD syndrome [ The father of a male with CK syndrome will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. If the mother of the proband is heterozygous for an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, If the proband represents a simplex case and if the Note: Heterozygous females may have a range of behavioral problems (see Clinical Description, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • CHILD syndrome (associated with • CK syndrome (associated with hypomorphic • A female proband may have inherited the • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Although CHILD syndrome-associated • If a male proband has CHILD syndrome as the result of mosaicism for a postzygotic • An affected male fetus may have inherited the • Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. • If the mother of the proband has an • 33% heterozygous (typically) affected females; • 33% unaffected females who have not inherited the • 33% unaffected males who have not inherited the • 33% heterozygous (typically) affected females; • 33% unaffected females who have not inherited the • 33% unaffected males who have not inherited the • If the proband represents a simplex case (i.e., a single affected family member) and if pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal gonadal mosaicism. • Theoretically, if the father of a female proband has gonadal mosaicism for an • 33% heterozygous (typically) affected females; • 33% unaffected females who have not inherited the • 33% unaffected males who have not inherited the • The risk to the offspring of a female with CHILD syndrome must take into consideration the presumed lethality to affected males during gestation. At conception, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, since male conceptuses with an • Of note, a female proband with comparatively minor skin lesions (e.g., an ichthyosiform nevus without any additional manifestations of CHILD syndrome) is at risk of having a daughter with typical CHILD syndrome [ • The father of a male with CK syndrome will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the • If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. • If the mother of the proband is heterozygous for an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. ## Mode of Inheritance CHILD syndrome (associated with CK syndrome (associated with hypomorphic • CHILD syndrome (associated with • CK syndrome (associated with hypomorphic ## CHILD Syndrome – Risk to Family Members A female proband may have inherited the Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Although CHILD syndrome-associated If a male proband has CHILD syndrome as the result of mosaicism for a postzygotic An affected male fetus may have inherited the Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. If the mother of the proband has an 33% heterozygous (typically) affected females; 33% unaffected females who have not inherited the 33% unaffected males who have not inherited the If the proband represents a simplex case (i.e., a single affected family member) and if pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal gonadal mosaicism. Theoretically, if the father of a female proband has gonadal mosaicism for an The risk to the offspring of a female with CHILD syndrome must take into consideration the presumed lethality to affected males during gestation. At conception, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, since male conceptuses with an Of note, a female proband with comparatively minor skin lesions (e.g., an ichthyosiform nevus without any additional manifestations of CHILD syndrome) is at risk of having a daughter with typical CHILD syndrome [ • A female proband may have inherited the • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Although CHILD syndrome-associated • If a male proband has CHILD syndrome as the result of mosaicism for a postzygotic • An affected male fetus may have inherited the • Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. • If the mother of the proband has an • 33% heterozygous (typically) affected females; • 33% unaffected females who have not inherited the • 33% unaffected males who have not inherited the • 33% heterozygous (typically) affected females; • 33% unaffected females who have not inherited the • 33% unaffected males who have not inherited the • If the proband represents a simplex case (i.e., a single affected family member) and if pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal gonadal mosaicism. • Theoretically, if the father of a female proband has gonadal mosaicism for an • 33% heterozygous (typically) affected females; • 33% unaffected females who have not inherited the • 33% unaffected males who have not inherited the • The risk to the offspring of a female with CHILD syndrome must take into consideration the presumed lethality to affected males during gestation. At conception, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, since male conceptuses with an • Of note, a female proband with comparatively minor skin lesions (e.g., an ichthyosiform nevus without any additional manifestations of CHILD syndrome) is at risk of having a daughter with typical CHILD syndrome [ ## Risk to Family Members ‒ CK Syndrome The father of a male with CK syndrome will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. If the mother of the proband is heterozygous for an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, If the proband represents a simplex case and if the Note: Heterozygous females may have a range of behavioral problems (see Clinical Description, • The father of a male with CK syndrome will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the • If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and allow reliable recurrence risk assessment. • If the mother of the proband is heterozygous for an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may have a range of behavioral problems (see Clinical Description, ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • • • • • Canada • ## Molecular Genetics NSDHL-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NSDHL-Related Disorders ( Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. ## Chapter Notes Cornelius F Boerkoel, MD, PhD; University of British Columbia (2010-2024)Christèle du Souich, MSc, CCGC, CGC; University of British Columbia (2010-2024)Jinia El Feghaly, MD (2024-present)Karl-Heinz Grzeschik, PhD; Philipps-Universität, Marburg (2010-2024)Lamiaa Hamie, MD, MSc (2024-present)Arne König, MD; Philipps-Universität, Marburg (2010-2015)Mazen Kurban, MD (2024-present)F Lucy Raymond, MD, PhD; University of Cambridge (2010-2024) 5 September 2024 (sw) Comprehensive update posted live 25 October 2018 (sw) Comprehensive update posted live 25 November 2015 (me) Comprehensive update posted live 27 June 2013 (me) Comprehensive update posted live 1 February 2011 (me) Review posted live 9 January 2010 (cb) Original submission • 5 September 2024 (sw) Comprehensive update posted live • 25 October 2018 (sw) Comprehensive update posted live • 25 November 2015 (me) Comprehensive update posted live • 27 June 2013 (me) Comprehensive update posted live • 1 February 2011 (me) Review posted live • 9 January 2010 (cb) Original submission ## Author History Cornelius F Boerkoel, MD, PhD; University of British Columbia (2010-2024)Christèle du Souich, MSc, CCGC, CGC; University of British Columbia (2010-2024)Jinia El Feghaly, MD (2024-present)Karl-Heinz Grzeschik, PhD; Philipps-Universität, Marburg (2010-2024)Lamiaa Hamie, MD, MSc (2024-present)Arne König, MD; Philipps-Universität, Marburg (2010-2015)Mazen Kurban, MD (2024-present)F Lucy Raymond, MD, PhD; University of Cambridge (2010-2024) ## Revision History 5 September 2024 (sw) Comprehensive update posted live 25 October 2018 (sw) Comprehensive update posted live 25 November 2015 (me) Comprehensive update posted live 27 June 2013 (me) Comprehensive update posted live 1 February 2011 (me) Review posted live 9 January 2010 (cb) Original submission • 5 September 2024 (sw) Comprehensive update posted live • 25 October 2018 (sw) Comprehensive update posted live • 25 November 2015 (me) Comprehensive update posted live • 27 June 2013 (me) Comprehensive update posted live • 1 February 2011 (me) Review posted live • 9 January 2010 (cb) Original submission ## References ## Literature Cited Photographs of a female with CHILD syndrome A. Upper left limb. Note the forearm hypoplasia, ectrodactyly, onychodystrophy, and characteristic ichthyosiform skin lesions with yellow scales. B. Lower left limb and groin. The leg was amputated at the knee to improve function. Note the verruciform xanthoma in the genital region. Photographs provided by Dr Amy Paller, Department of Dermatology, Northwestern University School of Medicine A male age 11 years (A, B) and a male age 22 years (C,D) with CK syndrome. Note the long thin face, epicanthal folds, almond-shaped palpebral fissures, prominent nasal bridge, and micrognathia. The long thin face becomes more apparent with age.	[]	1/2/2011	5/9/2024	16/2/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
nthl1-ts	nthl1-ts	[ "NTHL1-Associated Polyposis", "NTHL1-Associated Polyposis", "Endonuclease III-like protein 1", "NTHL1", "NTHL1 Tumor Syndrome" ]		Richarda M De Voer, Maartje Nielsen, Weilun Gao, Roland P Kuiper, Nicoline Hoogerbrugge	Summary The diagnosis is established in a proband by identification of germline biallelic pathogenic variants in	## Diagnosis Formal diagnostic criteria for Presence of multiple primary cancers before age 50 years, especially breast, colon, or urothelial cell cancer, meningiomas, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma Colorectal cancer (CRC) diagnosed before age 40 years One or more colorectal adenomas in an individual age ≤40 years A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When phenotypic findings suggest the diagnosis of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ • Presence of multiple primary cancers before age 50 years, especially breast, colon, or urothelial cell cancer, meningiomas, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma • Colorectal cancer (CRC) diagnosed before age 40 years • One or more colorectal adenomas in an individual age ≤40 years • A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years • A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age • For an introduction to multigene panels click ## Suggestive Findings Presence of multiple primary cancers before age 50 years, especially breast, colon, or urothelial cell cancer, meningiomas, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma Colorectal cancer (CRC) diagnosed before age 40 years One or more colorectal adenomas in an individual age ≤40 years A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age • Presence of multiple primary cancers before age 50 years, especially breast, colon, or urothelial cell cancer, meningiomas, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma • Colorectal cancer (CRC) diagnosed before age 40 years • One or more colorectal adenomas in an individual age ≤40 years • A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years • A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When phenotypic findings suggest the diagnosis of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ • For an introduction to multigene panels click ## Option 1 When phenotypic findings suggest the diagnosis of For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ ## Clinical Characteristics No clinically relevant genotype-phenotype correlations have been identified. This condition has been referred to as The prevalence of ## Clinical Description ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified. ## Nomenclature This condition has been referred to as ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of interest in the differential diagnosis of Genes of Interest in the Differential Diagnosis of ↑ CRC risk 10-100 adenomas Uveal melanomas Acute myeloid leukemia ↑ CRC risk 10-100 adenomas Duodenal adenomas Breast cancer in 1 female ↑ CRC risk Usually 10-100 adenomas Serrated polyps also observed Duodenal adenomas ↑ CRC risk Average of 30 colonic polyps Duodenal adenomas GI hamartomatous (juvenile) polyps ↑ risk of cancers of upper GI tract & pancreas Hereditary hemorrhagic telangiectasia ( ↑ CRC risk Endometrial cancer Usually <10 adenomas ↑ risk for ovarian cancer Sebaceous skin tumors Mismatch repair-deficient tumors Adenomatous polyps ↑ CRC risk 10-100 adenomas ↑ CRC & endometrial cancer risk 10-100 adenomas ↑ CRC, ureter cancer, & endometrial cancer Multiple hamartomatous & mixed polyps in GI tract Macrocephaly, lipomas of skin, & multinodular goiter ↑ risk for melanomas, thyroid cancer, & renal cancer GI hamartomatous polyps, most often in small bowel Typical mucocutaneous pigmentation ↑ risk for lung, gastric, pancreas, & sex organ cancers AD = autosomal dominant; AR = autosomal recessive; CRC = colorectal cancer; GI = gastrointestinal; MOI = mode of inheritance Listed by mode of inheritance, then alphabetically by gene. • ↑ CRC risk • 10-100 adenomas • Uveal melanomas • Acute myeloid leukemia • ↑ CRC risk • 10-100 adenomas • Duodenal adenomas • Breast cancer in 1 female • ↑ CRC risk • Usually 10-100 adenomas • Serrated polyps also observed • Duodenal adenomas • ↑ CRC risk • Average of 30 colonic polyps • Duodenal adenomas • GI hamartomatous (juvenile) polyps • ↑ risk of cancers of upper GI tract & pancreas • Hereditary hemorrhagic telangiectasia ( • ↑ CRC risk • Endometrial cancer • Usually <10 adenomas • ↑ risk for ovarian cancer • Sebaceous skin tumors • Mismatch repair-deficient tumors • Adenomatous polyps • ↑ CRC risk • 10-100 adenomas • ↑ CRC & endometrial cancer risk • 10-100 adenomas • ↑ CRC, ureter cancer, & endometrial cancer • Multiple hamartomatous & mixed polyps in GI tract • Macrocephaly, lipomas of skin, & multinodular goiter • ↑ risk for melanomas, thyroid cancer, & renal cancer • GI hamartomatous polyps, most often in small bowel • Typical mucocutaneous pigmentation • ↑ risk for lung, gastric, pancreas, & sex organ cancers ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with CRC = colorectal cancer; MOI = mode of inheritance Breast MRI sensitivity is greater than that of mammography. Evaluation may be considered in centers that recommend surveillance for endometrial cancer. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Polyp resection during colonoscopy When colonoscopy w/polypectomy can no longer manage the large size & density of polyps, subtotal colectomy or proctocolectomy is performed based on polyp features & location. Mgmt of polyps is similar to that in persons w/FAP; large polyps should be excised during endoscopy. Standard treatments CRC = colorectal cancer; FAP = familial adenomatous polyposis To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Breast MRI sensitivity is greater than that of mammography for detecting breast cancer. Frequency per Spigelman criteria [ May be considered depending on local guidelines for endometrial cancer surveillance It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with In general, molecular genetic testing for See Search • Polyp resection during colonoscopy • When colonoscopy w/polypectomy can no longer manage the large size & density of polyps, subtotal colectomy or proctocolectomy is performed based on polyp features & location. • Mgmt of polyps is similar to that in persons w/FAP; large polyps should be excised during endoscopy. • Standard treatments ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CRC = colorectal cancer; MOI = mode of inheritance Breast MRI sensitivity is greater than that of mammography. Evaluation may be considered in centers that recommend surveillance for endometrial cancer. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Polyp resection during colonoscopy When colonoscopy w/polypectomy can no longer manage the large size & density of polyps, subtotal colectomy or proctocolectomy is performed based on polyp features & location. Mgmt of polyps is similar to that in persons w/FAP; large polyps should be excised during endoscopy. Standard treatments CRC = colorectal cancer; FAP = familial adenomatous polyposis • Polyp resection during colonoscopy • When colonoscopy w/polypectomy can no longer manage the large size & density of polyps, subtotal colectomy or proctocolectomy is performed based on polyp features & location. • Mgmt of polyps is similar to that in persons w/FAP; large polyps should be excised during endoscopy. • Standard treatments ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Breast MRI sensitivity is greater than that of mammography for detecting breast cancer. Frequency per Spigelman criteria [ May be considered depending on local guidelines for endometrial cancer surveillance ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with In general, molecular genetic testing for See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. To date, there is no evidence that If both parents are known to be heterozygous for an To date, there is no evidence that Unless an affected individual's reproductive partner also has Given the very low carrier frequency of Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals known to have Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • To date, there is no evidence that • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • To date, there is no evidence that • Unless an affected individual's reproductive partner also has • Given the very low carrier frequency of • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals known to have ## Mode of Inheritance The parents of an affected individual are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. To date, there is no evidence that If both parents are known to be heterozygous for an To date, there is no evidence that Unless an affected individual's reproductive partner also has Given the very low carrier frequency of • The parents of an affected individual are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • To date, there is no evidence that • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • To date, there is no evidence that • Unless an affected individual's reproductive partner also has • Given the very low carrier frequency of ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of individuals known to have • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals known to have ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • • • ## Molecular Genetics NTHL1 Tumor Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NTHL1 Tumor Syndrome ( The protein encoded by To date, all identified Individuals with loss of NTHL1 function develop tumors that have somatic pathogenic variants strongly biased toward C>T transitions, predominantly at non-CpG sites [ Variants listed in the table have been provided by the authors. This variant is common in the Dutch population but has also been observed in affected individuals from different ethnic groups, suggesting that there may be multiple independent founders. Fifteen reported families have been homozygous for this variant [ ## Molecular Pathogenesis The protein encoded by To date, all identified Individuals with loss of NTHL1 function develop tumors that have somatic pathogenic variants strongly biased toward C>T transitions, predominantly at non-CpG sites [ Variants listed in the table have been provided by the authors. This variant is common in the Dutch population but has also been observed in affected individuals from different ethnic groups, suggesting that there may be multiple independent founders. Fifteen reported families have been homozygous for this variant [ ## Chapter Notes The authors are actively involved in clinical research regarding individuals with Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) International Society for Gastrointestinal Hereditary Tumours (InSiGHT) 20 March 2025 (sw) Comprehensive updated posted live 2 April 2020 (sw) Review posted live 17 June 2019 (nh/rk) Original submission • 20 March 2025 (sw) Comprehensive updated posted live • 2 April 2020 (sw) Review posted live • 17 June 2019 (nh/rk) Original submission ## Author Notes The authors are actively involved in clinical research regarding individuals with Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) International Society for Gastrointestinal Hereditary Tumours (InSiGHT) ## Revision History 20 March 2025 (sw) Comprehensive updated posted live 2 April 2020 (sw) Review posted live 17 June 2019 (nh/rk) Original submission • 20 March 2025 (sw) Comprehensive updated posted live • 2 April 2020 (sw) Review posted live • 17 June 2019 (nh/rk) Original submission ## References ## Literature Cited	[]	2/4/2020	20/3/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
oca-oa-ov	oca-oa-ov	[ "OCA and OA", "5,6-dihydroxyindole-2-carboxylic acid oxidase", "G-protein coupled receptor 143", "L-dopachrome tautomerase", "Leucine-rich melanocyte differentiation-associated protein", "Membrane-associated transporter protein", "P protein", "Sodium/potassium/calcium exchanger 5", "Tyrosinase", "DCT", "GPR143", "LRMDA", "OCA2", "SLC24A5", "SLC45A2", "TYR", "TYRP1", "Oculocutaneous Albinism and Ocular Albinism", "Overview" ]	Oculocutaneous Albinism and Ocular Albinism Overview	Mervyn G Thomas, Jonathan Zippin, Brian P Brooks	Summary The purpose of this overview is to: Briefly describe the Review the genetic Review the Provide an Review Inform	## Clinical Characteristics of Oculocutaneous Albinism and Ocular Albinism Albinism is a genetically heterogeneous hypopigmentary disorder characterized by cutaneous and ocular hypopigmentation [ The ophthalmic manifestations associated with albinism can include the following: To identify iris TIDs it is recommended that a retroillumination technique (thin axial light beam) on slit lamp biomicroscopy be performed in a dark room. Optical coherence tomography (OCT) examination to assess iris morphology often identifies a significantly thinner posterior epithelium layer in individuals with albinism compared to controls [ Iris TIDs can be graded using classification systems for objectively documenting iris involvement [ Jerk waveforms are most frequently observed in albinism. Periodic alternating nystagmus is reported to be more common in albinism compared to other etiologies associated with infantile nystagmus [ Individuals with albinism have a null zone where the nystagmus is the least intense. Assessment of nystagmus can be observational (e.g., while carrying out ocular movement assessment) or documented using a graphic representation with eye movement recordings (EMRs). Although nystagmus is generally considered a common characteristic of albinism, absence of nystagmus has been reported in up to 7.7% of individuals with albinism [ Nystagmus associated with albinism demonstrates similar characteristics to idiopathic infantile nystagmus both with and without Anomalous head posture (AHP) is more severe in albinism compared to Fundus examination can be performed with direct or indirect ophthalmoscopy, posterior slit lamp examination, or fundus photography. Fundus hypopigmentation associated with albinism varies in severity and can be graded using a classification system for objectively documenting degree of fundal involvement [ Unaffected female carriers of Foveal hypoplasia can be graded using a system devised by A spectrum of the severity of foveal hypoplasia has been reported in individuals with albinism [ Smaller cup-to-disc ratios are frequently observed. Often there is elongation in the horizontal plane, possibly related to decussation defects [ Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ Visual evoked potentials (VEPs) can be used to aid in diagnosis by identifying chiasmal misrouting. Chiasmal misrouting has been reported in between 84% [ Esotropia is most frequently observed in albinism [ Visual acuity is assessed using age-appropriate visual acuity charts. Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ The skin and hair color of an individual with albinism may change with age (see Skin and Hair Pigmentation Scores Based on Loss of pigmentation in the skin leads to a variety of psychosocial morbidities and susceptibility to diseases of the skin. It is appropriate to classify nonsyndromic OCA according to the gene involved rather than by phenotype (i.e., extent of skin and ophthalmologic involvement). Thus, two former classifications (based on skin and ophthalmologic findings and/or mode of inheritance) are confusing and no longer valid. This is partly due to phenotypic heterogeneity in different races despite having the same genetic variants. The authors recommend that these terms no longer be used. • To identify iris TIDs it is recommended that a retroillumination technique (thin axial light beam) on slit lamp biomicroscopy be performed in a dark room. • Optical coherence tomography (OCT) examination to assess iris morphology often identifies a significantly thinner posterior epithelium layer in individuals with albinism compared to controls [ • Iris TIDs can be graded using classification systems for objectively documenting iris involvement [ • Jerk waveforms are most frequently observed in albinism. Periodic alternating nystagmus is reported to be more common in albinism compared to other etiologies associated with infantile nystagmus [ • Individuals with albinism have a null zone where the nystagmus is the least intense. • Assessment of nystagmus can be observational (e.g., while carrying out ocular movement assessment) or documented using a graphic representation with eye movement recordings (EMRs). • Although nystagmus is generally considered a common characteristic of albinism, absence of nystagmus has been reported in up to 7.7% of individuals with albinism [ • Nystagmus associated with albinism demonstrates similar characteristics to idiopathic infantile nystagmus both with and without • Anomalous head posture (AHP) is more severe in albinism compared to • Fundus examination can be performed with direct or indirect ophthalmoscopy, posterior slit lamp examination, or fundus photography. • Fundus hypopigmentation associated with albinism varies in severity and can be graded using a classification system for objectively documenting degree of fundal involvement [ • Unaffected female carriers of • Foveal hypoplasia can be graded using a system devised by • A spectrum of the severity of foveal hypoplasia has been reported in individuals with albinism [ • Smaller cup-to-disc ratios are frequently observed. • Often there is elongation in the horizontal plane, possibly related to decussation defects [ • Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ • An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ • Smaller cup-to-disc ratios are frequently observed. • Often there is elongation in the horizontal plane, possibly related to decussation defects [ • Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ • An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ • Visual evoked potentials (VEPs) can be used to aid in diagnosis by identifying chiasmal misrouting. Chiasmal misrouting has been reported in between 84% [ • Esotropia is most frequently observed in albinism [ • Visual acuity is assessed using age-appropriate visual acuity charts. • Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. • In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ • Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. • In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ • Smaller cup-to-disc ratios are frequently observed. • Often there is elongation in the horizontal plane, possibly related to decussation defects [ • Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ • An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ • Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. • In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ ## Eyes/Vision The ophthalmic manifestations associated with albinism can include the following: To identify iris TIDs it is recommended that a retroillumination technique (thin axial light beam) on slit lamp biomicroscopy be performed in a dark room. Optical coherence tomography (OCT) examination to assess iris morphology often identifies a significantly thinner posterior epithelium layer in individuals with albinism compared to controls [ Iris TIDs can be graded using classification systems for objectively documenting iris involvement [ Jerk waveforms are most frequently observed in albinism. Periodic alternating nystagmus is reported to be more common in albinism compared to other etiologies associated with infantile nystagmus [ Individuals with albinism have a null zone where the nystagmus is the least intense. Assessment of nystagmus can be observational (e.g., while carrying out ocular movement assessment) or documented using a graphic representation with eye movement recordings (EMRs). Although nystagmus is generally considered a common characteristic of albinism, absence of nystagmus has been reported in up to 7.7% of individuals with albinism [ Nystagmus associated with albinism demonstrates similar characteristics to idiopathic infantile nystagmus both with and without Anomalous head posture (AHP) is more severe in albinism compared to Fundus examination can be performed with direct or indirect ophthalmoscopy, posterior slit lamp examination, or fundus photography. Fundus hypopigmentation associated with albinism varies in severity and can be graded using a classification system for objectively documenting degree of fundal involvement [ Unaffected female carriers of Foveal hypoplasia can be graded using a system devised by A spectrum of the severity of foveal hypoplasia has been reported in individuals with albinism [ Smaller cup-to-disc ratios are frequently observed. Often there is elongation in the horizontal plane, possibly related to decussation defects [ Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ Visual evoked potentials (VEPs) can be used to aid in diagnosis by identifying chiasmal misrouting. Chiasmal misrouting has been reported in between 84% [ Esotropia is most frequently observed in albinism [ Visual acuity is assessed using age-appropriate visual acuity charts. Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ • To identify iris TIDs it is recommended that a retroillumination technique (thin axial light beam) on slit lamp biomicroscopy be performed in a dark room. • Optical coherence tomography (OCT) examination to assess iris morphology often identifies a significantly thinner posterior epithelium layer in individuals with albinism compared to controls [ • Iris TIDs can be graded using classification systems for objectively documenting iris involvement [ • Jerk waveforms are most frequently observed in albinism. Periodic alternating nystagmus is reported to be more common in albinism compared to other etiologies associated with infantile nystagmus [ • Individuals with albinism have a null zone where the nystagmus is the least intense. • Assessment of nystagmus can be observational (e.g., while carrying out ocular movement assessment) or documented using a graphic representation with eye movement recordings (EMRs). • Although nystagmus is generally considered a common characteristic of albinism, absence of nystagmus has been reported in up to 7.7% of individuals with albinism [ • Nystagmus associated with albinism demonstrates similar characteristics to idiopathic infantile nystagmus both with and without • Anomalous head posture (AHP) is more severe in albinism compared to • Fundus examination can be performed with direct or indirect ophthalmoscopy, posterior slit lamp examination, or fundus photography. • Fundus hypopigmentation associated with albinism varies in severity and can be graded using a classification system for objectively documenting degree of fundal involvement [ • Unaffected female carriers of • Foveal hypoplasia can be graded using a system devised by • A spectrum of the severity of foveal hypoplasia has been reported in individuals with albinism [ • Smaller cup-to-disc ratios are frequently observed. • Often there is elongation in the horizontal plane, possibly related to decussation defects [ • Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ • An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ • Smaller cup-to-disc ratios are frequently observed. • Often there is elongation in the horizontal plane, possibly related to decussation defects [ • Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ • An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ • Visual evoked potentials (VEPs) can be used to aid in diagnosis by identifying chiasmal misrouting. Chiasmal misrouting has been reported in between 84% [ • Esotropia is most frequently observed in albinism [ • Visual acuity is assessed using age-appropriate visual acuity charts. • Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. • In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ • Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. • In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ • Smaller cup-to-disc ratios are frequently observed. • Often there is elongation in the horizontal plane, possibly related to decussation defects [ • Reduction of the thickness of the peripapillary retinal nerve fiber layer (the temporal quadrant being most significantly affected) is a highly consistent finding [ • An appearance of elevation, as a small cupless disc or oblique cup with situs inversus [ • Visual acuity is expressed as a fraction in which the numerator represents the distance at which the test was conducted. For example, visual acuity of 20/80 means that the individual can read at 20 feet what a person with normal vision can read at 80 feet. Visual acuity of 20/80 in the United States would correspond to visual acuity of 6/24 in in the United Kingdom, where meters are the unit of measurement. • In persons with albinism, visual acuity can range between -0.10 to 1.60 logMAR acuity [ ## Cutaneous Manifestations The skin and hair color of an individual with albinism may change with age (see Skin and Hair Pigmentation Scores Based on Loss of pigmentation in the skin leads to a variety of psychosocial morbidities and susceptibility to diseases of the skin. ## Nomenclature It is appropriate to classify nonsyndromic OCA according to the gene involved rather than by phenotype (i.e., extent of skin and ophthalmologic involvement). Thus, two former classifications (based on skin and ophthalmologic findings and/or mode of inheritance) are confusing and no longer valid. This is partly due to phenotypic heterogeneity in different races despite having the same genetic variants. The authors recommend that these terms no longer be used. ## Genetic Causes of Oculocutaneous Albinism and Ocular Albinism Nonsyndromic Oculocutaneous Albinism and Ocular Albinism by Gene OCA1A: absence or complete inactivity of TYR enzyme; severe reduction of retinal, iris, & skin pigmentation OCA1B: reduced TYR enzyme activity (due to hypomorphic Phenotypic spectrum incl "brown" OCA. Phenotype (previously described as "rufous" albinism) is characterized by red-bronze skin color, ginger-red hair, & blue or brown irides. OCA3 is more common in African populations than in other populations (e.g., South Asian, European). Most common OCA in Japan Few affected persons have cutaneous & ocular hypopigmentation; most have normal visual acuity & foveal structure. Ocular features overlap w/other forms of OCA. Typically, skin is hypopigmented w/ability to tan in some persons. Hair color can range from white to brown. Only a few affected persons have been reported. Significant phenotypic overlap exists w/other forms of OCA. Clinically, only ocular hypopigmentation is present. However, the ocular phenotype of OA & OCA overlap. In heterozygous females (i.e., carriers), "mud-splattered" fundus has been described due to interspersed regions of pigmentation. OA = ocular albinism; OCA = oculocutaneous albinism Where applicable, former gene symbols are listed in parenthesis after the current Genes are ordered by frequency of causation of OCA [ "Brown" OCA, described initially in Nigeria and Ghana and considered a separate entity based on early family studies, is now known to be part of the phenotypic continuum of Syndromic Oculocutaneous Albinism: Genes and Distinguishing Clinical Features Nearly all children w/HPS-related albinism have infantile nystagmus. Hair color ranges from white to brown. Skin color is generally at least a shade lighter than that of other family members. Only grades 3 & 4 foveal hypoplasia have been observed w/reduced visual acuity. Bleeding diathesis In some persons, pulmonary fibrosis, granulomatous colitis, or immunodeficiency Skin hypopigmentation w/characteristic silvery-gray hair Ocular features are variable. GS1: + neurologic deficits but no immunologic dysfunction GS2: ± neurologic deficits; + immunologic dysfunction GS3: no neurologic or immunologic deficits Syndromes listed in • OCA1A: absence or complete inactivity of TYR enzyme; severe reduction of retinal, iris, & skin pigmentation • OCA1B: reduced TYR enzyme activity (due to hypomorphic • Phenotypic spectrum incl "brown" OCA. • Phenotype (previously described as "rufous" albinism) is characterized by red-bronze skin color, ginger-red hair, & blue or brown irides. • OCA3 is more common in African populations than in other populations (e.g., South Asian, European). • Most common OCA in Japan • Few affected persons have cutaneous & ocular hypopigmentation; most have normal visual acuity & foveal structure. • Ocular features overlap w/other forms of OCA. • Typically, skin is hypopigmented w/ability to tan in some persons. • Hair color can range from white to brown. • Only a few affected persons have been reported. • Significant phenotypic overlap exists w/other forms of OCA. • Clinically, only ocular hypopigmentation is present. However, the ocular phenotype of OA & OCA overlap. • In heterozygous females (i.e., carriers), "mud-splattered" fundus has been described due to interspersed regions of pigmentation. • Nearly all children w/HPS-related albinism have infantile nystagmus. • Hair color ranges from white to brown. • Skin color is generally at least a shade lighter than that of other family members. • Only grades 3 & 4 foveal hypoplasia have been observed w/reduced visual acuity. • Bleeding diathesis • In some persons, pulmonary fibrosis, granulomatous colitis, or immunodeficiency • Skin hypopigmentation w/characteristic silvery-gray hair • Ocular features are variable. • GS1: + neurologic deficits but no immunologic dysfunction • GS2: ± neurologic deficits; + immunologic dysfunction • GS3: no neurologic or immunologic deficits ## Differential Diagnosis of Ocular Findings in Oculocutaneous Albinism and Ocular Albinism Disorders with Ophthalmologic Findings Overlapping Those of Nonsyndromic Oculocutaneous Albinism and Ocular Albinism AD = autosomal dominant; AR = autosomal recessive; ERG = electroretinogram; MOI = mode of inheritance; XL = X-linked To date, variants in 24 genes account for 70%-80% of individuals with Leber congenital amaurosis / early-onset severe retinal dystrophy. More commonly involved genes are listed in Oculodigital sign refers to poking, rubbing, and/or pressing of the eyes. ## Evaluation Strategies to Identify the Genetic Cause of Oculocutaneous Albinism or Ocular Albinism in a Proband Establishing a specific genetic cause of oculocutaneous albinism (OCA) or ocular albinism (OA) in a proband: Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing; Can influence treatments and surveillance of disease, particularly in syndromic forms of OCA due to implications to systemic health. Individuals with OCA often present with infantile nystagmus, poor vision, and hypopigmentation (see Identifying manifestations suggestive of syndromic forms of OCA is important, as management differs between nonsyndromic OCA (see Immune dysfunction Bleeding diathesis, including easy bruising, epistaxis, and prolonged bleeding after minor procedures or surgery Neurologic deficits such as developmental delay / intellectual disability and seizures Pulmonary fibrosis and granulomatous colitis Detailed ophthalmologic evaluation should include refraction, best corrected visual acuity, ocular motility (strabismus and nystagmus characteristics), measurement of anomalous head posture, slit lamp examination and/or optical coherence tomography (OCT) to detect iris transillumination defects (TIDs), assessment of fundus hypopigmentation, characterization of foveal morphology using OCT, and optic nerve misrouting using visual evoked potentials (VEPs) (see Clinical Characteristics, Examining parents of children with OCA can also be helpful, as they may exhibit subclinical features such as low grades of iris TIDs, fundus hypopigmentation, and foveal hypoplasia [ Similarly, unaffected female carriers of Due to the shared ocular and cutaneous phenotypic characteristics, differentiating between syndromic and nonsyndromic OCA can be challenging (see A three-generation family history should be taken, with attention to relatives with manifestations of OCA or OA. Note that relevant findings can be documented through direct examination and/or review of medical records, including results of molecular genetic testing. A family history consistent with X-linked inheritance (e.g., no male-to-male transmission) may be helpful in differentiating nonsyndromic Molecular genetic testing approaches can include a combination of targeted testing (multigene panel and chromosomal microarray to detect recurrent deletions) and comprehensive genomic testing (exome sequencing or genome sequencing). Gene-targeted testing (see For an introduction to multigene panels click Note: (1) The most common For an introduction to CMA click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing; • Can influence treatments and surveillance of disease, particularly in syndromic forms of OCA due to implications to systemic health. • Immune dysfunction • Bleeding diathesis, including easy bruising, epistaxis, and prolonged bleeding after minor procedures or surgery • Neurologic deficits such as developmental delay / intellectual disability and seizures • Pulmonary fibrosis and granulomatous colitis ## Medical History Individuals with OCA often present with infantile nystagmus, poor vision, and hypopigmentation (see Identifying manifestations suggestive of syndromic forms of OCA is important, as management differs between nonsyndromic OCA (see Immune dysfunction Bleeding diathesis, including easy bruising, epistaxis, and prolonged bleeding after minor procedures or surgery Neurologic deficits such as developmental delay / intellectual disability and seizures Pulmonary fibrosis and granulomatous colitis • Immune dysfunction • Bleeding diathesis, including easy bruising, epistaxis, and prolonged bleeding after minor procedures or surgery • Neurologic deficits such as developmental delay / intellectual disability and seizures • Pulmonary fibrosis and granulomatous colitis ## Physical Examination and Clinic-Based Investigations Detailed ophthalmologic evaluation should include refraction, best corrected visual acuity, ocular motility (strabismus and nystagmus characteristics), measurement of anomalous head posture, slit lamp examination and/or optical coherence tomography (OCT) to detect iris transillumination defects (TIDs), assessment of fundus hypopigmentation, characterization of foveal morphology using OCT, and optic nerve misrouting using visual evoked potentials (VEPs) (see Clinical Characteristics, Examining parents of children with OCA can also be helpful, as they may exhibit subclinical features such as low grades of iris TIDs, fundus hypopigmentation, and foveal hypoplasia [ Similarly, unaffected female carriers of Due to the shared ocular and cutaneous phenotypic characteristics, differentiating between syndromic and nonsyndromic OCA can be challenging (see ## Family History A three-generation family history should be taken, with attention to relatives with manifestations of OCA or OA. Note that relevant findings can be documented through direct examination and/or review of medical records, including results of molecular genetic testing. A family history consistent with X-linked inheritance (e.g., no male-to-male transmission) may be helpful in differentiating nonsyndromic ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of targeted testing (multigene panel and chromosomal microarray to detect recurrent deletions) and comprehensive genomic testing (exome sequencing or genome sequencing). Gene-targeted testing (see For an introduction to multigene panels click Note: (1) The most common For an introduction to CMA click For an introduction to comprehensive genomic testing click ## Option 1 For an introduction to multigene panels click Note: (1) The most common For an introduction to CMA click ## Option 2 For an introduction to comprehensive genomic testing click ## Management At present, no curative treatments are available for albinism. Supportive treatments are aimed at optimizing vision, managing clinical manifestations (e.g., nystagmus), and reducing risks of complications of cutaneous albinism (e.g., skin cancer). Because anisometropic and ametropic amblyopia may develop in children with albinism, prompt correction of refractive errors in children to reduce risk for amblyopia is essential. If amblyopia is present following a refractive adaptation period of 16-18 weeks, occlusion therapy should commence. Optical coherence tomography is useful in characterizing retinal development based on foveal hypoplasia grades (see Low vision aids may be useful in some individuals with albinism; these are typically issued following full refractive correction. Magnification apparatuses such as telescopes and near magnifiers may be used in individuals with significantly reduced visual acuity [ The evidence for the use of contact lenses to improve characteristics of nystagmus is unclear. A hat with a brim may be helpful to reduce overhead glare and, importantly, provide some sun protection for the face. Other approaches to alleviate glare described in the literature with either limited success or complications arising from the intervention include surgical implants or various designs of modified contact lenses. Because the evidence level is restricted to case reports, these interventions are not recommended. Individuals with cutaneous albinism are encouraged to have complete skin examinations at least yearly to identify evidence of sun damage or early signs of skin cancer. At these visits, education regarding methods of sun protection is stressed, including the following: Wearing sun-protective clothing (wide-brimmed hats, long-sleeve shirts, and long pants) with at least a sun protection factor (SPF) of 15 Application of sunscreens, and avoidance of midday sun exposure if possible [ The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. In most circumstances, especially when the parents do not have albinism, children with albinism are referred to a pediatric dermatologist at a young age to ensure that parents and family members are properly educated regarding sun protection. It is problematic for individuals with albinism to self-monitor their skin. Whereas skin cancers such as squamous cell carcinoma and basal cell carcinoma are clinically the same in individuals with normal pigmentation and in individuals with albinism, melanoma is different. Melanoma, the most dangerous of all skin cancers, is clinically diagnosed based on changes in pigmentation patterns [ The following information represents typical management recommendations for children of school age with educational issues related to decreased visual acuity. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, use of magnifiers, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Ophthalmologic examination (including assessment of refractive errors; strabismus and/or anomalous head posture; and the need for filter glasses) Assessment of psychosocial needs and support Assessment of educational needs and support For adults, the following evaluations are recommended: Ophthalmologic examinations as needed Review in a low vision clinic as needed Prolonged unprotected sun exposure should be avoided. • The evidence for the use of contact lenses to improve characteristics of nystagmus is unclear. • Wearing sun-protective clothing (wide-brimmed hats, long-sleeve shirts, and long pants) with at least a sun protection factor (SPF) of 15 • Application of sunscreens, and avoidance of midday sun exposure if possible [ • The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. • Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. • In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. • The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. • Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. • In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. • The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. • Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. • In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, use of magnifiers, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Ophthalmologic examination (including assessment of refractive errors; strabismus and/or anomalous head posture; and the need for filter glasses) • Assessment of psychosocial needs and support • Assessment of educational needs and support • Ophthalmologic examinations as needed • Review in a low vision clinic as needed ## Eyes/Vision Because anisometropic and ametropic amblyopia may develop in children with albinism, prompt correction of refractive errors in children to reduce risk for amblyopia is essential. If amblyopia is present following a refractive adaptation period of 16-18 weeks, occlusion therapy should commence. Optical coherence tomography is useful in characterizing retinal development based on foveal hypoplasia grades (see Low vision aids may be useful in some individuals with albinism; these are typically issued following full refractive correction. Magnification apparatuses such as telescopes and near magnifiers may be used in individuals with significantly reduced visual acuity [ The evidence for the use of contact lenses to improve characteristics of nystagmus is unclear. A hat with a brim may be helpful to reduce overhead glare and, importantly, provide some sun protection for the face. Other approaches to alleviate glare described in the literature with either limited success or complications arising from the intervention include surgical implants or various designs of modified contact lenses. Because the evidence level is restricted to case reports, these interventions are not recommended. • The evidence for the use of contact lenses to improve characteristics of nystagmus is unclear. ## Skin Individuals with cutaneous albinism are encouraged to have complete skin examinations at least yearly to identify evidence of sun damage or early signs of skin cancer. At these visits, education regarding methods of sun protection is stressed, including the following: Wearing sun-protective clothing (wide-brimmed hats, long-sleeve shirts, and long pants) with at least a sun protection factor (SPF) of 15 Application of sunscreens, and avoidance of midday sun exposure if possible [ The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. In most circumstances, especially when the parents do not have albinism, children with albinism are referred to a pediatric dermatologist at a young age to ensure that parents and family members are properly educated regarding sun protection. It is problematic for individuals with albinism to self-monitor their skin. Whereas skin cancers such as squamous cell carcinoma and basal cell carcinoma are clinically the same in individuals with normal pigmentation and in individuals with albinism, melanoma is different. Melanoma, the most dangerous of all skin cancers, is clinically diagnosed based on changes in pigmentation patterns [ • Wearing sun-protective clothing (wide-brimmed hats, long-sleeve shirts, and long pants) with at least a sun protection factor (SPF) of 15 • Application of sunscreens, and avoidance of midday sun exposure if possible [ • The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. • Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. • In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. • The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. • Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. • In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. • The general recommendation is application of sunscreen (which is at least SPF 15) every two hours to exposed skin. Although sunscreen with a higher SPF can be applied less often, adhering to a regimen of every two hours is still recommended. Of note, SPF levels above 30 tend to provide little additional protection. • Sunscreen comes in two different options based on the mechanism of sun protection: chemical blockers (e.g., oxybenzone, avobenzone) and physical blockers (e.g., titanium oxide, zinc oxide). In general, although the efficacy of these two options is relatively the same, use of chemical blockers is becoming restricted because of their effects on hormone-related biology and toxicity to coral reefs. • In addition to prevention of skin cancers, sun avoidance and use of sunscreen can also prevent early signs of sun damage and solar aging. ## Educational Management The following information represents typical management recommendations for children of school age with educational issues related to decreased visual acuity. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, use of magnifiers, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, use of magnifiers, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance Ophthalmologic examination (including assessment of refractive errors; strabismus and/or anomalous head posture; and the need for filter glasses) Assessment of psychosocial needs and support Assessment of educational needs and support For adults, the following evaluations are recommended: Ophthalmologic examinations as needed Review in a low vision clinic as needed • Ophthalmologic examination (including assessment of refractive errors; strabismus and/or anomalous head posture; and the need for filter glasses) • Assessment of psychosocial needs and support • Assessment of educational needs and support • Ophthalmologic examinations as needed • Review in a low vision clinic as needed ## Agents/Circumstances to Avoid Prolonged unprotected sun exposure should be avoided. ## Genetic Counseling Nonsyndromic oculocutaneous albinism (OCA) caused by pathogenic variants in Ocular albinism (OA) caused by pathogenic variants in If an individual has a specific syndrome associated with OCA (e.g., The parents of an affected child are presumed to be heterozygous for an OCA-causing pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an OCA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an OCA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has a Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Note: Molecular genetic testing may be able to identify the family member in whom a Note: Females who are heterozygotes (carriers) for this X-linked disorder will be heterozygotes and will usually not be affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the OCA- or OA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an OCA-causing pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an OCA-causing pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an OCA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ • If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Nonsyndromic oculocutaneous albinism (OCA) caused by pathogenic variants in Ocular albinism (OA) caused by pathogenic variants in If an individual has a specific syndrome associated with OCA (e.g., ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are presumed to be heterozygous for an OCA-causing pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an OCA-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an OCA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an OCA-causing pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an OCA-causing pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an OCA-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has a Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Note: Molecular genetic testing may be able to identify the family member in whom a Note: Females who are heterozygotes (carriers) for this X-linked disorder will be heterozygotes and will usually not be affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ • If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes (i.e., carriers). Heterozygotes are usually not affected, although they can exhibit iris transillumination defects, a "mud-splattered" fundus appearance, and foveal hypoplasia [ ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the OCA- or OA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • United Kingdom • ## Chapter Notes Mervyn Thomas's Jonathan Zippin's Brian Brooks's The authors thank the patients, families, and support groups that volunteer their time and engage in research to further our understanding of albinism. The authors thank their research teams, including the Ulverscroft Eye Unit (University of Leicester, UK), Zippin Lab (Weill Cornell Medical College of Cornell University, USA), and the National Eye Institute (NIH, USA). MT gratefully acknowledges the support from the National Institute for Health Research (CL-2017-11-003), Medical Research Council, Wellcome Trust, Fight for Sight, Ulverscroft Foundation, and the Academy of Medical Sciences. JZ gratefully acknowledges the support from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (R01-AR077664). BB gratefully acknowledges the support from the Intramural Program at the National Eye Institute, National Institutes of Health. 13 April 2023 (bp) Review posted live 30 November 2022 (mt) Original submission • 13 April 2023 (bp) Review posted live • 30 November 2022 (mt) Original submission ## Author Notes Mervyn Thomas's Jonathan Zippin's Brian Brooks's ## Acknowledgments The authors thank the patients, families, and support groups that volunteer their time and engage in research to further our understanding of albinism. The authors thank their research teams, including the Ulverscroft Eye Unit (University of Leicester, UK), Zippin Lab (Weill Cornell Medical College of Cornell University, USA), and the National Eye Institute (NIH, USA). MT gratefully acknowledges the support from the National Institute for Health Research (CL-2017-11-003), Medical Research Council, Wellcome Trust, Fight for Sight, Ulverscroft Foundation, and the Academy of Medical Sciences. JZ gratefully acknowledges the support from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (R01-AR077664). BB gratefully acknowledges the support from the Intramural Program at the National Eye Institute, National Institutes of Health. ## Revision History 13 April 2023 (bp) Review posted live 30 November 2022 (mt) Original submission • 13 April 2023 (bp) Review posted live • 30 November 2022 (mt) Original submission ## References ## Literature Cited (A) Illustration of the unique features of a normal fovea detectable on optical coherence tomography. (B) Illustration of typical and atypical grades of foveal hypoplasia. All grades of foveal hypoplasia have incursion of inner retinal layers. Atypical foveal hypoplasia also has incursion of the inner retinal layers. In OCA all four grades of foveal hypoplasia are observed; however, in OA and Grade 1: shallow foveal pit (near-normal pit in grade 1a vs shallow indent in grade 1b), outer nuclear layer (ONL) widening, and outer segment (OS) lengthening relative to the parafoveal ONL and OS length, respectively Grade 2: all the features of grade 1 present except the presence of a foveal pit Grade 3: all the features of grade 2 present except the widening of the cone OS Grade 4: all the features of grade 3 are present except no widening of the ONL at the fovea Atypical foveal hypoplasia: shallower foveal pit with disruption of the inner segment ellipsoid (Note: Not observed in albinism, but seen in other retinal disorders such as Adapted with permission from	[]	13/4/2023			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
oca1	oca1	[ "OCA1", "OCA1", "Oculocutaneous Albinism Type 1A (OCA1A)", "Oculocutaneous Albinism Type 1B (OCA1B)", "Tyrosinase", "TYR", "Oculocutaneous Albinism Type 1" ]	Oculocutaneous Albinism Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Richard Alan Lewis	Summary NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE. Oculocutaneous albinism type 1 (OCA1) is characterized by hypopigmentation of the skin and hair and the distinctive ocular changes found in all types of albinism, including: nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia with substantial reduction in visual acuity, usually in the range of 20/100 to 20/400; and misrouting of the optic nerve fiber radiations at the chiasm, resulting in strabismus, reduced stereoscopic vision, and altered visually evoked potentials (VEP). Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irides, none of which darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens minimally with age, white skin that over time develops some minimal generalized pigment and may tan slightly with judicious sun exposure, and blue irides that darken to green/hazel or light brown/tan with age, although transillumination defects persist. Visual acuity may be 20/60 or better in some eyes. The diagnosis of OCA1 is established by clinical findings of profound hypopigmentation of the skin and hair and characteristic ocular findings. Molecular genetic testing of Protection from sun exposure with appropriate skin-covering clothing and sunscreens prevents burning, consequent skin damage, and the enhanced risk of skin cancer. Skin cancer, including a slightly enhanced risk for cutaneous melanoma, is treated as for the general population. OCA1 is inherited in an autosomal recessive manner. In most situations, the parents of an affected individual are obligate heterozygotes, and therefore each carries one mutated allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible when both pathogenic variants in an affected family member are known.	Oculocutaneous albinism type 1A (OCA1A) Oculocutaneous albinism type 1B (OCA1B) For synonyms and outdated names see • Oculocutaneous albinism type 1A (OCA1A) • Oculocutaneous albinism type 1B (OCA1B) ## Diagnosis The diagnosis of oculocutaneous albinism type 1 (OCA1) [ Hypopigmentation of the skin and hair (including brows and lashes) on physical examination Infantile nystagmus (usually noticed between ages 3 and 12 weeks) Markedly reduced iris pigment with iris transillumination Reduced retinal (pigment epithelial) pigmentation with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with substantial reduction in visual acuity Misrouting of the optic nerve fiber projections at the optic chiasm frequently associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visually evoked potentials (VEP) Note: The VEP is performed with a technique specifically designed to demonstrate selective misrouting; thus, a conventional simultaneous binocular VEP will not demonstrate this anomaly. Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. The VEP is not necessary for the diagnosis of albinism because misrouting is implied by the observation of strabismus and reduced stereoscopic vision. In some persons with mild hypopigmentation (a few with OCA1B) and foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections [ Most individuals with OCA1 are compound heterozygotes with different paternal and maternal Evidence that additional undetected pathogenic variants are responsible for OCA1 comes from individuals with the OCA1A phenotype with only a single identifiable pathogenic variant, but who are likely to be compound heterozygotes with a second, as-yet unidentified, pathogenic variant. Molecular Genetic Testing Used in OCA1 See See Data are only estimates only, based on clinical, assumed diagnoses. In early life, often before age one year, it is difficult to distinguish OCA1A from OCA1B. Other forms of OCA2-4 may result in light pigmentation that may be difficult to distinguish from OCA1, especially OCA1B. Mild forms of albinism are underdiagnosed and confused with other forms of early-onset, infantile nystagmus. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic.Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In some populations, laboratories may only sequence select exons or specific targeted variants This estimate includes individuals who may have milder forms of oculocutaneous albinism (caused by pathogenic variants in genes other than Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Large deletions are quite rare ( • Hypopigmentation of the skin and hair (including brows and lashes) on physical examination • Infantile nystagmus (usually noticed between ages 3 and 12 weeks) • Markedly reduced iris pigment with iris transillumination • Reduced retinal (pigment epithelial) pigmentation with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with substantial reduction in visual acuity • Misrouting of the optic nerve fiber projections at the optic chiasm frequently associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visually evoked potentials (VEP) • Note: The VEP is performed with a technique specifically designed to demonstrate selective misrouting; thus, a conventional simultaneous binocular VEP will not demonstrate this anomaly. Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. The VEP is not necessary for the diagnosis of albinism because misrouting is implied by the observation of strabismus and reduced stereoscopic vision. In some persons with mild hypopigmentation (a few with OCA1B) and foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections [ ## Clinical Diagnosis The diagnosis of oculocutaneous albinism type 1 (OCA1) [ Hypopigmentation of the skin and hair (including brows and lashes) on physical examination Infantile nystagmus (usually noticed between ages 3 and 12 weeks) Markedly reduced iris pigment with iris transillumination Reduced retinal (pigment epithelial) pigmentation with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with substantial reduction in visual acuity Misrouting of the optic nerve fiber projections at the optic chiasm frequently associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visually evoked potentials (VEP) Note: The VEP is performed with a technique specifically designed to demonstrate selective misrouting; thus, a conventional simultaneous binocular VEP will not demonstrate this anomaly. Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. The VEP is not necessary for the diagnosis of albinism because misrouting is implied by the observation of strabismus and reduced stereoscopic vision. In some persons with mild hypopigmentation (a few with OCA1B) and foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections [ • Hypopigmentation of the skin and hair (including brows and lashes) on physical examination • Infantile nystagmus (usually noticed between ages 3 and 12 weeks) • Markedly reduced iris pigment with iris transillumination • Reduced retinal (pigment epithelial) pigmentation with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with substantial reduction in visual acuity • Misrouting of the optic nerve fiber projections at the optic chiasm frequently associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visually evoked potentials (VEP) • Note: The VEP is performed with a technique specifically designed to demonstrate selective misrouting; thus, a conventional simultaneous binocular VEP will not demonstrate this anomaly. Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. The VEP is not necessary for the diagnosis of albinism because misrouting is implied by the observation of strabismus and reduced stereoscopic vision. In some persons with mild hypopigmentation (a few with OCA1B) and foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections [ ## Molecular Genetic Testing Most individuals with OCA1 are compound heterozygotes with different paternal and maternal Evidence that additional undetected pathogenic variants are responsible for OCA1 comes from individuals with the OCA1A phenotype with only a single identifiable pathogenic variant, but who are likely to be compound heterozygotes with a second, as-yet unidentified, pathogenic variant. Molecular Genetic Testing Used in OCA1 See See Data are only estimates only, based on clinical, assumed diagnoses. In early life, often before age one year, it is difficult to distinguish OCA1A from OCA1B. Other forms of OCA2-4 may result in light pigmentation that may be difficult to distinguish from OCA1, especially OCA1B. Mild forms of albinism are underdiagnosed and confused with other forms of early-onset, infantile nystagmus. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic.Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In some populations, laboratories may only sequence select exons or specific targeted variants This estimate includes individuals who may have milder forms of oculocutaneous albinism (caused by pathogenic variants in genes other than Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Large deletions are quite rare ( ## Testing Strategy ## Clinical Characteristics Individuals with all variations of OCA1 have white or nearly white scalp hair, brows, and lashes; white skin; and blue irides with extensive transillumination at birth. The presence of white scalp hair at birth should not be the exclusive clinical criterion for OCA1 because some persons with OCA2 may seem exceedingly fair in the first six to twelve months of life as well. The claim of "white" scalp hair is not universally understood in some infants because of sparse, short hair, and because of the discoloration that occurs with some yellow-tinted shampoos. Parents may describe hair that is light yellow/blond as "white." In families with darker constitutional pigmentation, the white hair and skin are an immediate indication of hypopigmentation, and the diagnosis of OCA1 may be suspected at birth. In families with lighter constitutional pigmentation, the presence of a "towheaded" child may not seem unusual and the diagnosis of oculocutaneous albinism may be suspected only after the ocular findings of nystagmus, photodysphoria, and reduced visual function are noted. Indeed, the initial diagnosis of oculocutaneous albinism may be delayed into adolescence until confirmed by an ophthalmologist aware of the spectrum of its clinical features. Rarely, children with albinism have been reported to have nystagmus at birth; however, most children with albinism develop nystagmus between ages three weeks and three months. The nystagmus can be very rapid in early life but its speed and amplitude generally slow with time; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when an individual is tired, ill, or anxious, and less marked when s/he is well rested. Many years of unprotected exposure to solar radiation of lightly pigmented skin may result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer, both basal cell carcinoma and squamous cell carcinoma. Melanoma is rare in individuals with OCA, but may occur because dermal melanocytes are present. Skin cancer is unusual in individuals with OCA1 in the US because of the availability of sunscreens, the social acceptability of wearing clothes that cover most of the exposed skin, and the reality that individuals with albinism can be educated to minimize unprotected solar exposure. In regions of the planet where solar exposure is extensive and sunscreen difficult to obtain, the malignant cutaneous manifestations of oculocutaneous albinism are life-shortening. OCA1 is divided into two categories: OCA1A, associated with no melanin synthesis in any tissue, and OCA1B, associated with minimal amounts of melanin synthesis in the hair, skin, and eyes. The ocular features of OCA1A and OCA1B are identical except for the amount of iris pigment. The skin color remains white and burns in prolonged solar exposure but may develop some generalized tan. Lightly pigmented nevi and freckles appear with time. Iris color may remain blue or change slowly in adolescence to a green/hazel or light tan color. Fine granular pigment may develop in the retina. The evolution of pigment in the iris and/or retina does not affect the nystagmus, which persists throughout life but does tend to dampen in speed and amplitude with age. Best corrected visual acuity is usually between 20/100 and 20/200, and tends to improve slowly until the late teens. Some affected individuals report modest improvements in visual acuity over time; however, part of the response may be improved understanding of the ophthalmic acuity tests with maturation of the child. No longitudinal data have been published to firmly assess the frequency or extent of visual "improvement" over time. It is critically important that all parents of affected children realize that, although visually impaired, children with albinism never lose the visual acuity that they achieve, unless an intervening event such as amblyopia occurs. OCA1A is the classic "tyrosinase-negative" OCA phenotype, but the term "tyrosinase-negative OCA" should no longer be used. In the past, numerous clinical descriptions have attempted to quantitate the amount of pigment in persons with OCA, such as minimal pigment OCA, platinum OCA, temperature-sensitive OCA, and yellow OCA. Still, no universal nomenclature has been established for the various levels of pigmentation resulting from combinations of hypomorphic alleles and, indeed, the overlap of clinical phenotypes with variants of OCA2. OCA1 is estimated to occur at a frequency of approximately 1/40,000 in most populations throughout the world. Most individuals with OCA1 identified to date are those with OCA1A who are diagnosed by the obvious phenotype. The frequency of OCA1B is unknown. The calculated carrier frequency for OCA1 is approximately 1/100 in most populations. • The skin color remains white and burns in prolonged solar exposure but may develop some generalized tan. Lightly pigmented nevi and freckles appear with time. • Iris color may remain blue or change slowly in adolescence to a green/hazel or light tan color. Fine granular pigment may develop in the retina. The evolution of pigment in the iris and/or retina does not affect the nystagmus, which persists throughout life but does tend to dampen in speed and amplitude with age. Best corrected visual acuity is usually between 20/100 and 20/200, and tends to improve slowly until the late teens. ## Clinical Description Individuals with all variations of OCA1 have white or nearly white scalp hair, brows, and lashes; white skin; and blue irides with extensive transillumination at birth. The presence of white scalp hair at birth should not be the exclusive clinical criterion for OCA1 because some persons with OCA2 may seem exceedingly fair in the first six to twelve months of life as well. The claim of "white" scalp hair is not universally understood in some infants because of sparse, short hair, and because of the discoloration that occurs with some yellow-tinted shampoos. Parents may describe hair that is light yellow/blond as "white." In families with darker constitutional pigmentation, the white hair and skin are an immediate indication of hypopigmentation, and the diagnosis of OCA1 may be suspected at birth. In families with lighter constitutional pigmentation, the presence of a "towheaded" child may not seem unusual and the diagnosis of oculocutaneous albinism may be suspected only after the ocular findings of nystagmus, photodysphoria, and reduced visual function are noted. Indeed, the initial diagnosis of oculocutaneous albinism may be delayed into adolescence until confirmed by an ophthalmologist aware of the spectrum of its clinical features. Rarely, children with albinism have been reported to have nystagmus at birth; however, most children with albinism develop nystagmus between ages three weeks and three months. The nystagmus can be very rapid in early life but its speed and amplitude generally slow with time; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when an individual is tired, ill, or anxious, and less marked when s/he is well rested. Many years of unprotected exposure to solar radiation of lightly pigmented skin may result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer, both basal cell carcinoma and squamous cell carcinoma. Melanoma is rare in individuals with OCA, but may occur because dermal melanocytes are present. Skin cancer is unusual in individuals with OCA1 in the US because of the availability of sunscreens, the social acceptability of wearing clothes that cover most of the exposed skin, and the reality that individuals with albinism can be educated to minimize unprotected solar exposure. In regions of the planet where solar exposure is extensive and sunscreen difficult to obtain, the malignant cutaneous manifestations of oculocutaneous albinism are life-shortening. OCA1 is divided into two categories: OCA1A, associated with no melanin synthesis in any tissue, and OCA1B, associated with minimal amounts of melanin synthesis in the hair, skin, and eyes. The ocular features of OCA1A and OCA1B are identical except for the amount of iris pigment. The skin color remains white and burns in prolonged solar exposure but may develop some generalized tan. Lightly pigmented nevi and freckles appear with time. Iris color may remain blue or change slowly in adolescence to a green/hazel or light tan color. Fine granular pigment may develop in the retina. The evolution of pigment in the iris and/or retina does not affect the nystagmus, which persists throughout life but does tend to dampen in speed and amplitude with age. Best corrected visual acuity is usually between 20/100 and 20/200, and tends to improve slowly until the late teens. Some affected individuals report modest improvements in visual acuity over time; however, part of the response may be improved understanding of the ophthalmic acuity tests with maturation of the child. No longitudinal data have been published to firmly assess the frequency or extent of visual "improvement" over time. It is critically important that all parents of affected children realize that, although visually impaired, children with albinism never lose the visual acuity that they achieve, unless an intervening event such as amblyopia occurs. • The skin color remains white and burns in prolonged solar exposure but may develop some generalized tan. Lightly pigmented nevi and freckles appear with time. • Iris color may remain blue or change slowly in adolescence to a green/hazel or light tan color. Fine granular pigment may develop in the retina. The evolution of pigment in the iris and/or retina does not affect the nystagmus, which persists throughout life but does tend to dampen in speed and amplitude with age. Best corrected visual acuity is usually between 20/100 and 20/200, and tends to improve slowly until the late teens. ## Genotype-Phenotype Correlations ## Nomenclature OCA1A is the classic "tyrosinase-negative" OCA phenotype, but the term "tyrosinase-negative OCA" should no longer be used. In the past, numerous clinical descriptions have attempted to quantitate the amount of pigment in persons with OCA, such as minimal pigment OCA, platinum OCA, temperature-sensitive OCA, and yellow OCA. Still, no universal nomenclature has been established for the various levels of pigmentation resulting from combinations of hypomorphic alleles and, indeed, the overlap of clinical phenotypes with variants of OCA2. ## Prevalence OCA1 is estimated to occur at a frequency of approximately 1/40,000 in most populations throughout the world. Most individuals with OCA1 identified to date are those with OCA1A who are diagnosed by the obvious phenotype. The frequency of OCA1B is unknown. The calculated carrier frequency for OCA1 is approximately 1/100 in most populations. ## Genetically Related Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Biallelic null variants of The differential diagnosis for individuals with albinism who have pigment in the skin and hair (OCA1B) includes OCA2, OCA3, Newborns with OCA2 almost always have lightly pigmented hair, brows, and lashes, with color ranging from light yellow to blond to brown. Hair color may darken with age but does not vary substantially from adolescence to adulthood. Brown OCA, initially identified in Africans and African Americans with light brown hair and skin, is part of the spectrum of OCA2. The diagnosis of OCA2 is based on clinical findings. OCA2 is inherited in an autosomal recessive manner. The diagnosis of HPS is established by clinical findings of hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absent dense bodies on whole mount electron microscopy of platelets. Biallelic pathogenic variants in OA1 is caused by pathogenic variants in Ophthalmologic findings, history of recurrent or severe infections, and abnormal platelet aggregation studies should prompt evaluation for CHS. Diagnosis is based on identification of abnormal WBC granules on blood smear. Biallelic Many other ocular disorders present with infantile nystagmus; that differential diagnosis is beyond the scope of this review. See ## Management To establish the extent of disease and needs of an individual diagnosed oculocutaneous albinism type 1 (OCA1), the following evaluations are recommended: Complete ophthalmologic evaluation, including assessment for the presence of nystagmus, ocular alignment and strabismus, iris pigmentation and transillumination, dilated retinal examination assessing retinal pigment epithelial hypopigmentation and foveal hypoplasia, and best corrected visual acuity (with cycloplegic refraction); Evaluation of the pigmentation status of the skin, especially the solar-exposed skin, and the adnexa (brows, lashes, and when appropriate extremity hair and pubic hair), linked to a (pediatric) dermatologic consultation for sun-protective clothing, lotions, and future self-care; Clinical genetics consultation to review natural history, pattern of inheritance and recurrence risks, and to clarify genotype. Parents should be assured repeatedly that the visual disability with OCA1 does not deteriorate over time, that changes in acuity are usually refractive in nature, that the nystagmus tends to dampen with age (but never disappears), that many children with OCA1B manifest slow improvement in acuity and some plateau by their teen years, and that intellectual disabilities are not a component of this group of disorders. Strabismus surgery is usually not mandatory but may be performed if the strabismus is marked. Surgery may improve peripheral binocularity or appearance. When an anomalous null point creates a substantial face turn or head tilt, strabismus surgery may reposition the null point to a more central, straight-ahead location to allow more socially acceptable head position. Nystagmus surgery remains highly controversial; no comparative clinical trial has compared the surgical reduction of amplitude of nystagmus to the outcomes of the natural history of dampened nystagmus with age among those forms of albinism in which increasing pigment occurs normally over time. Photodysphoria (discomfort in bright light; as distinct from "photophobia," which is painful aversion of light associated with intraocular inflammation) is common among all individuals with OCA; however, the severity of discomfort varies and is not completely concordant with the amount of pigment present in the iris or the skin. Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in acuity from the dark lenses. Note: Going without dark glasses does not harm vision. Darkly tinted contact lenses do not improve visual function substantively because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. Most children with albinism should remain in mainstream classrooms, as long as the school attends to their special needs resulting from visual limitation. Preschoool evaluations allow teachers and parents to develop an Individual Education Plan (IEP). Neither Braille nor "white cane" mobility training is needed in the overwhelming majority of children with albinism. Additional classroom aids may include: High contrast reading materials (black on white); Large font texts or xerographically enlarged worksheets; Preferential seating near the front of the class and work boards; Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and Computers and tablets with zoom-magnification text software. A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare, to reduce some photodysphoria, and to provide some sun protection to the face. For individuals with OCA1A, the white skin is completely devoid of melanin and needs to be protected whenever exposed to the sun. Sun exposure as short as five to ten minutes can be substantial in very sensitive individuals, and exposure of 30 minutes or more is usually substantial in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves, pants, and socks) and sunscreens with a high SPF value (blocks with SPF 45-50+). Even early in life, a (pediatric) dermatologic consultation is warranted to teach parents about the use of sun-protective clothing and interpretation of the often confusing validity of numerical values and contents of sun-protective lotions and formulas. For individuals with OCA1B, the amount of skin pigmentation varies and the use of sunscreen should correlate with skin pigmentation and the ability to tan. Skin that burns with sun exposure needs protection. An early (pediatric) dermatologic consultation is warranted. The following are appropriate: During the first few years of life, annual ophthalmologic examination, including assessment of refractive error and strabismus In adults, dermatologic surveillance of unusual skin thickening, hyperkeratosis, and erosive lesions that may be harbingers of skin cancer Other than the avoidance of prolonged solar exposure because of the enhanced damage to the skin and increasing cumulative risk of cutaneous neoplasms, no special precautions are needed. See In classic OCA1 of either type, an affected mother who is pregnant needs no exceptional consideration. Similarly, a pregnancy affected with OCA1 requires no exceptional prenatal care. Search • Complete ophthalmologic evaluation, including assessment for the presence of nystagmus, ocular alignment and strabismus, iris pigmentation and transillumination, dilated retinal examination assessing retinal pigment epithelial hypopigmentation and foveal hypoplasia, and best corrected visual acuity (with cycloplegic refraction); • Evaluation of the pigmentation status of the skin, especially the solar-exposed skin, and the adnexa (brows, lashes, and when appropriate extremity hair and pubic hair), linked to a (pediatric) dermatologic consultation for sun-protective clothing, lotions, and future self-care; • Clinical genetics consultation to review natural history, pattern of inheritance and recurrence risks, and to clarify genotype. • Parents should be assured repeatedly that the visual disability with OCA1 does not deteriorate over time, that changes in acuity are usually refractive in nature, that the nystagmus tends to dampen with age (but never disappears), that many children with OCA1B manifest slow improvement in acuity and some plateau by their teen years, and that intellectual disabilities are not a component of this group of disorders. • Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in acuity from the dark lenses. Note: Going without dark glasses does not harm vision. • Darkly tinted contact lenses do not improve visual function substantively because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. • Most children with albinism should remain in mainstream classrooms, as long as the school attends to their special needs resulting from visual limitation. Preschoool evaluations allow teachers and parents to develop an Individual Education Plan (IEP). Neither Braille nor "white cane" mobility training is needed in the overwhelming majority of children with albinism. • Additional classroom aids may include: • High contrast reading materials (black on white); • Large font texts or xerographically enlarged worksheets; • Preferential seating near the front of the class and work boards; • Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and • Computers and tablets with zoom-magnification text software. • High contrast reading materials (black on white); • Large font texts or xerographically enlarged worksheets; • Preferential seating near the front of the class and work boards; • Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and • Computers and tablets with zoom-magnification text software. • High contrast reading materials (black on white); • Large font texts or xerographically enlarged worksheets; • Preferential seating near the front of the class and work boards; • Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and • Computers and tablets with zoom-magnification text software. • During the first few years of life, annual ophthalmologic examination, including assessment of refractive error and strabismus • In adults, dermatologic surveillance of unusual skin thickening, hyperkeratosis, and erosive lesions that may be harbingers of skin cancer ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed oculocutaneous albinism type 1 (OCA1), the following evaluations are recommended: Complete ophthalmologic evaluation, including assessment for the presence of nystagmus, ocular alignment and strabismus, iris pigmentation and transillumination, dilated retinal examination assessing retinal pigment epithelial hypopigmentation and foveal hypoplasia, and best corrected visual acuity (with cycloplegic refraction); Evaluation of the pigmentation status of the skin, especially the solar-exposed skin, and the adnexa (brows, lashes, and when appropriate extremity hair and pubic hair), linked to a (pediatric) dermatologic consultation for sun-protective clothing, lotions, and future self-care; Clinical genetics consultation to review natural history, pattern of inheritance and recurrence risks, and to clarify genotype. Parents should be assured repeatedly that the visual disability with OCA1 does not deteriorate over time, that changes in acuity are usually refractive in nature, that the nystagmus tends to dampen with age (but never disappears), that many children with OCA1B manifest slow improvement in acuity and some plateau by their teen years, and that intellectual disabilities are not a component of this group of disorders. • Complete ophthalmologic evaluation, including assessment for the presence of nystagmus, ocular alignment and strabismus, iris pigmentation and transillumination, dilated retinal examination assessing retinal pigment epithelial hypopigmentation and foveal hypoplasia, and best corrected visual acuity (with cycloplegic refraction); • Evaluation of the pigmentation status of the skin, especially the solar-exposed skin, and the adnexa (brows, lashes, and when appropriate extremity hair and pubic hair), linked to a (pediatric) dermatologic consultation for sun-protective clothing, lotions, and future self-care; • Clinical genetics consultation to review natural history, pattern of inheritance and recurrence risks, and to clarify genotype. • Parents should be assured repeatedly that the visual disability with OCA1 does not deteriorate over time, that changes in acuity are usually refractive in nature, that the nystagmus tends to dampen with age (but never disappears), that many children with OCA1B manifest slow improvement in acuity and some plateau by their teen years, and that intellectual disabilities are not a component of this group of disorders. ## Treatment of Manifestations Strabismus surgery is usually not mandatory but may be performed if the strabismus is marked. Surgery may improve peripheral binocularity or appearance. When an anomalous null point creates a substantial face turn or head tilt, strabismus surgery may reposition the null point to a more central, straight-ahead location to allow more socially acceptable head position. Nystagmus surgery remains highly controversial; no comparative clinical trial has compared the surgical reduction of amplitude of nystagmus to the outcomes of the natural history of dampened nystagmus with age among those forms of albinism in which increasing pigment occurs normally over time. Photodysphoria (discomfort in bright light; as distinct from "photophobia," which is painful aversion of light associated with intraocular inflammation) is common among all individuals with OCA; however, the severity of discomfort varies and is not completely concordant with the amount of pigment present in the iris or the skin. Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in acuity from the dark lenses. Note: Going without dark glasses does not harm vision. Darkly tinted contact lenses do not improve visual function substantively because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. Most children with albinism should remain in mainstream classrooms, as long as the school attends to their special needs resulting from visual limitation. Preschoool evaluations allow teachers and parents to develop an Individual Education Plan (IEP). Neither Braille nor "white cane" mobility training is needed in the overwhelming majority of children with albinism. Additional classroom aids may include: High contrast reading materials (black on white); Large font texts or xerographically enlarged worksheets; Preferential seating near the front of the class and work boards; Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and Computers and tablets with zoom-magnification text software. A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare, to reduce some photodysphoria, and to provide some sun protection to the face. • Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in acuity from the dark lenses. Note: Going without dark glasses does not harm vision. • Darkly tinted contact lenses do not improve visual function substantively because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. • Most children with albinism should remain in mainstream classrooms, as long as the school attends to their special needs resulting from visual limitation. Preschoool evaluations allow teachers and parents to develop an Individual Education Plan (IEP). Neither Braille nor "white cane" mobility training is needed in the overwhelming majority of children with albinism. • Additional classroom aids may include: • High contrast reading materials (black on white); • Large font texts or xerographically enlarged worksheets; • Preferential seating near the front of the class and work boards; • Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and • Computers and tablets with zoom-magnification text software. • High contrast reading materials (black on white); • Large font texts or xerographically enlarged worksheets; • Preferential seating near the front of the class and work boards; • Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and • Computers and tablets with zoom-magnification text software. • High contrast reading materials (black on white); • Large font texts or xerographically enlarged worksheets; • Preferential seating near the front of the class and work boards; • Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and • Computers and tablets with zoom-magnification text software. ## Prevention of Primary Manifestations For individuals with OCA1A, the white skin is completely devoid of melanin and needs to be protected whenever exposed to the sun. Sun exposure as short as five to ten minutes can be substantial in very sensitive individuals, and exposure of 30 minutes or more is usually substantial in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves, pants, and socks) and sunscreens with a high SPF value (blocks with SPF 45-50+). Even early in life, a (pediatric) dermatologic consultation is warranted to teach parents about the use of sun-protective clothing and interpretation of the often confusing validity of numerical values and contents of sun-protective lotions and formulas. For individuals with OCA1B, the amount of skin pigmentation varies and the use of sunscreen should correlate with skin pigmentation and the ability to tan. Skin that burns with sun exposure needs protection. An early (pediatric) dermatologic consultation is warranted. ## Surveillance The following are appropriate: During the first few years of life, annual ophthalmologic examination, including assessment of refractive error and strabismus In adults, dermatologic surveillance of unusual skin thickening, hyperkeratosis, and erosive lesions that may be harbingers of skin cancer • During the first few years of life, annual ophthalmologic examination, including assessment of refractive error and strabismus • In adults, dermatologic surveillance of unusual skin thickening, hyperkeratosis, and erosive lesions that may be harbingers of skin cancer ## Agents/Circumstances to Avoid Other than the avoidance of prolonged solar exposure because of the enhanced damage to the skin and increasing cumulative risk of cutaneous neoplasms, no special precautions are needed. ## Evaluation of Relatives at Risk See ## Pregnancy Management In classic OCA1 of either type, an affected mother who is pregnant needs no exceptional consideration. Similarly, a pregnancy affected with OCA1 requires no exceptional prenatal care. ## Therapies Under Investigation Search ## Genetic Counseling OCA1 is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes; therefore, each carries a single copy of a pathogenic variant in Heterozygotes (carriers) are asymptomatic. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. Once an at-risk sib is known to be unaffected clinically, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members is possible if both pathogenic variants in the affected individual in the family have been identified. Molecular genetic testing is not offered routinely to the reproductive partners of family members identified as carriers because of the difficulty of interpreting test results in an unaffected individual with a negative family history. Rarely, families displaying two-generation "pseudodominant" inheritance have been identified; this results from an affected individual having children with a reproductive partner who is heterozygous (i.e., a carrier). The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes; therefore, each carries a single copy of a pathogenic variant in • Heterozygotes (carriers) are asymptomatic. • At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. • Once an at-risk sib is known to be unaffected clinically, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance OCA1 is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes; therefore, each carries a single copy of a pathogenic variant in Heterozygotes (carriers) are asymptomatic. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. Once an at-risk sib is known to be unaffected clinically, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. • The parents of an affected child are obligate heterozygotes; therefore, each carries a single copy of a pathogenic variant in • Heterozygotes (carriers) are asymptomatic. • At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. • Once an at-risk sib is known to be unaffected clinically, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. ## Carrier Detection Carrier testing for at-risk family members is possible if both pathogenic variants in the affected individual in the family have been identified. Molecular genetic testing is not offered routinely to the reproductive partners of family members identified as carriers because of the difficulty of interpreting test results in an unaffected individual with a negative family history. ## Related Genetic Counseling Issues Rarely, families displaying two-generation "pseudodominant" inheritance have been identified; this results from an affected individual having children with a reproductive partner who is heterozygous (i.e., a carrier). The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources PO Box 959 East Hampstead NH 03826-0959 437 Syndertown Road Craryville NY 12521 • • PO Box 959 • East Hampstead NH 03826-0959 • • • • • • • • 437 Syndertown Road • Craryville NY 12521 • • • ## Molecular Genetics Oculocutaneous Albinism Type 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Oculocutaneous Albinism Type 1 ( The benign variants c.575C>A (p.Ser192Tyr) and c.1205G>A (p.Arg402Gln) result in amino acid substitutions. The c.575C>A (p.Ser192Tyr) variant has not been associated with any pigmentation phenotype. The c.1205G>A (p.Arg402Gln) variant has been associated with an OCA1B phenotype in persons who are compound heterozygous for a pathogenic variant on the other allele; however, this association has not been shown to occur in the homozygous state in unaffected individuals. • The benign variants c.575C>A (p.Ser192Tyr) and c.1205G>A (p.Arg402Gln) result in amino acid substitutions. • The c.575C>A (p.Ser192Tyr) variant has not been associated with any pigmentation phenotype. • The c.1205G>A (p.Arg402Gln) variant has been associated with an OCA1B phenotype in persons who are compound heterozygous for a pathogenic variant on the other allele; however, this association has not been shown to occur in the homozygous state in unaffected individuals. ## References ## Literature Cited ## Chapter Notes Richard King, MD, PhD, FACMG; University of Minnesota (1999-2013)Richard Alan Lewis, MD, MS (2013-present) 7 January 2021 (ma) Chapter retired: outdated 16 May 2013 (me) Comprehensive update posted live 1 October 2004 (me) Comprehensive update posted live 3 December 2002 (rk) Revisions 16 September 2002 (me) Comprehensive update posted live 19 January 2000 (me) Review posted live 23 July 1999 (rk) Original submission • 7 January 2021 (ma) Chapter retired: outdated • 16 May 2013 (me) Comprehensive update posted live • 1 October 2004 (me) Comprehensive update posted live • 3 December 2002 (rk) Revisions • 16 September 2002 (me) Comprehensive update posted live • 19 January 2000 (me) Review posted live • 23 July 1999 (rk) Original submission ## Author History Richard King, MD, PhD, FACMG; University of Minnesota (1999-2013)Richard Alan Lewis, MD, MS (2013-present) ## Revision History 7 January 2021 (ma) Chapter retired: outdated 16 May 2013 (me) Comprehensive update posted live 1 October 2004 (me) Comprehensive update posted live 3 December 2002 (rk) Revisions 16 September 2002 (me) Comprehensive update posted live 19 January 2000 (me) Review posted live 23 July 1999 (rk) Original submission • 7 January 2021 (ma) Chapter retired: outdated • 16 May 2013 (me) Comprehensive update posted live • 1 October 2004 (me) Comprehensive update posted live • 3 December 2002 (rk) Revisions • 16 September 2002 (me) Comprehensive update posted live • 19 January 2000 (me) Review posted live • 23 July 1999 (rk) Original submission	[ "PW Chiang, E Spector, AC Tsai. Oculocutaneous albinism spectrum.. Am J Med Genet A 2009;149A:1590-1", "DJ Creel, CG Summers, RA King. Visual anomalies associated with albinism.. Ophthalmic Paediatr Genet 1990;11:193-200", "K Grønskov, CM Dooley, E Østergaard, RN Kelsh, L Hansen, MP Levesque, K Vilhelmsen, K Møllgård, DL Stemple, T Rosenberg. Mutations in. Am J Hum Genet 2013;92:415-21", "K Grønskov, J Ek, K Brondum-Nielsen. Oculocutaneous albinism.. Orphanet J Rare Dis 2007;2:43-7", "K Grønskov, J Ek, A Sand, R Scheller, A Bygum, K Brixen, K Brondum-Nielsen, T Rosenberg. Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism.. Invest Ophthalmol Vis Sci 2009;50:1058-64", "SM Hutton, RA Spritz. Comprehensive analysis of oculocutaneous albinism among non-Hispanic Caucasians shows that OCA1 is the most prevalent OCA type.. J Invest Dermatol 2008;128:2442-50", "K Inagaki, T Suzuki, H Shimizu, N Ishii, Y Umezawa, J Tada, N Kikuchi, M Takata, K Takamori, M Kishibe, M Tanaka, Y Miyamura, S Ito, Y Tomita. Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan.. Am J Hum Genet 2004;74:466-71", "G Jeffery, G Brem, L Montoliu. Correction of retinal abnormalities found in albinism by introduction of a functional tyrosinase gene in transgenic mice and rabbits.. Brain Res Dev Brain Res 1997;99:95-102", "T Kobayashi, VJ Hearing. Direct interaction of tyrosinase with Tyrp1 to form heterodimeric complexes in vivo.. J Cell Sci 2007;120:4261-8", "JM Newton, O Cohen-Barak, N Hagiwara, JM Gardner, MT Davisson, RA King, MH Brilliant. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4.. Am J Hum Genet 2001;69:981-8", "JW Pott, NM Jansonius, AC Kooijman. Chiasmal coefficient of flash and pattern visual evoked potentials for detection of chiasmal misrouting in albinism.. Doc Ophthalmol 2003;106:137-43", "C Rooryck, F Morice-Picard, NH Elcioglu, D Lacombe, A Taieb, B Arveiler. Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1-4 genes and practical aspects.. Pigment Cell Melanoma Res 2008;21:583-7", "B Schmitz, T Schaefer, CM Krick, W Reith, M Backens, B Kasmann-Kellner. Configuration of the optic chiasm in humans with albinism as revealed by magnetic resonance imaging.. Invest Ophthalmol Vis Sci 2003;44:16-21", "DR Simeonov, X Wang, C Wang, Y Seergeev, M Dolinska, M Bower, R Fischer, D Winer, G Dubrovsky, JZ Balog, M Huizing. hart R, Zein WM, Gahl WA, Brooks BP, Adams DR. DNA Variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics.. Hum Mutat. 2013;34:827-35", "A Wei, Y Wang, Y Long, X Guo, Z Zhou, W Zhu, J Liu, X Bian, S Lian, W Li. A comprehensive analysis reveals mutational spectra and common alleles in Chinese patients with oculocutaneous albinism.. J Invest Dermatol 2010;130:716-24" ]	19/1/2000	16/5/2013		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
oca2	oca2	[ "OCA2", "OCA2", "Brown OCA", "P protein", "OCA2", "Oculocutaneous Albinism Type 2" ]	Oculocutaneous Albinism Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Richard Alan Lewis	Summary NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE. Oculocutaneous albinism type 2 (OCA2) is characterized by hypopigmentation of the skin and hair and the characteristic ocular changes found in all types of albinism, including nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity; and misrouting of the optic nerve fiber radiations at the chiasm, associated with strabismus, reduced stereoscopic vision, and altered visual evoked potentials (VEP). Individuals with OCA2 are usually recognized within the first three to six months of life because of the ocular features of visual inattention, nystagmus, and strabismus. Vision is stable to slowly improving after early childhood until mid- to late teens, and no major change or loss of established visual acuity occurs related to the albinism. The amount of cutaneous pigmentation in OCA2 ranges from minimal to near-normal compared to others of the same ethnic and family backgrounds. Newborns with OCA2 almost always have lightly pigmented hair, brows, and lashes, with color ranging from light yellow to blond to brown. Hair color may darken with age but does not vary substantially from adolescence to adulthood. Brown OCA, initially identified in Africans and African Americans with light brown hair and skin, is part of the spectrum of OCA2. The diagnosis of OCA2 is based on clinical findings. Protection from sun exposure with appropriate skin-covering clothing and sunscreens prevents burning, consequent skin damage, and the enhanced risk of skin cancer. Skin cancer, including a slightly enhanced risk for cutaneous melanoma, is treated as for the general population. OCA2 is inherited in an autosomal recessive manner. The parents of a proband are obligate heterozygotes and therefore carry one mutated allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in an affected family member are known.	Brown OCA For synonyms and outdated names see • Brown OCA ## Diagnosis The diagnosis of oculocutaneous albinism type 2 (OCA2) [ Hypopigmentation of the skin and hair Characteristic ocular changes found in all types of albinism, including the following findings detected on complete ophthalmologic examination: Infantile nystagmus (usually noticed between ages three and 12 weeks of life Reduced iris pigment with iris transillumination Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with reduction in visual acuity Misrouting of the optic nerve fiber projections at the chiasm associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visual evoked potentials (VEP). Note: (1) The VEP is performed with a technique specifically designed to demonstrate the selective misrouting; a standard (conventional) simultaneous binocular VEP will not demonstrate this anomaly. (2) Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. (3) A VEP is not necessary for the diagnosis of albinism because misrouting is implied by the finding of strabismus and reduced stereoscopic vision. In some individuals, particularly those who have near normal amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections. The clinical diagnosis of OCA is usually made in an individual who has poor visual fixation and/or reduced visual acuity early in life, and nystagmus, associated with hypopigmentation of the skin, hair, and eye. The diagnosis is often suspected by the pediatrician at the two- or four-month well-baby check-up, and the diagnosis is usually established after a thorough medical eye examination by an ophthalmologist. Molecular Genetic Testing Used in Oculocutaneous Albinism Type 2 See See The ability of the test method used to detect a variant that is present in the indicated gene Most individuals of sub-Saharan African heritage with OCA2 are homozygous for a common 2.7-kb deletion. The 2.7-kb deletion is less common in the US African American population and has been found in the Puerto Rican population [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The majority of pathogenic variants in the non-African heritage population are missense variants, but deletions of one or a small number of bases and base changes in introns are common. The missense variant p.Ala481Thr has been described in the Japanese population; normally pigmented individuals who are homozygous and individuals who are compound heterozygous for this pathogenic variant have been identified [ Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) Although some adult carriers may manifest clinically insignificant punctate iris transillumination defects at diligent biomicroscopic examination, a fraction of the normal population also does (depending on ethnic or national origin), thus making this observation useless for clinical counseling. • Hypopigmentation of the skin and hair • Characteristic ocular changes found in all types of albinism, including the following findings detected on complete ophthalmologic examination: • Infantile nystagmus (usually noticed between ages three and 12 weeks of life • Reduced iris pigment with iris transillumination • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Infantile nystagmus (usually noticed between ages three and 12 weeks of life • Reduced iris pigment with iris transillumination • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Misrouting of the optic nerve fiber projections at the chiasm associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visual evoked potentials (VEP). • Note: (1) The VEP is performed with a technique specifically designed to demonstrate the selective misrouting; a standard (conventional) simultaneous binocular VEP will not demonstrate this anomaly. (2) Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. (3) A VEP is not necessary for the diagnosis of albinism because misrouting is implied by the finding of strabismus and reduced stereoscopic vision. In some individuals, particularly those who have near normal amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections. • Infantile nystagmus (usually noticed between ages three and 12 weeks of life • Reduced iris pigment with iris transillumination • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • ## Clinical Diagnosis The diagnosis of oculocutaneous albinism type 2 (OCA2) [ Hypopigmentation of the skin and hair Characteristic ocular changes found in all types of albinism, including the following findings detected on complete ophthalmologic examination: Infantile nystagmus (usually noticed between ages three and 12 weeks of life Reduced iris pigment with iris transillumination Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with reduction in visual acuity Misrouting of the optic nerve fiber projections at the chiasm associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visual evoked potentials (VEP). Note: (1) The VEP is performed with a technique specifically designed to demonstrate the selective misrouting; a standard (conventional) simultaneous binocular VEP will not demonstrate this anomaly. (2) Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. (3) A VEP is not necessary for the diagnosis of albinism because misrouting is implied by the finding of strabismus and reduced stereoscopic vision. In some individuals, particularly those who have near normal amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections. The clinical diagnosis of OCA is usually made in an individual who has poor visual fixation and/or reduced visual acuity early in life, and nystagmus, associated with hypopigmentation of the skin, hair, and eye. The diagnosis is often suspected by the pediatrician at the two- or four-month well-baby check-up, and the diagnosis is usually established after a thorough medical eye examination by an ophthalmologist. • Hypopigmentation of the skin and hair • Characteristic ocular changes found in all types of albinism, including the following findings detected on complete ophthalmologic examination: • Infantile nystagmus (usually noticed between ages three and 12 weeks of life • Reduced iris pigment with iris transillumination • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Infantile nystagmus (usually noticed between ages three and 12 weeks of life • Reduced iris pigment with iris transillumination • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Misrouting of the optic nerve fiber projections at the chiasm associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visual evoked potentials (VEP). • Note: (1) The VEP is performed with a technique specifically designed to demonstrate the selective misrouting; a standard (conventional) simultaneous binocular VEP will not demonstrate this anomaly. (2) Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. (3) A VEP is not necessary for the diagnosis of albinism because misrouting is implied by the finding of strabismus and reduced stereoscopic vision. In some individuals, particularly those who have near normal amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections. • Infantile nystagmus (usually noticed between ages three and 12 weeks of life • Reduced iris pigment with iris transillumination • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity ## Molecular Genetic Testing Molecular Genetic Testing Used in Oculocutaneous Albinism Type 2 See See The ability of the test method used to detect a variant that is present in the indicated gene Most individuals of sub-Saharan African heritage with OCA2 are homozygous for a common 2.7-kb deletion. The 2.7-kb deletion is less common in the US African American population and has been found in the Puerto Rican population [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The majority of pathogenic variants in the non-African heritage population are missense variants, but deletions of one or a small number of bases and base changes in introns are common. The missense variant p.Ala481Thr has been described in the Japanese population; normally pigmented individuals who are homozygous and individuals who are compound heterozygous for this pathogenic variant have been identified [ Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See • ## Testing Strategy Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) Although some adult carriers may manifest clinically insignificant punctate iris transillumination defects at diligent biomicroscopic examination, a fraction of the normal population also does (depending on ethnic or national origin), thus making this observation useless for clinical counseling. ## Clinical Characteristics The amount of cutaneous (including hair, lash, brow, and iris) pigmentation in OCA2 forms a continuum from minimal to near normal [ Individuals with OCA2 are usually recognized within the first few months of life because of the ocular features of nystagmus and strabismus. In many families, particularly in those with darker constitutional pigmentation, the cutaneous hypopigmentation is also obvious at birth and suggests the diagnosis. Most children with albinism develop nystagmus before age three to four months, and the diagnosis is often raised at the two- to four-month well-baby checkup. The nystagmus, which can be rapid early in life, generally slows during the first decade; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when the individual is tired, angry, or anxious, and less marked when they are well rested and feeling well. For some, the nystagmus has a "null point" or direction of gaze in which the movement is minimized, leading to a compensatory face-turn that may be socially disconcerting and may lead to eye-muscle surgical intervention as the child matures. The strabismus found in most individuals with albinism is usually not associated with the development of amblyopia unless the often substantial refractive errors are ignored in infancy and childhood. Iris color ranges from blue to brown; the extreme iris transillumination associated with diaphanous light "grey-blue," "pink," or "ruby" eyes seen with the OCA1A subtype of OCA1 is typically not present in OCA2. However, transillumination of the globe and/or the iris in a darkened room will be seen by the careful and skilled observer. Visual acuity in OCA2 is generally better than that in OCA1 (and always better than in OCA1A), but overlap is observed [ Some individuals of northern European ancestry who have OCA2 have red rather than blond hair and typical ophthalmologic findings [ "Brown OCA," initially characterized in the African (of Nigerian and Ghanan ancestry) and African American population, is now recognized as part of the spectrum of OCA2; individuals with the "brown" phenotype in these populations are born with light brown hair and skin, but individuals from other populations (northern European, Asian) with the ocular features of albinism can have moderate to near-normal cutaneous pigmentation and only appear hypopigmented when compared to sibs and other family members [ When hair color is "blond" or yellow, the skin usually has little generalized pigmentation and the skin color is creamy white. It should be noted that skin color in OCA2 is not as "white" as that found in the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that the melanocytes in the skin of individuals with OCA2 still can synthesize some melanin (as seen with the pigmented hairs), but that most melanin is yellow pheomelanin rather than black-brown eumelanin. With the OCA2 brown phenotype, generalized skin pigmentation is present and may darken over time and with sun exposure. Skin color is usually lighter than that of sibs and unaffected relatives. Skin cancer is unusual in individuals with all forms of OCA in the US because of the availability of sunscreens and the social acceptability of wearing clothes that cover the exposed skin, and because individuals with albinism often avoid prolonged time outside in the sun. In contrast, skin cancers in individuals with albinism are common in parts of the world such as sub-Saharan Africa because of the increased amount of sun exposure through the year, the cultural differences in protective dress, and the lack of skin-protective agents [ The lack of a functional assay for the activity of the protein product of Genotype-phenotype correlations are not useful clinically and the amount of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular pathogenic variants in this gene cannot be predicted with any certainty. Homozygosity for the 2.7-kb deletion in the African and African American populations is associated with yellow/blond hair, creamy tan skin, and blue-to-tan irides, but this phenotype varies even in those who are homozygous for this pathogenic variant. African individuals with the "brown" phenotype are usually compound heterozygotes for this deletion; the pathogenic variant on the homologous Individuals with OCA2 and red hair have common variants in Individuals with OCA2 and moderate to near-normal cutaneous pigmentation were previously classified as having autosomal recessive or even X-linked ocular albinism because of the presence of the cutaneous pigmentation. However, this description is both confusing and no longer valid; it is now appropriate to classify oculocutaneous albinism according to the gene involved. Individuals with Individuals with Brown OCA was described initially in Nigeria and Ghana as a separate entity, and early family studies suggested that it was distinct from the classic OCA2 phenotype in Africa. Molecular studies now show that in the African, African American, and white populations, brown OCA is actually part of the clinical spectrum of OCA2. Individuals with OCA2 may present with the classic OCA2 phenotype (yellow/blond hair, creamy-tan skin, and blue/hazel irides), a more pigmented phenotype like brown OCA, or an intermediate phenotype between the classic and the brown phenotype [ Prevalence of OCA2 is approximately 1:38,000-1:40,000 in most populations throughout the world except the African population, in which the prevalence is estimated at 1:1,500-1:3,900, and the African-American population, in which the prevalence is estimated to be as high as 1:10,000 [ OCA2 has been described in all major ethnic groups, including northern, central, eastern, and southern European, other white, African, African-American, and Asian populations. In Japan, 8% of albinism is caused by The proportion of individuals with OCA2 with moderate-to-near-normal cutaneous pigmentation is unknown in most populations. The prevalence of "brown" OCA in African populations is less than that of classic OCA2, but exact figures are not available. The carrier frequency for OCA2 is: Approximately 1:100 in most populations, based on disorder prevalence of 1:38,000-1:40,000 1:22-1:32 in the sub-Sahara African population, based on disorder prevalence of 1:1,500-1:3,900 1:50 or less in the African American population, based on disorder prevalence of 1:10,000 • Homozygosity for the 2.7-kb deletion in the African and African American populations is associated with yellow/blond hair, creamy tan skin, and blue-to-tan irides, but this phenotype varies even in those who are homozygous for this pathogenic variant. • African individuals with the "brown" phenotype are usually compound heterozygotes for this deletion; the pathogenic variant on the homologous • Individuals with • Individuals with • Approximately 1:100 in most populations, based on disorder prevalence of 1:38,000-1:40,000 • 1:22-1:32 in the sub-Sahara African population, based on disorder prevalence of 1:1,500-1:3,900 • 1:50 or less in the African American population, based on disorder prevalence of 1:10,000 ## Clinical Description The amount of cutaneous (including hair, lash, brow, and iris) pigmentation in OCA2 forms a continuum from minimal to near normal [ Individuals with OCA2 are usually recognized within the first few months of life because of the ocular features of nystagmus and strabismus. In many families, particularly in those with darker constitutional pigmentation, the cutaneous hypopigmentation is also obvious at birth and suggests the diagnosis. Most children with albinism develop nystagmus before age three to four months, and the diagnosis is often raised at the two- to four-month well-baby checkup. The nystagmus, which can be rapid early in life, generally slows during the first decade; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when the individual is tired, angry, or anxious, and less marked when they are well rested and feeling well. For some, the nystagmus has a "null point" or direction of gaze in which the movement is minimized, leading to a compensatory face-turn that may be socially disconcerting and may lead to eye-muscle surgical intervention as the child matures. The strabismus found in most individuals with albinism is usually not associated with the development of amblyopia unless the often substantial refractive errors are ignored in infancy and childhood. Iris color ranges from blue to brown; the extreme iris transillumination associated with diaphanous light "grey-blue," "pink," or "ruby" eyes seen with the OCA1A subtype of OCA1 is typically not present in OCA2. However, transillumination of the globe and/or the iris in a darkened room will be seen by the careful and skilled observer. Visual acuity in OCA2 is generally better than that in OCA1 (and always better than in OCA1A), but overlap is observed [ Some individuals of northern European ancestry who have OCA2 have red rather than blond hair and typical ophthalmologic findings [ "Brown OCA," initially characterized in the African (of Nigerian and Ghanan ancestry) and African American population, is now recognized as part of the spectrum of OCA2; individuals with the "brown" phenotype in these populations are born with light brown hair and skin, but individuals from other populations (northern European, Asian) with the ocular features of albinism can have moderate to near-normal cutaneous pigmentation and only appear hypopigmented when compared to sibs and other family members [ When hair color is "blond" or yellow, the skin usually has little generalized pigmentation and the skin color is creamy white. It should be noted that skin color in OCA2 is not as "white" as that found in the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that the melanocytes in the skin of individuals with OCA2 still can synthesize some melanin (as seen with the pigmented hairs), but that most melanin is yellow pheomelanin rather than black-brown eumelanin. With the OCA2 brown phenotype, generalized skin pigmentation is present and may darken over time and with sun exposure. Skin color is usually lighter than that of sibs and unaffected relatives. Skin cancer is unusual in individuals with all forms of OCA in the US because of the availability of sunscreens and the social acceptability of wearing clothes that cover the exposed skin, and because individuals with albinism often avoid prolonged time outside in the sun. In contrast, skin cancers in individuals with albinism are common in parts of the world such as sub-Saharan Africa because of the increased amount of sun exposure through the year, the cultural differences in protective dress, and the lack of skin-protective agents [ ## Genotype-Phenotype Correlations The lack of a functional assay for the activity of the protein product of Genotype-phenotype correlations are not useful clinically and the amount of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular pathogenic variants in this gene cannot be predicted with any certainty. Homozygosity for the 2.7-kb deletion in the African and African American populations is associated with yellow/blond hair, creamy tan skin, and blue-to-tan irides, but this phenotype varies even in those who are homozygous for this pathogenic variant. African individuals with the "brown" phenotype are usually compound heterozygotes for this deletion; the pathogenic variant on the homologous Individuals with OCA2 and red hair have common variants in • Homozygosity for the 2.7-kb deletion in the African and African American populations is associated with yellow/blond hair, creamy tan skin, and blue-to-tan irides, but this phenotype varies even in those who are homozygous for this pathogenic variant. • African individuals with the "brown" phenotype are usually compound heterozygotes for this deletion; the pathogenic variant on the homologous ## Nomenclature Individuals with OCA2 and moderate to near-normal cutaneous pigmentation were previously classified as having autosomal recessive or even X-linked ocular albinism because of the presence of the cutaneous pigmentation. However, this description is both confusing and no longer valid; it is now appropriate to classify oculocutaneous albinism according to the gene involved. Individuals with Individuals with Brown OCA was described initially in Nigeria and Ghana as a separate entity, and early family studies suggested that it was distinct from the classic OCA2 phenotype in Africa. Molecular studies now show that in the African, African American, and white populations, brown OCA is actually part of the clinical spectrum of OCA2. Individuals with OCA2 may present with the classic OCA2 phenotype (yellow/blond hair, creamy-tan skin, and blue/hazel irides), a more pigmented phenotype like brown OCA, or an intermediate phenotype between the classic and the brown phenotype [ • Individuals with • Individuals with ## Prevalence Prevalence of OCA2 is approximately 1:38,000-1:40,000 in most populations throughout the world except the African population, in which the prevalence is estimated at 1:1,500-1:3,900, and the African-American population, in which the prevalence is estimated to be as high as 1:10,000 [ OCA2 has been described in all major ethnic groups, including northern, central, eastern, and southern European, other white, African, African-American, and Asian populations. In Japan, 8% of albinism is caused by The proportion of individuals with OCA2 with moderate-to-near-normal cutaneous pigmentation is unknown in most populations. The prevalence of "brown" OCA in African populations is less than that of classic OCA2, but exact figures are not available. The carrier frequency for OCA2 is: Approximately 1:100 in most populations, based on disorder prevalence of 1:38,000-1:40,000 1:22-1:32 in the sub-Sahara African population, based on disorder prevalence of 1:1,500-1:3,900 1:50 or less in the African American population, based on disorder prevalence of 1:10,000 • Approximately 1:100 in most populations, based on disorder prevalence of 1:38,000-1:40,000 • 1:22-1:32 in the sub-Sahara African population, based on disorder prevalence of 1:1,500-1:3,900 • 1:50 or less in the African American population, based on disorder prevalence of 1:10,000 ## Genetically Related (Allelic) Disorders No other type of albinism or genetic form of congenital hypopigmentation has been associated with pathogenic variants in A paradox exists in the association of Single-nucleotide polymorphisms of ## Differential Diagnosis Clinically, albinism is associated with the development of some cutaneous pigmentation (except in OCA1A), and the differential diagnosis for individuals with albinism who have pigment in their skin and hair includes the OCA1B subtype of oculocutaneous albinism type 1, OCA2, OCA3, OCA4, Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, Griscelli syndrome, and The diagnosis of albinism is made with an ophthalmologic examination. Different types can be distinguished in the following manner: A careful history of pigment development usually identifies individuals with OCA1. Molecular studies can distinguish OCA2 and OCA4 A detailed medical history focused on bleeding or bruising and an analysis of platelet dense bodies are necessary to establish the diagnosis of HPS. A detailed medical history of recurrent infections and an examination of peripheral leukocytes may reveal findings that suggest the diagnosis of Chediak-Higashi syndrome. The presence of pancytopenia, immunodeficiency, hemophagocytic syndrome, and/or demyelination of the white matter of the brain suggest the diagnosis of Griscelli syndrome. Many of the ocular features of oculocutaneous albinism (OCA) and The existence of another autosomal gene that is related to ocular or oculocutaneous albinism has not been substantiated, although families with OCA that do not map to the loci for Naturally blond hair is rare in humans and found almost exclusively in Europe and Oceania. Recently an arginine-to-cysteine change at a highly conserved residue in tyrosinase-related protein 1 (TYRP1) was found as a major determinant of blond hair in Solomon Islanders. This pathogenic missense variant is predicted to affect catalytic activity of TYRP1 and causes blond hair through a recessive mode of inheritance. The pathogenic variant, occurring at a frequency of 26% in the Solomon Islands, is absent outside of Oceania [ Additional confusion may occur in infants with blue cone monochromacy (males) (red-green color vision defects) or rod monochromacy ( See • A careful history of pigment development usually identifies individuals with OCA1. • Molecular studies can distinguish OCA2 and OCA4 • A detailed medical history focused on bleeding or bruising and an analysis of platelet dense bodies are necessary to establish the diagnosis of HPS. • A detailed medical history of recurrent infections and an examination of peripheral leukocytes may reveal findings that suggest the diagnosis of Chediak-Higashi syndrome. • The presence of pancytopenia, immunodeficiency, hemophagocytic syndrome, and/or demyelination of the white matter of the brain suggest the diagnosis of Griscelli syndrome. ## Management To establish the extent of disease and needs of an individual diagnosed with oculocutaneous albinism (OCA), the following evaluations are recommended: Evaluation of the pigmentation status of the skin and adnexa (eyebrows, eyelashes, and where appropriate, pubic hair) Consultation with a clinical geneticist and/or genetic counselor Correction of refractive errors with spectacles or (when age-appropriate) contact lenses of the refractive errors of either hyperopia or myopia and astigmatism found in most individuals with albinism can optimize visual acuity. Of note, visual acuity is never correctable to normal. Strabismus surgery is usually not mandatory (because the strabismus in most individuals with albinism is not associated with the development of amblyopia); however, if the strabismus is marked or fixed, surgery can be considered to improve peripheral binocular fusion or appearance. When an anomalous null point creates a substantial face turn, strabismus surgery may reposition the null point into a more central, straight-ahead location to allow more socially acceptable head position. Photodysphoria (discomfort in bright light; as distinct from photophobia, painful aversion of light associated with intraocular inflammation) is common among individuals with OCA; however, the severity of discomfort varies and is not completely concordant with the amount of pigment present in the iris or the skin. Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in vision from the dark lenses. Note: Going without dark glasses does not harm vision. Darkly tinted contact lenses do not improve visual function because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare and to reduce some photodysphoria and to provide some sun protection to the face. Skin care in OCA2 is determined by the amount of pigment in the skin and the cutaneous response to sunlight. Individuals with white skin that does not tan need to be protected from any prolonged sun exposure for prevention of burning, skin damage, and skin cancer. This can be for exposures as short as five to ten minutes in highly sensitive individuals and 30 minutes or more in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, and long sleeves, pants, and socks) and appropriate sunscreens after the guidance and education from a dermatologist. Even early in life, a (pediatric) dermatologic consultation is warranted to teach parents about the use of sun-protective clothing and interpretation of the often confusing numerical values and contents of sun-protective lotions and formulas. Skin cancer is treated as for the general population. No dietary or ophthalmologic procedures or exercises will prevent or alter the clinical features of albinism. The following are appropriate: Annual ophthalmologic examination and reassessment and accurate correction of refractive errors, and related strabismus or face turn Annual to biennial search for evidence of sun-related skin damage and pre-cancerous or cancerous lesions, especially in areas of high intensity or prolonged sunlight exposure Prolonged unprotected sun exposure should be avoided. Relatives at risk for OCA2 can be identified by clinical findings (hypopigmentation and eye features); additional testing is not indicated. See No form of classic OCA impairs fertility or compromises pregnancy or gestation. An obligate carrier (heterozygous) fetus of a mother with OCA2 faces no additional risks over an unaffected fetus of an unaffected mother. Search • Evaluation of the pigmentation status of the skin and adnexa (eyebrows, eyelashes, and where appropriate, pubic hair) • Consultation with a clinical geneticist and/or genetic counselor • Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in vision from the dark lenses. Note: Going without dark glasses does not harm vision. • Darkly tinted contact lenses do not improve visual function because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. • Annual ophthalmologic examination and reassessment and accurate correction of refractive errors, and related strabismus or face turn • Annual to biennial search for evidence of sun-related skin damage and pre-cancerous or cancerous lesions, especially in areas of high intensity or prolonged sunlight exposure ## Evaluation Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with oculocutaneous albinism (OCA), the following evaluations are recommended: Evaluation of the pigmentation status of the skin and adnexa (eyebrows, eyelashes, and where appropriate, pubic hair) Consultation with a clinical geneticist and/or genetic counselor • Evaluation of the pigmentation status of the skin and adnexa (eyebrows, eyelashes, and where appropriate, pubic hair) • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Correction of refractive errors with spectacles or (when age-appropriate) contact lenses of the refractive errors of either hyperopia or myopia and astigmatism found in most individuals with albinism can optimize visual acuity. Of note, visual acuity is never correctable to normal. Strabismus surgery is usually not mandatory (because the strabismus in most individuals with albinism is not associated with the development of amblyopia); however, if the strabismus is marked or fixed, surgery can be considered to improve peripheral binocular fusion or appearance. When an anomalous null point creates a substantial face turn, strabismus surgery may reposition the null point into a more central, straight-ahead location to allow more socially acceptable head position. Photodysphoria (discomfort in bright light; as distinct from photophobia, painful aversion of light associated with intraocular inflammation) is common among individuals with OCA; however, the severity of discomfort varies and is not completely concordant with the amount of pigment present in the iris or the skin. Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in vision from the dark lenses. Note: Going without dark glasses does not harm vision. Darkly tinted contact lenses do not improve visual function because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare and to reduce some photodysphoria and to provide some sun protection to the face. Skin care in OCA2 is determined by the amount of pigment in the skin and the cutaneous response to sunlight. Individuals with white skin that does not tan need to be protected from any prolonged sun exposure for prevention of burning, skin damage, and skin cancer. This can be for exposures as short as five to ten minutes in highly sensitive individuals and 30 minutes or more in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, and long sleeves, pants, and socks) and appropriate sunscreens after the guidance and education from a dermatologist. Even early in life, a (pediatric) dermatologic consultation is warranted to teach parents about the use of sun-protective clothing and interpretation of the often confusing numerical values and contents of sun-protective lotions and formulas. Skin cancer is treated as for the general population. • Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in vision from the dark lenses. Note: Going without dark glasses does not harm vision. • Darkly tinted contact lenses do not improve visual function because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. ## Prevention of Primary Manifestations No dietary or ophthalmologic procedures or exercises will prevent or alter the clinical features of albinism. ## Surveillance The following are appropriate: Annual ophthalmologic examination and reassessment and accurate correction of refractive errors, and related strabismus or face turn Annual to biennial search for evidence of sun-related skin damage and pre-cancerous or cancerous lesions, especially in areas of high intensity or prolonged sunlight exposure • Annual ophthalmologic examination and reassessment and accurate correction of refractive errors, and related strabismus or face turn • Annual to biennial search for evidence of sun-related skin damage and pre-cancerous or cancerous lesions, especially in areas of high intensity or prolonged sunlight exposure ## Agents/Circumstances to Avoid Prolonged unprotected sun exposure should be avoided. ## Evaluation of Relatives at Risk Relatives at risk for OCA2 can be identified by clinical findings (hypopigmentation and eye features); additional testing is not indicated. See ## Pregnancy Management No form of classic OCA impairs fertility or compromises pregnancy or gestation. An obligate carrier (heterozygous) fetus of a mother with OCA2 faces no additional risks over an unaffected fetus of an unaffected mother. ## Therapies Under Investigation Search ## Genetic Counseling OCA2 is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. Heterozygotes (carriers) are asymptomatic. At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. All unaffected offspring of an individual with OCA2 are obligate heterozygotes (carriers) for one pathogenic variant in Most families have no history of OCA2, but families with two-generation pseudodominance have been reported. Two-generation pseudodominance results from an affected individual having children with an individual who is a heterozygote. Because of the high carrier rate for A few reports document two parents with OCA having unaffected children. In these reports, one parent had OCA1 and the other parent had OCA2; the offspring were double heterozygotes, but they had normal pigmentation and normal ocular and visual function. Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Requests for prenatal testing for conditions which (like OCA2) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. • Heterozygotes (carriers) are asymptomatic. • At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • All unaffected offspring of an individual with OCA2 are obligate heterozygotes (carriers) for one pathogenic variant in • Most families have no history of OCA2, but families with two-generation pseudodominance have been reported. Two-generation pseudodominance results from an affected individual having children with an individual who is a heterozygote. • Because of the high carrier rate for • A few reports document two parents with OCA having unaffected children. In these reports, one parent had OCA1 and the other parent had OCA2; the offspring were double heterozygotes, but they had normal pigmentation and normal ocular and visual function. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance OCA2 is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. Heterozygotes (carriers) are asymptomatic. At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. All unaffected offspring of an individual with OCA2 are obligate heterozygotes (carriers) for one pathogenic variant in Most families have no history of OCA2, but families with two-generation pseudodominance have been reported. Two-generation pseudodominance results from an affected individual having children with an individual who is a heterozygote. Because of the high carrier rate for A few reports document two parents with OCA having unaffected children. In these reports, one parent had OCA1 and the other parent had OCA2; the offspring were double heterozygotes, but they had normal pigmentation and normal ocular and visual function. • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele. • Heterozygotes (carriers) are asymptomatic. • At conception, each full sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic. • All unaffected offspring of an individual with OCA2 are obligate heterozygotes (carriers) for one pathogenic variant in • Most families have no history of OCA2, but families with two-generation pseudodominance have been reported. Two-generation pseudodominance results from an affected individual having children with an individual who is a heterozygote. • Because of the high carrier rate for • A few reports document two parents with OCA having unaffected children. In these reports, one parent had OCA1 and the other parent had OCA2; the offspring were double heterozygotes, but they had normal pigmentation and normal ocular and visual function. ## Carrier Detection Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Requests for prenatal testing for conditions which (like OCA2) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources PO Box 959 East Hampstead NH 03826-0959 • • PO Box 959 • East Hampstead NH 03826-0959 • • • • • ## Molecular Genetics Oculocutaneous Albinism Type 2: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Oculocutaneous Albinism Type 2 ( ## References ## Literature Cited ## Chapter Notes Richard A King, MD, PhD, FACMG; University of Minnesota (2003-2012)Richard Alan Lewis, MD, MS (2012-present)William S Oetting, PhD; University of Minnesota (2003-2012) 7 January 2021 (ma) Chapter retired: outdated 16 August 2012 (me) Comprehensive update posted live 20 June 2007 (cd) Revision: mutation scanning and sequence analysis available clinically 20 December 2005 (me) Comprehensive update posted live 17 July 2003 (me) Review posted live 25 April 2003 (rk) Original submission • 7 January 2021 (ma) Chapter retired: outdated • 16 August 2012 (me) Comprehensive update posted live • 20 June 2007 (cd) Revision: mutation scanning and sequence analysis available clinically • 20 December 2005 (me) Comprehensive update posted live • 17 July 2003 (me) Review posted live • 25 April 2003 (rk) Original submission ## Author History Richard A King, MD, PhD, FACMG; University of Minnesota (2003-2012)Richard Alan Lewis, MD, MS (2012-present)William S Oetting, PhD; University of Minnesota (2003-2012) ## Revision History 7 January 2021 (ma) Chapter retired: outdated 16 August 2012 (me) Comprehensive update posted live 20 June 2007 (cd) Revision: mutation scanning and sequence analysis available clinically 20 December 2005 (me) Comprehensive update posted live 17 July 2003 (me) Review posted live 25 April 2003 (rk) Original submission • 7 January 2021 (ma) Chapter retired: outdated • 16 August 2012 (me) Comprehensive update posted live • 20 June 2007 (cd) Revision: mutation scanning and sequence analysis available clinically • 20 December 2005 (me) Comprehensive update posted live • 17 July 2003 (me) Review posted live • 25 April 2003 (rk) Original submission	[ "GS Barsh. 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A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q.. Twin Res 2004;7:197-210" ]	17/7/2003	16/8/2012		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
oca4	oca4	[ "OCA4", "OCA4", "Membrane-associated transporter protein", "SLC45A2", "Oculocutaneous Albinism Type 4" ]	Oculocutaneous Albinism Type 4	Masahiro Hayashi, Tamio Suzuki	Summary Oculocutaneous albinism type 4 (OCA4) is characterized by hypopigmentation of the hair and skin plus the characteristic ocular changes found in all other types of albinism, including: nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity; and misrouting of the optic nerves at the chiasm associated with alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP). Individuals with OCA4 are usually recognized within the first year of life because of hypopigmentation of the hair and skin and the ocular features of nystagmus and strabismus. Vision is likely to be stable after early childhood. The amount of cutaneous pigmentation in OCA4 ranges from minimal to near normal. Newborns with OCA4 usually have some pigment in their hair, with color ranging from silvery white to light yellow. Hair color may darken with time, but does not vary significantly from childhood to adulthood. Because the phenotype of OCA4 overlaps that of the other genetic forms of albinism (oculocutaneous and ocular), the diagnosis of OCA4 is established by molecular genetic testing with the identification of biallelic pathogenic variants in OCA4 is typically inherited in an autosomal recessive manner. The parents of a proband are obligate heterozygotes and thus carriers of one	## Diagnosis Oculocutaneous albinism type 4 (OCA4) Nystagmus Reduced iris pigment with iris translucency Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with reduction in visual acuity Alternating strabismus Reduced stereoscopic vision Altered visual evoked potential (VEP) Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. The diagnosis of OCA4 Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include the use of a Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of OCA4 overlaps that of the other genetic forms of albinism (oculocutaneous and ocular), a multigene panel or comprehensive genomic testing (when available) is the preferred molecular genetic testing method for this disorder. Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click For this disorder a multigene panel that also includes deletion/duplication analysis or exome array is recommended if no or only one pathogenic variant is identified. Molecular Genetic Testing Used in OCA4 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Note: • Nystagmus • Reduced iris pigment with iris translucency • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Nystagmus • Reduced iris pigment with iris translucency • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Alternating strabismus • Reduced stereoscopic vision • Altered visual evoked potential (VEP) • Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. • Alternating strabismus • Reduced stereoscopic vision • Altered visual evoked potential (VEP) • Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. • Nystagmus • Reduced iris pigment with iris translucency • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Alternating strabismus • Reduced stereoscopic vision • Altered visual evoked potential (VEP) • Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Oculocutaneous albinism type 4 (OCA4) Nystagmus Reduced iris pigment with iris translucency Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination Foveal hypoplasia associated with reduction in visual acuity Alternating strabismus Reduced stereoscopic vision Altered visual evoked potential (VEP) Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. • Nystagmus • Reduced iris pigment with iris translucency • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Nystagmus • Reduced iris pigment with iris translucency • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Alternating strabismus • Reduced stereoscopic vision • Altered visual evoked potential (VEP) • Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. • Alternating strabismus • Reduced stereoscopic vision • Altered visual evoked potential (VEP) • Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. • Nystagmus • Reduced iris pigment with iris translucency • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination • Foveal hypoplasia associated with reduction in visual acuity • Alternating strabismus • Reduced stereoscopic vision • Altered visual evoked potential (VEP) • Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA. ## Establishing the Diagnosis The diagnosis of OCA4 Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include the use of a Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of OCA4 overlaps that of the other genetic forms of albinism (oculocutaneous and ocular), a multigene panel or comprehensive genomic testing (when available) is the preferred molecular genetic testing method for this disorder. Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click For this disorder a multigene panel that also includes deletion/duplication analysis or exome array is recommended if no or only one pathogenic variant is identified. Molecular Genetic Testing Used in OCA4 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Note: • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics A wide range of clinical phenotypes has been recognized to date [ Individuals with albinism (including OCA4) are usually recognized within the first year of life because of the ocular features of nystagmus and strabismus. In many families, particularly in those with darker constitutional pigmentation, the cutaneous hypopigmentation is also obvious at birth and suggests the diagnosis. The range of hair and skin pigment in individuals with OCA4 is broad [ Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [ Skin color in individuals with OCA4 is not usually as white as that in individuals with the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that skin melanocytes in individuals with OCA4 can still synthesize some melanin; however, the majority of the melanin is yellow pheomelanin rather than black-brown eumelanin. Skin cancer is unusual in individuals with OCA4 in the US because of the availability of sunscreens, the social acceptability of wearing clothes that cover most of the exposed skin, and the fact that individuals with albinism often do not spend a great deal of time outside in the sun. Skin cancer in an individual with any type of OCA is very rare in northern areas of the US. Skin cancer in individuals with albinism is common particularly in some parts of Africa because of the increased amount of sun exposure throughout the year, the cultural differences in protective dress, and lack of skin-protective agents such as sunscreens. In addition, African individuals with albinism tend to have poorer prognosis with skin cancer because of late presentation to care and failure to complete treatment for economic reasons [ The lack of a functional assay for the Two common pathogenic alleles, Recently, a family with autosomal dominant OCA4 has been reported [ The degree of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular The ocular features of all types of oculocutaneous albinism (OCA) and X-linked ocular albinism (OA1) are similar and the terms "oculocutaneous albinism" and "albinism" can be used interchangeably when referring to these clinical features. Prevalence of OCA4 is thought to be on the order of 1:100,000 in most populations throughout the world. It is likely to be more common in Japan, where it accounts for 24% of individuals with OCA [ OCA4 has also been described in individuals of German, Turkish, Korean, Indian, Chinese, Danish, and Moroccan descent [ • Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. • Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. • It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. • Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [ ## Clinical Description A wide range of clinical phenotypes has been recognized to date [ Individuals with albinism (including OCA4) are usually recognized within the first year of life because of the ocular features of nystagmus and strabismus. In many families, particularly in those with darker constitutional pigmentation, the cutaneous hypopigmentation is also obvious at birth and suggests the diagnosis. The range of hair and skin pigment in individuals with OCA4 is broad [ Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [ Skin color in individuals with OCA4 is not usually as white as that in individuals with the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that skin melanocytes in individuals with OCA4 can still synthesize some melanin; however, the majority of the melanin is yellow pheomelanin rather than black-brown eumelanin. Skin cancer is unusual in individuals with OCA4 in the US because of the availability of sunscreens, the social acceptability of wearing clothes that cover most of the exposed skin, and the fact that individuals with albinism often do not spend a great deal of time outside in the sun. Skin cancer in an individual with any type of OCA is very rare in northern areas of the US. Skin cancer in individuals with albinism is common particularly in some parts of Africa because of the increased amount of sun exposure throughout the year, the cultural differences in protective dress, and lack of skin-protective agents such as sunscreens. In addition, African individuals with albinism tend to have poorer prognosis with skin cancer because of late presentation to care and failure to complete treatment for economic reasons [ • Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. • Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. • It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. • Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [ ## Eye ## Hair/Skin The range of hair and skin pigment in individuals with OCA4 is broad [ Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [ Skin color in individuals with OCA4 is not usually as white as that in individuals with the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that skin melanocytes in individuals with OCA4 can still synthesize some melanin; however, the majority of the melanin is yellow pheomelanin rather than black-brown eumelanin. Skin cancer is unusual in individuals with OCA4 in the US because of the availability of sunscreens, the social acceptability of wearing clothes that cover most of the exposed skin, and the fact that individuals with albinism often do not spend a great deal of time outside in the sun. Skin cancer in an individual with any type of OCA is very rare in northern areas of the US. Skin cancer in individuals with albinism is common particularly in some parts of Africa because of the increased amount of sun exposure throughout the year, the cultural differences in protective dress, and lack of skin-protective agents such as sunscreens. In addition, African individuals with albinism tend to have poorer prognosis with skin cancer because of late presentation to care and failure to complete treatment for economic reasons [ • Scalp hair may be very light, but it is usually not completely white (not as white as a sheet of paper or fresh snow); some parents may refer to light yellow/blond hair color as "white" or "nearly white" if it is very lightly pigmented or is much lighter than the hair color of other family members at a similar age. • Furthermore, the definition of "white" scalp hair is not easy in some young children because the hair may be sparse and short and because some shampoos discolor hair. • It is helpful to hold a piece of white paper next to the hair to determine if it is truly white. • Hair color may darken with time, but usually the hair color does not change dramatically between childhood and adulthood [ ## Genotype-Phenotype Correlations The lack of a functional assay for the Two common pathogenic alleles, Recently, a family with autosomal dominant OCA4 has been reported [ The degree of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular ## Nomenclature The ocular features of all types of oculocutaneous albinism (OCA) and X-linked ocular albinism (OA1) are similar and the terms "oculocutaneous albinism" and "albinism" can be used interchangeably when referring to these clinical features. ## Prevalence Prevalence of OCA4 is thought to be on the order of 1:100,000 in most populations throughout the world. It is likely to be more common in Japan, where it accounts for 24% of individuals with OCA [ OCA4 has also been described in individuals of German, Turkish, Korean, Indian, Chinese, Danish, and Moroccan descent [ ## Genetically Related (Allelic) Disorders OCA4 is the only phenotype known to be associated with pathogenic variants in ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of OCA4 AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked ## Management To establish the extent of disease in an individual diagnosed with oculocutaneous albinism type 4 (OCA4), the following evaluations are recommended if they have not already been completed: Complete ophthalmologic evaluation including measurement of visual acuity and refractive error Assessment for strabismus Assessment by dermatologist to instruct parents regarding use of sun-protective clothing, lotions, and formulas Consultation with a clinical geneticist and/or genetic counselor Ophthalmologic care is the most important part of the ongoing care for most individuals with OCA4. The majority of individuals with albinism have significant hyperopia or myopia and astigmatism. Correction of these refractive errors with spectacles or contact lenses can improve visual acuity. Except in the very unusual individual, correction of refractive errors cannot restore visual acuity to normal because of the foveal hypoplasia. The alternating strabismus found in most individuals with albinism is generally not associated with the development of amblyopia. Strabismus surgery is usually not required, but can be considered for cosmetic reasons if the strabismus is marked or fixed. Photophobia is common in individuals with OCA4, but the degree of discomfort varies and does not depend entirely on the amount of melanin pigment present in the iris or skin. In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because of the reduction in vision from the dark lenses. A hat with a brim (e.g., a baseball hat with a visor) is often the best way to achieve reduction in photophobia and sun protection. Protection from the sun through the wearing of protective clothing and the regular application of sunscreen is essential to prevent sunburn and secondary skin changes, and to decrease the risk of skin cancer in later life. Regular skin check-ups for skin cancer are recommended for adult individuals with OCA4, especially in cases of severe hypopigmentation. Individuals with OCA4 should stay out of the sun from an early age, as cumulative ultraviolet exposure is a major risk factor for skin cancers (see Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, socks) and sunscreen with a high SPF number (total blocks with SPF 45-50+). There is no scientific evidence to indicate how high an SPF value is enough; individuals with OCA4 should use sunscreen with higher SPF values (45-50+) to lessen as much as possible the cumulative effect of ultraviolet to their skin. Annual ophthalmologic examination and reassessment for accurate correction of refractive error are appropriate. There is no definitive guideline supported by scientific evidence as to how often an individual should be evaluated by a dermatologist, though an evaluation of the skin for cancer screening every six months is recommended. Avoid prolonged exposure of the skin to the sun. See Search • Complete ophthalmologic evaluation including measurement of visual acuity and refractive error • Assessment for strabismus • Assessment by dermatologist to instruct parents regarding use of sun-protective clothing, lotions, and formulas • Consultation with a clinical geneticist and/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with oculocutaneous albinism type 4 (OCA4), the following evaluations are recommended if they have not already been completed: Complete ophthalmologic evaluation including measurement of visual acuity and refractive error Assessment for strabismus Assessment by dermatologist to instruct parents regarding use of sun-protective clothing, lotions, and formulas Consultation with a clinical geneticist and/or genetic counselor • Complete ophthalmologic evaluation including measurement of visual acuity and refractive error • Assessment for strabismus • Assessment by dermatologist to instruct parents regarding use of sun-protective clothing, lotions, and formulas • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Ophthalmologic care is the most important part of the ongoing care for most individuals with OCA4. The majority of individuals with albinism have significant hyperopia or myopia and astigmatism. Correction of these refractive errors with spectacles or contact lenses can improve visual acuity. Except in the very unusual individual, correction of refractive errors cannot restore visual acuity to normal because of the foveal hypoplasia. The alternating strabismus found in most individuals with albinism is generally not associated with the development of amblyopia. Strabismus surgery is usually not required, but can be considered for cosmetic reasons if the strabismus is marked or fixed. Photophobia is common in individuals with OCA4, but the degree of discomfort varies and does not depend entirely on the amount of melanin pigment present in the iris or skin. In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because of the reduction in vision from the dark lenses. A hat with a brim (e.g., a baseball hat with a visor) is often the best way to achieve reduction in photophobia and sun protection. Protection from the sun through the wearing of protective clothing and the regular application of sunscreen is essential to prevent sunburn and secondary skin changes, and to decrease the risk of skin cancer in later life. Regular skin check-ups for skin cancer are recommended for adult individuals with OCA4, especially in cases of severe hypopigmentation. ## Prevention of Secondary Complications Individuals with OCA4 should stay out of the sun from an early age, as cumulative ultraviolet exposure is a major risk factor for skin cancers (see Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, socks) and sunscreen with a high SPF number (total blocks with SPF 45-50+). There is no scientific evidence to indicate how high an SPF value is enough; individuals with OCA4 should use sunscreen with higher SPF values (45-50+) to lessen as much as possible the cumulative effect of ultraviolet to their skin. ## Surveillance Annual ophthalmologic examination and reassessment for accurate correction of refractive error are appropriate. There is no definitive guideline supported by scientific evidence as to how often an individual should be evaluated by a dermatologist, though an evaluation of the skin for cancer screening every six months is recommended. ## Agents/Circumstances to Avoid Avoid prolonged exposure of the skin to the sun. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling OCA4 is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder; they may be light in pigmentation for their ethnic group. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although they may be light in pigmentation for their ethnic group. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the A fetal skin biopsy will not provide an accurate diagnosis and is not appropriate for prenatal diagnosis of OCA4. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder; they may be light in pigmentation for their ethnic group. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although they may be light in pigmentation for their ethnic group. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance OCA4 is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder; they may be light in pigmentation for their ethnic group. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although they may be light in pigmentation for their ethnic group. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder; they may be light in pigmentation for their ethnic group. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although they may be light in pigmentation for their ethnic group. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the A fetal skin biopsy will not provide an accurate diagnosis and is not appropriate for prenatal diagnosis of OCA4. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • • • United Kingdom • ## Molecular Genetics Oculocutaneous Albinism Type 4: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Oculocutaneous Albinism Type 4 ( The phenotype resulting from heterozygosity of a single Most individuals with OCA4 are compound heterozygotes for Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The phenotype resulting from heterozygosity of a single Most individuals with OCA4 are compound heterozygotes for Variants listed in the table have been provided by the authors. ## Chapter Notes Murray H Brilliant, PhD; University of Wisconsin School of Medicine (2005-2011)Masahiro Hayashi, MD, PhD (2011-present)Tamio Suzuki, MD, PhD (2011-present) 7 September 2017 (ha) Comprehensive update posted live 15 September 2011 (cd) Revision: deletion/duplication analysis of 5 May 2011 (me) Comprehensive updated posted live 14 June 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically 17 November 2005 (me) Review posted live 21 April 2005 (mb) Original submission • 7 September 2017 (ha) Comprehensive update posted live • 15 September 2011 (cd) Revision: deletion/duplication analysis of • 5 May 2011 (me) Comprehensive updated posted live • 14 June 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically • 17 November 2005 (me) Review posted live • 21 April 2005 (mb) Original submission ## Author History Murray H Brilliant, PhD; University of Wisconsin School of Medicine (2005-2011)Masahiro Hayashi, MD, PhD (2011-present)Tamio Suzuki, MD, PhD (2011-present) ## Revision History 7 September 2017 (ha) Comprehensive update posted live 15 September 2011 (cd) Revision: deletion/duplication analysis of 5 May 2011 (me) Comprehensive updated posted live 14 June 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically 17 November 2005 (me) Review posted live 21 April 2005 (mb) Original submission • 7 September 2017 (ha) Comprehensive update posted live • 15 September 2011 (cd) Revision: deletion/duplication analysis of • 5 May 2011 (me) Comprehensive updated posted live • 14 June 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically • 17 November 2005 (me) Review posted live • 21 April 2005 (mb) Original submission ## References ## Literature Cited	[ "ME Asuquo, O Ngim, G Ebughe, EE Bassey. 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ofd1	ofd1	[ "OFD1", "Orofaciodigital Syndrome I", "OFD1", "Orofaciodigital Syndrome I", "Centriole and centriolar satellite protein OFD1", "OFD1", "Oral-Facial-Digital Syndrome Type I" ]	Oral-Facial-Digital Syndrome Type I	Brunella Franco, Ange-Line Bruel, Christel Thauvin-Robinet	Summary Oral-facial-digital syndrome type I (OFD1) is usually male lethal during gestation and predominantly affects females. OFD1 is characterized by the following: oral features (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities); facial features (widely spaced eyes, telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft of the upper lip, micrognathia); digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe); polycystic kidney disease; brain MRI findings (intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation); and intellectual disability (in approximately 50% of affected individuals). The diagnosis of OFD1 is established in a female proband with suggestive findings and a heterozygous OFD1 is inherited in an X-linked manner with, typically, male lethality. The full OFD1 phenotype has not been described in males beyond the perinatal period. Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a	## Diagnosis No consensus clinical diagnostic criteria for oral-facial-digital syndrome type I (OFD1) have been published. OFD1 Tongue anomalies (e.g., lobulated, nodules, ankyloglossia) Cleft palate Alveolar clefts and accessory gingival frenulae Dental anomalies (e.g., missing teeth, extra teeth) Widely spaced eyes, telecanthus, downslanting palpebral fissures Hypoplasia of the alae nasi Median cleft lip, pseudocleft of the upper lip Micrognathia Brachydactyly, syndactyly Clinodactyly of the fifth finger Radial or ulnar deviation of the other fingers, particularly the third Unilateral duplicated hallux (great toe) Polycystic kidney disease Intellectual disability Milia Family history is consistent with X-linked inheritance predominantly affecting females due to male lethality. Absence of a known family history does not preclude the diagnosis. Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [ Molecular testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One study found that six of 131 individuals with OFD1 had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a pathogenic variant identified on gene sequencing were found on qPCR to have a single- or multiexon deletion [ • Tongue anomalies (e.g., lobulated, nodules, ankyloglossia) • Cleft palate • Alveolar clefts and accessory gingival frenulae • Dental anomalies (e.g., missing teeth, extra teeth) • Widely spaced eyes, telecanthus, downslanting palpebral fissures • Hypoplasia of the alae nasi • Median cleft lip, pseudocleft of the upper lip • Micrognathia • Brachydactyly, syndactyly • Clinodactyly of the fifth finger • Radial or ulnar deviation of the other fingers, particularly the third • Unilateral duplicated hallux (great toe) • Polycystic kidney disease • Intellectual disability • Milia ## Suggestive Findings OFD1 Tongue anomalies (e.g., lobulated, nodules, ankyloglossia) Cleft palate Alveolar clefts and accessory gingival frenulae Dental anomalies (e.g., missing teeth, extra teeth) Widely spaced eyes, telecanthus, downslanting palpebral fissures Hypoplasia of the alae nasi Median cleft lip, pseudocleft of the upper lip Micrognathia Brachydactyly, syndactyly Clinodactyly of the fifth finger Radial or ulnar deviation of the other fingers, particularly the third Unilateral duplicated hallux (great toe) Polycystic kidney disease Intellectual disability Milia Family history is consistent with X-linked inheritance predominantly affecting females due to male lethality. Absence of a known family history does not preclude the diagnosis. • Tongue anomalies (e.g., lobulated, nodules, ankyloglossia) • Cleft palate • Alveolar clefts and accessory gingival frenulae • Dental anomalies (e.g., missing teeth, extra teeth) • Widely spaced eyes, telecanthus, downslanting palpebral fissures • Hypoplasia of the alae nasi • Median cleft lip, pseudocleft of the upper lip • Micrognathia • Brachydactyly, syndactyly • Clinodactyly of the fifth finger • Radial or ulnar deviation of the other fingers, particularly the third • Unilateral duplicated hallux (great toe) • Polycystic kidney disease • Intellectual disability • Milia ## Clinical Features Tongue anomalies (e.g., lobulated, nodules, ankyloglossia) Cleft palate Alveolar clefts and accessory gingival frenulae Dental anomalies (e.g., missing teeth, extra teeth) Widely spaced eyes, telecanthus, downslanting palpebral fissures Hypoplasia of the alae nasi Median cleft lip, pseudocleft of the upper lip Micrognathia Brachydactyly, syndactyly Clinodactyly of the fifth finger Radial or ulnar deviation of the other fingers, particularly the third Unilateral duplicated hallux (great toe) Polycystic kidney disease Intellectual disability Milia • Tongue anomalies (e.g., lobulated, nodules, ankyloglossia) • Cleft palate • Alveolar clefts and accessory gingival frenulae • Dental anomalies (e.g., missing teeth, extra teeth) • Widely spaced eyes, telecanthus, downslanting palpebral fissures • Hypoplasia of the alae nasi • Median cleft lip, pseudocleft of the upper lip • Micrognathia • Brachydactyly, syndactyly • Clinodactyly of the fifth finger • Radial or ulnar deviation of the other fingers, particularly the third • Unilateral duplicated hallux (great toe) • Polycystic kidney disease • Intellectual disability • Milia ## Imaging Features ## Family History Family history is consistent with X-linked inheritance predominantly affecting females due to male lethality. Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [ Molecular testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One study found that six of 131 individuals with OFD1 had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a pathogenic variant identified on gene sequencing were found on qPCR to have a single- or multiexon deletion [ ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One study found that six of 131 individuals with OFD1 had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a pathogenic variant identified on gene sequencing were found on qPCR to have a single- or multiexon deletion [ ## Clinical Characteristics The diagnosis of oral-facial-digital syndrome type I (OFD1) is suspected at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood. Almost all affected individuals with OFD1 are female; however, a few affected males have been reported. Most affected males are described as malformed fetuses delivered by a female with OFD1. To date, 234 individuals have been identified with a pathogenic variant in Oral-Facial-Digital Syndrome Type I: Frequency of Select Features Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy. Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [ No convincing genotype-phenotype correlations have been reported. The majority of OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females [ OFD1 was previously called Papillon-Léage-Psaume syndrome. Prevalence estimates range from 1:50,000 to 1:250,000. ## Clinical Description The diagnosis of oral-facial-digital syndrome type I (OFD1) is suspected at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood. Almost all affected individuals with OFD1 are female; however, a few affected males have been reported. Most affected males are described as malformed fetuses delivered by a female with OFD1. To date, 234 individuals have been identified with a pathogenic variant in Oral-Facial-Digital Syndrome Type I: Frequency of Select Features Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy. Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [ ## Genotype-Phenotype Correlations No convincing genotype-phenotype correlations have been reported. The majority of ## Penetrance OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females [ ## Nomenclature OFD1 was previously called Papillon-Léage-Psaume syndrome. ## Prevalence Prevalence estimates range from 1:50,000 to 1:250,000. ## Genetically Related (Allelic) Disorders An An A male fetus with a hemizygous • An • An • A male fetus with a hemizygous ## Differential Diagnosis The differential diagnosis of oral-facial-digital syndrome type I (OFD1) includes other oral-facial-digital syndromes and cystic renal diseases. Genes of Interest in the Differential Diagnosis of Oral-Facial-Digital Syndrome Type I AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; ID = intellectual disability; JS = Joubert syndrome; JS-OFD = Joubert syndrome with oral-facial-digital features; MOI = mode of inheritance; MTS = molar tooth sign; OFD = oral-facial-digital; SRPS = short-rib polydactyly syndrome Note: OFD types of unknown genetic cause include the following: OFD3 (OMIM OFD8 (OMIM OFD9 (OMIM OFD10 (OMIM OFD11 (OMIM OFD12 is described in only one individual with brain malformations, myelomeningocele, short tibiae, and central Y-shaped metacarpal [ OFD13 is described in only one individual with neuropsychiatric disturbances and leukoaraiosis [ • OFD3 (OMIM • OFD8 (OMIM • OFD9 (OMIM • OFD10 (OMIM • OFD11 (OMIM • OFD12 is described in only one individual with brain malformations, myelomeningocele, short tibiae, and central Y-shaped metacarpal [ • OFD13 is described in only one individual with neuropsychiatric disturbances and leukoaraiosis [ ## Management No clinical practice guidelines for oral-facial-digital syndrome type I (OFD1) have been published. To establish the extent of disease and needs in an individual diagnosed with OFD1, the evaluations summarized in Oral-Facial-Digital Syndrome Type I: Recommended Evaluations Eval of CNS involvement incl brain MRI Neurologic eval w/movement disorder specialist for ataxia EEG in those w/suspected seizures Blood pressure Serum creatinine concentration Serum chemistries Urinalysis Community or Social work involvement for parental support; Home nursing referral. CNS = central nervous system; MOI = mode of inheritance; OFD1 = oral-facial-digital syndrome type I Medical geneticist, certified genetic counselor, certified advanced genetic nurse Oral-Facial-Digital Syndrome Type I: Treatment of Manifestations Reconstructive surgery for clefts of lip &/or palate, tongue nodules, & accessory frenulae Treatment is the same as as that for isolated cleft palate, incl speech therapy & assessment for & aggressive treatment of otitis media. Removal of accessory teeth Orthodontia for malocclusion Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Early intervention & IEP for those w/developmental issues, learning disabilities, & other cognitive impairments Standard treatments for ADHD &/or autistic features ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; IEP = individualized education plan Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Oral-Facial-Digital Syndrome Type I: Recommended Surveillance Blood pressure exam Serum creatinine concentration Renal ultrasound for renal cysts Incl ultrasound of liver, pancreas, & ovaries for cystic disease It is appropriate to evaluate the genetic status of apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for renal disease. See Affected pregnant women should undergo careful monitoring of their blood pressure and renal function during pregnancy. Search • Eval of CNS involvement incl brain MRI • Neurologic eval w/movement disorder specialist for ataxia • EEG in those w/suspected seizures • Blood pressure • Serum creatinine concentration • Serum chemistries • Urinalysis • Community or • Social work involvement for parental support; • Home nursing referral. • Reconstructive surgery for clefts of lip &/or palate, tongue nodules, & accessory frenulae • Treatment is the same as as that for isolated cleft palate, incl speech therapy & assessment for & aggressive treatment of otitis media. • Removal of accessory teeth • Orthodontia for malocclusion • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Early intervention & IEP for those w/developmental issues, learning disabilities, & other cognitive impairments • Standard treatments for ADHD &/or autistic features • Blood pressure exam • Serum creatinine concentration • Renal ultrasound for renal cysts • Incl ultrasound of liver, pancreas, & ovaries for cystic disease ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with OFD1, the evaluations summarized in Oral-Facial-Digital Syndrome Type I: Recommended Evaluations Eval of CNS involvement incl brain MRI Neurologic eval w/movement disorder specialist for ataxia EEG in those w/suspected seizures Blood pressure Serum creatinine concentration Serum chemistries Urinalysis Community or Social work involvement for parental support; Home nursing referral. CNS = central nervous system; MOI = mode of inheritance; OFD1 = oral-facial-digital syndrome type I Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Eval of CNS involvement incl brain MRI • Neurologic eval w/movement disorder specialist for ataxia • EEG in those w/suspected seizures • Blood pressure • Serum creatinine concentration • Serum chemistries • Urinalysis • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Oral-Facial-Digital Syndrome Type I: Treatment of Manifestations Reconstructive surgery for clefts of lip &/or palate, tongue nodules, & accessory frenulae Treatment is the same as as that for isolated cleft palate, incl speech therapy & assessment for & aggressive treatment of otitis media. Removal of accessory teeth Orthodontia for malocclusion Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Early intervention & IEP for those w/developmental issues, learning disabilities, & other cognitive impairments Standard treatments for ADHD &/or autistic features ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; IEP = individualized education plan Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Reconstructive surgery for clefts of lip &/or palate, tongue nodules, & accessory frenulae • Treatment is the same as as that for isolated cleft palate, incl speech therapy & assessment for & aggressive treatment of otitis media. • Removal of accessory teeth • Orthodontia for malocclusion • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Early intervention & IEP for those w/developmental issues, learning disabilities, & other cognitive impairments • Standard treatments for ADHD &/or autistic features ## Surveillance Oral-Facial-Digital Syndrome Type I: Recommended Surveillance Blood pressure exam Serum creatinine concentration Renal ultrasound for renal cysts Incl ultrasound of liver, pancreas, & ovaries for cystic disease • Blood pressure exam • Serum creatinine concentration • Renal ultrasound for renal cysts • Incl ultrasound of liver, pancreas, & ovaries for cystic disease ## Evaluation of Relatives at Risk It is appropriate to evaluate the genetic status of apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for renal disease. See ## Pregnancy Management Affected pregnant women should undergo careful monitoring of their blood pressure and renal function during pregnancy. ## Therapies Under Investigation Search ## Genetic Counseling Oral-facial-digital syndrome type I (OFD1) is inherited in an X-linked manner with, typically, male lethality. Almost all affected individuals with OFD1 are female. The full OFD1 phenotype has not been described in males beyond the perinatal period. Males with a hemizygous A female proband may have inherited the Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) Recommendations for the evaluation of the mother of a proband with an apparent If the mother of the proband has an If the proband represents a simplex case and if the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • A female proband may have inherited the • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) • Recommendations for the evaluation of the mother of a proband with an apparent • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) • If the mother of the proband has an • If the proband represents a simplex case and if the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an ## Mode of Inheritance Oral-facial-digital syndrome type I (OFD1) is inherited in an X-linked manner with, typically, male lethality. Almost all affected individuals with OFD1 are female. The full OFD1 phenotype has not been described in males beyond the perinatal period. Males with a hemizygous ## Risk to Family Members A female proband may have inherited the Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) Recommendations for the evaluation of the mother of a proband with an apparent If the mother of the proband has an If the proband represents a simplex case and if the • A female proband may have inherited the • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) • Recommendations for the evaluation of the mother of a proband with an apparent • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.) • If the mother of the proband has an • If the proband represents a simplex case and if the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having an ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Canada • • • • • • United Kingdom • • • • • Canada • • • ## Molecular Genetics Oral-Facial-Digital Syndrome Type I: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Oral-Facial-Digital Syndrome Type I ( Oral-facial-digital syndrome 1 protein (also called centriole and centriolar satellite protein OFD1) occurs in two forms, OFD1-1 (Cxorf5-1) and OFD1-2 (Cxorf5-2), which are differentiated by the use of an alternative splice site. OFD1-1 is a 1,012-amino acid protein (reference sequence ## Molecular Pathogenesis Oral-facial-digital syndrome 1 protein (also called centriole and centriolar satellite protein OFD1) occurs in two forms, OFD1-1 (Cxorf5-1) and OFD1-2 (Cxorf5-2), which are differentiated by the use of an alternative splice site. OFD1-1 is a 1,012-amino acid protein (reference sequence ## Chapter Notes We thank the Italian Fondazione telethon for continuous support of our research and the patients and their families for participating in research activities. We also thank all the researchers who have contributed to the understanding of this disorder. Ange-Line Bruel, PhD (2016-present)Brunella Franco, MD (2010-present)Danilo Moretti-Ferreira, PhD; São Paulo State University (2002-2010)Izolda Nunes Guimaraes, PhD; São Paulo State University (2002-2010)Christel Thauvin-Robinet, MD, PhD (2016-present)Helga V Toriello, PhD; Genetics Services Spectrum Health (2002-2023) 11 May 2023 (sw) Comprehensive update posted live 4 August 2016 (sw) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 14 October 2010 (me) Comprehensive update posted live 9 March 2007 (ht, cd) Revision: sequence analysis and prenatal diagnosis clinically available 14 August 2006 (me) Comprehensive update posted live 29 June 2004 (me) Comprehensive update posted live 24 July 2002 (me) Review posted live 27 February 2002 (ht) Original submission • 11 May 2023 (sw) Comprehensive update posted live • 4 August 2016 (sw) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 14 October 2010 (me) Comprehensive update posted live • 9 March 2007 (ht, cd) Revision: sequence analysis and prenatal diagnosis clinically available • 14 August 2006 (me) Comprehensive update posted live • 29 June 2004 (me) Comprehensive update posted live • 24 July 2002 (me) Review posted live • 27 February 2002 (ht) Original submission ## Acknowledgments We thank the Italian Fondazione telethon for continuous support of our research and the patients and their families for participating in research activities. We also thank all the researchers who have contributed to the understanding of this disorder. ## Author History Ange-Line Bruel, PhD (2016-present)Brunella Franco, MD (2010-present)Danilo Moretti-Ferreira, PhD; São Paulo State University (2002-2010)Izolda Nunes Guimaraes, PhD; São Paulo State University (2002-2010)Christel Thauvin-Robinet, MD, PhD (2016-present)Helga V Toriello, PhD; Genetics Services Spectrum Health (2002-2023) ## Revision History 11 May 2023 (sw) Comprehensive update posted live 4 August 2016 (sw) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 14 October 2010 (me) Comprehensive update posted live 9 March 2007 (ht, cd) Revision: sequence analysis and prenatal diagnosis clinically available 14 August 2006 (me) Comprehensive update posted live 29 June 2004 (me) Comprehensive update posted live 24 July 2002 (me) Review posted live 27 February 2002 (ht) Original submission • 11 May 2023 (sw) Comprehensive update posted live • 4 August 2016 (sw) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 14 October 2010 (me) Comprehensive update posted live • 9 March 2007 (ht, cd) Revision: sequence analysis and prenatal diagnosis clinically available • 14 August 2006 (me) Comprehensive update posted live • 29 June 2004 (me) Comprehensive update posted live • 24 July 2002 (me) Review posted live • 27 February 2002 (ht) Original submission ## References ## Literature Cited	[ "CL Alamillo, Z Powis, K Farwell, L Shahmirzadi, EC Weltmer, J Turocy, T Lowe, C Kobelka, E Chen, D Basel, E Ashkinadze, L D'Augelli, E Chao, S Tang. 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og-dysp	og-dysp	[ "FGFR1-Related Osteoglophonic Dysplasia", "Osteoglophonic Dwarfism", "Fairbank-Keats Syndrome", "FGFR1-Related Osteoglophonic Dysplasia", "Osteoglophonic Dwarfism", "Fairbank-Keats Syndrome", "Fibroblast growth factor receptor 1", "FGFR1", "Osteoglophonic Dysplasia" ]	Osteoglophonic Dysplasia	Amna A Othman, Holly E Babcock, Carlos R Ferreira	Summary Osteoglophonic dysplasia (OGD) is characterized by multisuture craniosynostosis (including cloverleaf skull), distinctive craniofacial features (prominent forehead, proptosis, widely spaced eyes, low-set ears, midface retrusion, short nose, anteverted nares, prognathism, high palate, failure of tooth eruption, and gingival overgrowth), profound short stature with rhizomelia, and short, broad hands and feet. Radiographs show copper beaten appearance to skull, multiple cystic long bone lesions consistent with non-ossifying fibromas, irregular vertebral bodies, and osteopenia with increased risk of fractures. The diagnosis of OGD is established in a proband with characteristic clinical and imaging findings and a heterozygous pathogenic gain-of-function variant in OGD is inherited in an autosomal dominant manner. Most individuals diagnosed with OGD represent simplex cases; some individuals diagnosed with OGD have an affected parent. Each child of an individual with OGD has a 50% chance of inheriting the	## Diagnosis Osteoglophonic dysplasia (OGD) Multisuture craniosynostosis (including cloverleaf skull) Prominent forehead Proptosis Widely spaced eyes Low-set ears Midface retrusion Short nose Anteverted nares Prognathism High palate Failure of tooth eruption Gingival overgrowth Short stature Rhizomelic limb shortening Short, broad hands and feet Genu varum Overlapping toes Pathologic fractures Poor weight gain Increased body temperature Increased sensitivity to heat Excessive sweating Nasal obstruction Short neck Inguinal hernia Developmental delay (primarily speech delay) Skull. Copper beaten appearance Teeth. Multiple unerupted permanent tooth buds in mandible and maxilla Long bones. Multiple cystic bone lesions consistent with non-ossifying fibromas Vertebral bodies. Irregular platyspondyly with anterior projection and concavity of their posterior portions Osteopenia Hypophosphatemia Normal to increased serum fibroblast growth factor 23 (FGF23) The diagnosis of OGD Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Osteoglophonic Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Including two individuals known to authors and others reported by Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with osteoglophonic dysplasia. • • Multisuture craniosynostosis (including cloverleaf skull) • Prominent forehead • Proptosis • Widely spaced eyes • Low-set ears • Midface retrusion • Short nose • Anteverted nares • Prognathism • High palate • Failure of tooth eruption • Gingival overgrowth • Multisuture craniosynostosis (including cloverleaf skull) • Prominent forehead • Proptosis • Widely spaced eyes • Low-set ears • Midface retrusion • Short nose • Anteverted nares • Prognathism • High palate • Failure of tooth eruption • Gingival overgrowth • • Short stature • Rhizomelic limb shortening • Short, broad hands and feet • Genu varum • Overlapping toes • Pathologic fractures • Short stature • Rhizomelic limb shortening • Short, broad hands and feet • Genu varum • Overlapping toes • Pathologic fractures • • Poor weight gain • Increased body temperature • Increased sensitivity to heat • Excessive sweating • Nasal obstruction • Short neck • Inguinal hernia • Developmental delay (primarily speech delay) • Poor weight gain • Increased body temperature • Increased sensitivity to heat • Excessive sweating • Nasal obstruction • Short neck • Inguinal hernia • Developmental delay (primarily speech delay) • Multisuture craniosynostosis (including cloverleaf skull) • Prominent forehead • Proptosis • Widely spaced eyes • Low-set ears • Midface retrusion • Short nose • Anteverted nares • Prognathism • High palate • Failure of tooth eruption • Gingival overgrowth • Short stature • Rhizomelic limb shortening • Short, broad hands and feet • Genu varum • Overlapping toes • Pathologic fractures • Poor weight gain • Increased body temperature • Increased sensitivity to heat • Excessive sweating • Nasal obstruction • Short neck • Inguinal hernia • Developmental delay (primarily speech delay) • Skull. Copper beaten appearance • Teeth. Multiple unerupted permanent tooth buds in mandible and maxilla • Long bones. Multiple cystic bone lesions consistent with non-ossifying fibromas • Vertebral bodies. Irregular platyspondyly with anterior projection and concavity of their posterior portions • Osteopenia • Hypophosphatemia • Normal to increased serum fibroblast growth factor 23 (FGF23) ## Suggestive Findings Osteoglophonic dysplasia (OGD) Multisuture craniosynostosis (including cloverleaf skull) Prominent forehead Proptosis Widely spaced eyes Low-set ears Midface retrusion Short nose Anteverted nares Prognathism High palate Failure of tooth eruption Gingival overgrowth Short stature Rhizomelic limb shortening Short, broad hands and feet Genu varum Overlapping toes Pathologic fractures Poor weight gain Increased body temperature Increased sensitivity to heat Excessive sweating Nasal obstruction Short neck Inguinal hernia Developmental delay (primarily speech delay) Skull. Copper beaten appearance Teeth. Multiple unerupted permanent tooth buds in mandible and maxilla Long bones. Multiple cystic bone lesions consistent with non-ossifying fibromas Vertebral bodies. Irregular platyspondyly with anterior projection and concavity of their posterior portions Osteopenia Hypophosphatemia Normal to increased serum fibroblast growth factor 23 (FGF23) • • Multisuture craniosynostosis (including cloverleaf skull) • Prominent forehead • Proptosis • Widely spaced eyes • Low-set ears • Midface retrusion • Short nose • Anteverted nares • Prognathism • High palate • Failure of tooth eruption • Gingival overgrowth • Multisuture craniosynostosis (including cloverleaf skull) • Prominent forehead • Proptosis • Widely spaced eyes • Low-set ears • Midface retrusion • Short nose • Anteverted nares • Prognathism • High palate • Failure of tooth eruption • Gingival overgrowth • • Short stature • Rhizomelic limb shortening • Short, broad hands and feet • Genu varum • Overlapping toes • Pathologic fractures • Short stature • Rhizomelic limb shortening • Short, broad hands and feet • Genu varum • Overlapping toes • Pathologic fractures • • Poor weight gain • Increased body temperature • Increased sensitivity to heat • Excessive sweating • Nasal obstruction • Short neck • Inguinal hernia • Developmental delay (primarily speech delay) • Poor weight gain • Increased body temperature • Increased sensitivity to heat • Excessive sweating • Nasal obstruction • Short neck • Inguinal hernia • Developmental delay (primarily speech delay) • Multisuture craniosynostosis (including cloverleaf skull) • Prominent forehead • Proptosis • Widely spaced eyes • Low-set ears • Midface retrusion • Short nose • Anteverted nares • Prognathism • High palate • Failure of tooth eruption • Gingival overgrowth • Short stature • Rhizomelic limb shortening • Short, broad hands and feet • Genu varum • Overlapping toes • Pathologic fractures • Poor weight gain • Increased body temperature • Increased sensitivity to heat • Excessive sweating • Nasal obstruction • Short neck • Inguinal hernia • Developmental delay (primarily speech delay) • Skull. Copper beaten appearance • Teeth. Multiple unerupted permanent tooth buds in mandible and maxilla • Long bones. Multiple cystic bone lesions consistent with non-ossifying fibromas • Vertebral bodies. Irregular platyspondyly with anterior projection and concavity of their posterior portions • Osteopenia • Hypophosphatemia • Normal to increased serum fibroblast growth factor 23 (FGF23) ## Establishing the Diagnosis The diagnosis of OGD Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Osteoglophonic Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Including two individuals known to authors and others reported by Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with osteoglophonic dysplasia. ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Osteoglophonic Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Including two individuals known to authors and others reported by Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with osteoglophonic dysplasia. ## Clinical Characteristics Osteoglophonic dysplasia (OGD) is a skeletal dysplasia characterized by multisuture craniosynostosis (including premature fusion of the coronal, sagittal, lambdoid, and metopic sutures), distinctive craniofacial features, unerupted teeth, profound short stature, and multiple cystic bone lesions consistent with non-ossifying fibromas. To date, 24 individuals with OGD from 19 families have been reported and/or identified; of these, 14 individuals have had molecular genetic testing with a pathogenic variant identified in Osteoglophonic Dysplasia: Frequency of Select Features FGF23 = fibroblast growth factor 23 Poor weight gain can be attributed to feeding difficulties, choanal atresia, or nasal obstruction with airway and breathing problems, which can occur during infancy as a result of craniofacial abnormalities and may rarely lead to death [ Delayed primary and secondary teeth eruption is a common feature during childhood. Skull radiographs typically show impacted permanent tooth buds, with a characteristic copper beaten appearance that may regress by adulthood [ No genotype-phenotype correlations have been identified. Penetrance is complete. The term osteoglophonic is derived from the Greek word meaning "hollowed out" and refers to the characteristic multiple non-ossifying fibromas that appear as cystic radiolucent lesions on radiologic images. This phenotype is thought to have been first described by Sir Thomas Fairbank [ In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ OGD is rare, with 22 individuals (from 17 different families) reported to date [ ## Clinical Description Osteoglophonic dysplasia (OGD) is a skeletal dysplasia characterized by multisuture craniosynostosis (including premature fusion of the coronal, sagittal, lambdoid, and metopic sutures), distinctive craniofacial features, unerupted teeth, profound short stature, and multiple cystic bone lesions consistent with non-ossifying fibromas. To date, 24 individuals with OGD from 19 families have been reported and/or identified; of these, 14 individuals have had molecular genetic testing with a pathogenic variant identified in Osteoglophonic Dysplasia: Frequency of Select Features FGF23 = fibroblast growth factor 23 Poor weight gain can be attributed to feeding difficulties, choanal atresia, or nasal obstruction with airway and breathing problems, which can occur during infancy as a result of craniofacial abnormalities and may rarely lead to death [ Delayed primary and secondary teeth eruption is a common feature during childhood. Skull radiographs typically show impacted permanent tooth buds, with a characteristic copper beaten appearance that may regress by adulthood [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance Penetrance is complete. ## Nomenclature The term osteoglophonic is derived from the Greek word meaning "hollowed out" and refers to the characteristic multiple non-ossifying fibromas that appear as cystic radiolucent lesions on radiologic images. This phenotype is thought to have been first described by Sir Thomas Fairbank [ In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ ## Prevalence OGD is rare, with 22 individuals (from 17 different families) reported to date [ ## Genetically Related (Allelic) Disorders Germline pathogenic variants in GnRH = gonadotropin-releasing hormone; HPE = holoprosencephaly Mosaic activating pathogenic variants in ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Osteoglophonic Dysplasia Multisuture craniosynostosis Moderate-to-severe midface retrusion Proptosis Airway obstruction Dental crowding Less pronounced short stature Broad thumbs & great toes Medially deviated thumbs & great toes CHL Multisuture craniosynostosis Moderate-to-severe midface retrusion Proptosis Dental anomalies Airway obstruction Soft tissue & bony syndactyly ± polydactyly of fingers & toes Synonychia Cleft palate CHL Multisuture craniosynostosis Moderate-to-severe midface retrusion Proptosis Airway obstruction CHL & SNHL Normal hands & feet Multisuture craniosynostosis Proptosis Airway obstruction Broad & medially deviated great toes 2/3 toe syndactyly Non-ossifying fibromas Pseudoarthrosis Giant cell granulomas of the jaw Intellectual & learning disabilities Café au lait macules Above average head circumference for age Optic glioma Neurofibroma AD = autosomal dominant; CHL = conductive hearing loss; MOI = mode of inheritance; OGD = osteoglophonic dysplasia; SNHL = sensorineural hearing loss • Multisuture craniosynostosis • Moderate-to-severe midface retrusion • Proptosis • Airway obstruction • Dental crowding • Less pronounced short stature • Broad thumbs & great toes • Medially deviated thumbs & great toes • CHL • Multisuture craniosynostosis • Moderate-to-severe midface retrusion • Proptosis • Dental anomalies • Airway obstruction • Soft tissue & bony syndactyly ± polydactyly of fingers & toes • Synonychia • Cleft palate • CHL • Multisuture craniosynostosis • Moderate-to-severe midface retrusion • Proptosis • Airway obstruction • CHL & SNHL • Normal hands & feet • Multisuture craniosynostosis • Proptosis • Airway obstruction • Broad & medially deviated great toes • 2/3 toe syndactyly • Non-ossifying fibromas • Pseudoarthrosis • Giant cell granulomas of the jaw • Intellectual & learning disabilities • Café au lait macules • Above average head circumference for age • Optic glioma • Neurofibroma ## Management No clinical practice guidelines for osteoglophonic dysplasia (OGD) have been published. To establish the extent of disease and needs in an individual diagnosed with OGD, the evaluations summarized in Osteoglophonic Dysplasia: Recommended Evaluations Following Initial Diagnosis Referral to orthopedist Spine & long bone radiographs to detect platyspondyly & non-ossifying fibromas Assess for developmental disabilities incl speech & swallowing eval. Refer to early intervention services. Consider referral to neurodevelopmental specialist. Assess for airway symptoms (snoring, stridor, apnea, respiratory distress). Consider consultation w/otolaryngologist & sleep medicine specialist to identify & quantify degree of sleep apnea. Community or Social work involvement for parental support; Home nursing referral. FGF23 = fibroblast growth factor 23; MOI = mode of inheritance; OGD = osteoglophonic dysplasia Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for OGD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Osteoglophonic Dysplasia: Treatment of Manifestations Typically in childhood or adolescence Early midface advancement may be pursued to treat airway obstruction. BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Osteoglophonic Dysplasia: Recommended Surveillance Assess for recurrent/pathologic fractures. Monitor growth. Closely monitor head circumference / head growth. Evaluate for signs of ↑ intracranial pressure (e.g., headaches, vomiting). Clinical eval at least every 3 mos in 1st year of life Can be done in conjunction w/team visits to assess for craniosynostosis. FGF23 = fibroblast growth factor 23 Individuals with OGD may require sports restrictions for activities that carry a potential for head or neck injury. Individuals with severe proptosis need to wear protective eyewear during activities with risk of eye injury (e.g., ball sports). It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment of developmental and craniofacial manifestations. See No published studies address management of pregnancy in women with OGD. See Search • Referral to orthopedist • Spine & long bone radiographs to detect platyspondyly & non-ossifying fibromas • Assess for developmental disabilities incl speech & swallowing eval. • Refer to early intervention services. • Consider referral to neurodevelopmental specialist. • Assess for airway symptoms (snoring, stridor, apnea, respiratory distress). • Consider consultation w/otolaryngologist & sleep medicine specialist to identify & quantify degree of sleep apnea. • Community or • Social work involvement for parental support; • Home nursing referral. • Typically in childhood or adolescence • Early midface advancement may be pursued to treat airway obstruction. • Assess for recurrent/pathologic fractures. • Monitor growth. • Closely monitor head circumference / head growth. • Evaluate for signs of ↑ intracranial pressure (e.g., headaches, vomiting). • Clinical eval at least every 3 mos in 1st year of life • Can be done in conjunction w/team visits to assess for craniosynostosis. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with OGD, the evaluations summarized in Osteoglophonic Dysplasia: Recommended Evaluations Following Initial Diagnosis Referral to orthopedist Spine & long bone radiographs to detect platyspondyly & non-ossifying fibromas Assess for developmental disabilities incl speech & swallowing eval. Refer to early intervention services. Consider referral to neurodevelopmental specialist. Assess for airway symptoms (snoring, stridor, apnea, respiratory distress). Consider consultation w/otolaryngologist & sleep medicine specialist to identify & quantify degree of sleep apnea. Community or Social work involvement for parental support; Home nursing referral. FGF23 = fibroblast growth factor 23; MOI = mode of inheritance; OGD = osteoglophonic dysplasia Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Referral to orthopedist • Spine & long bone radiographs to detect platyspondyly & non-ossifying fibromas • Assess for developmental disabilities incl speech & swallowing eval. • Refer to early intervention services. • Consider referral to neurodevelopmental specialist. • Assess for airway symptoms (snoring, stridor, apnea, respiratory distress). • Consider consultation w/otolaryngologist & sleep medicine specialist to identify & quantify degree of sleep apnea. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for OGD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Osteoglophonic Dysplasia: Treatment of Manifestations Typically in childhood or adolescence Early midface advancement may be pursued to treat airway obstruction. BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OT = occupational therapy; PT = physical therapy • Typically in childhood or adolescence • Early midface advancement may be pursued to treat airway obstruction. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Osteoglophonic Dysplasia: Recommended Surveillance Assess for recurrent/pathologic fractures. Monitor growth. Closely monitor head circumference / head growth. Evaluate for signs of ↑ intracranial pressure (e.g., headaches, vomiting). Clinical eval at least every 3 mos in 1st year of life Can be done in conjunction w/team visits to assess for craniosynostosis. FGF23 = fibroblast growth factor 23 • Assess for recurrent/pathologic fractures. • Monitor growth. • Closely monitor head circumference / head growth. • Evaluate for signs of ↑ intracranial pressure (e.g., headaches, vomiting). • Clinical eval at least every 3 mos in 1st year of life • Can be done in conjunction w/team visits to assess for craniosynostosis. ## Agents/Circumstances to Avoid Individuals with OGD may require sports restrictions for activities that carry a potential for head or neck injury. Individuals with severe proptosis need to wear protective eyewear during activities with risk of eye injury (e.g., ball sports). ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment of developmental and craniofacial manifestations. See ## Pregnancy Management No published studies address management of pregnancy in women with OGD. See ## Therapies Under Investigation Search ## Genetic Counseling Osteoglophonic dysplasia (OGD) is inherited in an autosomal dominant manner. Most individuals diagnosed with OGD represent simplex cases (i.e., the only family member known to be affected). Some individuals diagnosed with OGD have an affected parent. Of the 19 families reported and/or identified to date, parent-to-child transmission of an If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If a molecular diagnosis has been established in the proband and the If the parents have not been tested for the Each child of an individual with OGD has a 50% chance of inheriting the Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with OGD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [ The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Once the Pregnant women carrying fetuses affected by OGD should be monitored during pregnancy for features that can affect early morbidity and mortality (including craniosynostosis and respiratory obstructions) and should be encouraged to deliver in a hospital with ready access to a pediatric otolaryngologist, plastic surgeon, neurosurgeon, and pulmonary medicine specialist. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with OGD represent simplex cases (i.e., the only family member known to be affected). • Some individuals diagnosed with OGD have an affected parent. Of the 19 families reported and/or identified to date, parent-to-child transmission of an • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If a molecular diagnosis has been established in the proband and the • If the parents have not been tested for the • Each child of an individual with OGD has a 50% chance of inheriting the • Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with OGD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance Osteoglophonic dysplasia (OGD) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with OGD represent simplex cases (i.e., the only family member known to be affected). Some individuals diagnosed with OGD have an affected parent. Of the 19 families reported and/or identified to date, parent-to-child transmission of an If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If a molecular diagnosis has been established in the proband and the If the parents have not been tested for the Each child of an individual with OGD has a 50% chance of inheriting the Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with OGD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [ • Most individuals diagnosed with OGD represent simplex cases (i.e., the only family member known to be affected). • Some individuals diagnosed with OGD have an affected parent. Of the 19 families reported and/or identified to date, parent-to-child transmission of an • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If a molecular diagnosis has been established in the proband and the • If the parents have not been tested for the • Each child of an individual with OGD has a 50% chance of inheriting the • Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with OGD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [ ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the Pregnant women carrying fetuses affected by OGD should be monitored during pregnancy for features that can affect early morbidity and mortality (including craniosynostosis and respiratory obstructions) and should be encouraged to deliver in a hospital with ready access to a pediatric otolaryngologist, plastic surgeon, neurosurgeon, and pulmonary medicine specialist. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • • • United Kingdom • • • ## Molecular Genetics Osteoglophonic Dysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Osteoglophonic Dysplasia ( Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Amna A Othman ( Contact 18 April 2024 (sw) Review posted live 27 December 2023 (cf) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 18 April 2024 (sw) Review posted live • 27 December 2023 (cf) Original submission ## Author Notes Dr Amna A Othman ( Contact 18 April 2024 (sw) Review posted live 27 December 2023 (cf) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 18 April 2024 (sw) Review posted live • 27 December 2023 (cf) Original submission ## Revision History 18 April 2024 (sw) Review posted live 27 December 2023 (cf) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 18 April 2024 (sw) Review posted live • 27 December 2023 (cf) Original submission ## References ## Literature Cited Radiographs of individuals with osteoglophonic dysplasia A, B, and C. Lateral imaging of the skull showing copper beaten appearance and unerupted teeth D. Lateral spine radiograph. Note mild platyspondyly with prominent anterior beaking of the lower thoracic and lumbar vertebral bodies. E, and F. Long bone radiographs highlighting multiple non-ossifying fibromas	[]	18/4/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
oi	oi	[ "Brittle Bone Disease", "OI", "Brittle Bone Disease", "OI", "Collagen alpha-1(I) chain", "Collagen alpha-2(I) chain", "COL1A1", "COL1A2", "COL1A1- and COL1A2-Related Osteogenesis Imperfecta" ]		Mercedes Rodriguez Celin, Robert D Steiner, Donald Basel	Summary Classic non-deforming OI with blue sclerae (OI type I) Perinatally lethal OI (OI type II) Progressively deforming OI (OI type III) Common variable OI with normal sclerae (OI type IV) The diagnosis of	## Diagnosis Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known bone disorders Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity Blue/gray scleral hue Dentinogenesis imperfecta (DI) Progressive, postpubertal hearing loss Ligamentous laxity and other signs of connective tissue abnormality DI = dentinogenesis imperfecta; NA = not applicable; OI = osteogenesis imperfecta Osteopenia, slender bones Intrauterine long bone fractures or bowing are very rare. Severely deformed Broad, crumpled, bent femurs Narrow thorax w/beaded ribs (pathognomonic) Prenatal shortening, bowing, & fractures w/severe undermodeling of long bones (thick & crumpled) Wormian bones present in 96% Platybasia present in 70% Thin ribs, severe osteoporosis w/defective calvarial ossification & bowing of long bones In utero & perinatal fractures frequent Wormian bones present in 78% Platybasia present in 20% OI = osteogenesis imperfecta Based on The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by bone fragility and/or skeletal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. PH Byers, personal communication Sequence analysis of • Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known bone disorders • Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity • Blue/gray scleral hue • Dentinogenesis imperfecta (DI) • Progressive, postpubertal hearing loss • Ligamentous laxity and other signs of connective tissue abnormality • Osteopenia, slender bones • Intrauterine long bone fractures or bowing are very rare. • Severely deformed • Broad, crumpled, bent femurs • Narrow thorax w/beaded ribs (pathognomonic) • Prenatal shortening, bowing, & fractures w/severe undermodeling of long bones (thick & crumpled) • Wormian bones present in 96% • Platybasia present in 70% • Thin ribs, severe osteoporosis w/defective calvarial ossification & bowing of long bones • In utero & perinatal fractures frequent • Wormian bones present in 78% • Platybasia present in 20% • For an introduction to multigene panels click ## Suggestive Findings Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known bone disorders Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity Blue/gray scleral hue Dentinogenesis imperfecta (DI) Progressive, postpubertal hearing loss Ligamentous laxity and other signs of connective tissue abnormality DI = dentinogenesis imperfecta; NA = not applicable; OI = osteogenesis imperfecta Osteopenia, slender bones Intrauterine long bone fractures or bowing are very rare. Severely deformed Broad, crumpled, bent femurs Narrow thorax w/beaded ribs (pathognomonic) Prenatal shortening, bowing, & fractures w/severe undermodeling of long bones (thick & crumpled) Wormian bones present in 96% Platybasia present in 70% Thin ribs, severe osteoporosis w/defective calvarial ossification & bowing of long bones In utero & perinatal fractures frequent Wormian bones present in 78% Platybasia present in 20% OI = osteogenesis imperfecta Based on • Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known bone disorders • Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity • Blue/gray scleral hue • Dentinogenesis imperfecta (DI) • Progressive, postpubertal hearing loss • Ligamentous laxity and other signs of connective tissue abnormality • Osteopenia, slender bones • Intrauterine long bone fractures or bowing are very rare. • Severely deformed • Broad, crumpled, bent femurs • Narrow thorax w/beaded ribs (pathognomonic) • Prenatal shortening, bowing, & fractures w/severe undermodeling of long bones (thick & crumpled) • Wormian bones present in 96% • Platybasia present in 70% • Thin ribs, severe osteoporosis w/defective calvarial ossification & bowing of long bones • In utero & perinatal fractures frequent • Wormian bones present in 78% • Platybasia present in 20% ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by bone fragility and/or skeletal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. PH Byers, personal communication Sequence analysis of • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by bone fragility and/or skeletal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. PH Byers, personal communication Sequence analysis of ## Clinical Characteristics The severity of Most affected individuals have normal or near-normal stature but are often shorter than other members of their families and shorter than predicted based on parental heights. A large longitudinal study of individuals with Joint hypermobility predisposes to a number of minor comorbidities. The primary clinical concern is early-onset degenerative joint disease due to malalignment of articular surfaces. Progressive hearing loss occurs in more than 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss, but often sensorineural hearing loss develops over time. Hearing loss was rarely noted in children with this OI type. Scoliosis affects less than one third of the individuals in this group and if present is usually mild (Cobb angle <30 degrees in all individuals) [ In their classification of OI, Histologic evaluation of bone from infants with perinatally lethal OI shows marked reduction in collagen in secondary trabeculae and cortical bone [ Infants who survive this period generally fare well, although most do not walk without assistance and usually use a wheelchair or other assistance for mobility because of severe bone fragility and marked bone deformity. Affected individuals have as many as 200 fractures and progressive deformity even in the absence of obvious fracture. Progressively deforming OI is often difficult to manage orthopedically, even with intramedullary rod placement. Growth velocity is extremely diminished and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter. A large longitudinal study of individuals with Intellect is normal except in those with intracerebral hemorrhage (ICH), which is extremely rare. An increased risk for ICH was reported in a "small number" of individuals with Considerable clinical variability occurs in individuals with progressively deforming OI. Some individuals have normal-appearing teeth and facies, whereas the large majority of individuals with progressively deforming OI caused by glycine substitutions in the triple-helical domain of type I collagen alpha chains have characteristic craniofacial features including frontal bossing, triangular face, smaller and retro-positioned midface, and mandible positioned forward in relation to the cranial base, resulting in a concave facial profile [ Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal cerebrospinal fluid flow [ Stature is variable and may vary markedly within the family. A large longitudinal study of individuals with In general, quantitative impacts on type I collagen tend to result in a milder phenotype when compared to qualitative changes that result in a dominant-negative effect [ The most common pathogenic variants result in substitution of another amino acid for glycine in the triple-helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon, and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon. Glycine is the least bulky amino acid, and other substituting amino acids do not fit well into the collagen triple helix. Substitutions in the pro-alpha-1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain. For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized. Much more variability occurs with pathogenic variants that affect glycine residues in the pro-alpha-2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship. The other common disease-causing variants affect splice sites. Variants that lead to exon skipping in the pro-alpha-1(I) chain beyond exon 14 and in the pro-alpha-2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from pathogenic variants in the upstream region are more variable and may lead to significant joint hypermobility. A relatively small number of pathogenic variants that alter amino acid sequences in the carboxyl-terminal regions of both chains have been identified. These domains are used for chain association, and pathogenic variants have the capacity to destroy this property or lead to abnormalities in chain association. The phenotypic effects of pathogenic variants that affect this domain appear to be milder when they result in exclusion rather than inclusion of the chain. Individuals with somatic mosaicism for variants that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the variant is present in a majority of somatic cells. Somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype if the variant is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic. The penetrance in individuals heterozygous for a Current OI nomenclature and classification systems are listed in OI, non-deforming (Sillence type 1), OI, non-deforming (Sillence type 1), OI, severe perinatal form (Sillence type 2), OI, severe perinatal form (Sillence type 2), OI, progressively deforming (Sillence type 3), OI, progressively deforming (Sillence type 3), OI, moderate form (Sillence type 4), OI, moderate form (Sillence type 4), OI = osteogenesis imperfecta * Note: For consistency throughout this The historical classification scheme of "OI congenita" and "OI tarda" was discarded because fractures at birth can be noted in mild OI and infants with severe OI may not have fractures at birth. In classifications of genetic conditions, OI may be considered a skeletal dysplasia, a connective tissue disorder, a disorder of collagen or extracellular matrix, or a disorder of bone fragility. In the latest revision of the Nosology of Genetic Skeletal Disorders, OI is included in the osteogenesis imperfecta and bone fragility group [ Considering all types, OI has a prevalence of approximately 6-7:100,000. • Substitutions in the pro-alpha-1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain. • For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized. • Much more variability occurs with pathogenic variants that affect glycine residues in the pro-alpha-2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship. • Individuals with somatic mosaicism for variants that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the variant is present in a majority of somatic cells. • Somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype if the variant is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic. • OI, non-deforming (Sillence type 1), • OI, non-deforming (Sillence type 1), • OI, severe perinatal form (Sillence type 2), • OI, severe perinatal form (Sillence type 2), • OI, progressively deforming (Sillence type 3), • OI, progressively deforming (Sillence type 3), • OI, moderate form (Sillence type 4), • OI, moderate form (Sillence type 4), ## Clinical Description The severity of Most affected individuals have normal or near-normal stature but are often shorter than other members of their families and shorter than predicted based on parental heights. A large longitudinal study of individuals with Joint hypermobility predisposes to a number of minor comorbidities. The primary clinical concern is early-onset degenerative joint disease due to malalignment of articular surfaces. Progressive hearing loss occurs in more than 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss, but often sensorineural hearing loss develops over time. Hearing loss was rarely noted in children with this OI type. Scoliosis affects less than one third of the individuals in this group and if present is usually mild (Cobb angle <30 degrees in all individuals) [ In their classification of OI, Histologic evaluation of bone from infants with perinatally lethal OI shows marked reduction in collagen in secondary trabeculae and cortical bone [ Infants who survive this period generally fare well, although most do not walk without assistance and usually use a wheelchair or other assistance for mobility because of severe bone fragility and marked bone deformity. Affected individuals have as many as 200 fractures and progressive deformity even in the absence of obvious fracture. Progressively deforming OI is often difficult to manage orthopedically, even with intramedullary rod placement. Growth velocity is extremely diminished and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter. A large longitudinal study of individuals with Intellect is normal except in those with intracerebral hemorrhage (ICH), which is extremely rare. An increased risk for ICH was reported in a "small number" of individuals with Considerable clinical variability occurs in individuals with progressively deforming OI. Some individuals have normal-appearing teeth and facies, whereas the large majority of individuals with progressively deforming OI caused by glycine substitutions in the triple-helical domain of type I collagen alpha chains have characteristic craniofacial features including frontal bossing, triangular face, smaller and retro-positioned midface, and mandible positioned forward in relation to the cranial base, resulting in a concave facial profile [ Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal cerebrospinal fluid flow [ Stature is variable and may vary markedly within the family. A large longitudinal study of individuals with ## Other Considerations ## Genotype-Phenotype Correlations In general, quantitative impacts on type I collagen tend to result in a milder phenotype when compared to qualitative changes that result in a dominant-negative effect [ The most common pathogenic variants result in substitution of another amino acid for glycine in the triple-helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon, and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon. Glycine is the least bulky amino acid, and other substituting amino acids do not fit well into the collagen triple helix. Substitutions in the pro-alpha-1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain. For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized. Much more variability occurs with pathogenic variants that affect glycine residues in the pro-alpha-2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship. The other common disease-causing variants affect splice sites. Variants that lead to exon skipping in the pro-alpha-1(I) chain beyond exon 14 and in the pro-alpha-2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from pathogenic variants in the upstream region are more variable and may lead to significant joint hypermobility. A relatively small number of pathogenic variants that alter amino acid sequences in the carboxyl-terminal regions of both chains have been identified. These domains are used for chain association, and pathogenic variants have the capacity to destroy this property or lead to abnormalities in chain association. The phenotypic effects of pathogenic variants that affect this domain appear to be milder when they result in exclusion rather than inclusion of the chain. Individuals with somatic mosaicism for variants that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the variant is present in a majority of somatic cells. Somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype if the variant is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic. • Substitutions in the pro-alpha-1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain. • For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized. • Much more variability occurs with pathogenic variants that affect glycine residues in the pro-alpha-2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship. • Individuals with somatic mosaicism for variants that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the variant is present in a majority of somatic cells. • Somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype if the variant is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic. ## Penetrance The penetrance in individuals heterozygous for a ## Nomenclature Current OI nomenclature and classification systems are listed in OI, non-deforming (Sillence type 1), OI, non-deforming (Sillence type 1), OI, severe perinatal form (Sillence type 2), OI, severe perinatal form (Sillence type 2), OI, progressively deforming (Sillence type 3), OI, progressively deforming (Sillence type 3), OI, moderate form (Sillence type 4), OI, moderate form (Sillence type 4), OI = osteogenesis imperfecta * Note: For consistency throughout this The historical classification scheme of "OI congenita" and "OI tarda" was discarded because fractures at birth can be noted in mild OI and infants with severe OI may not have fractures at birth. In classifications of genetic conditions, OI may be considered a skeletal dysplasia, a connective tissue disorder, a disorder of collagen or extracellular matrix, or a disorder of bone fragility. In the latest revision of the Nosology of Genetic Skeletal Disorders, OI is included in the osteogenesis imperfecta and bone fragility group [ • OI, non-deforming (Sillence type 1), • OI, non-deforming (Sillence type 1), • OI, severe perinatal form (Sillence type 2), • OI, severe perinatal form (Sillence type 2), • OI, progressively deforming (Sillence type 3), • OI, progressively deforming (Sillence type 3), • OI, moderate form (Sillence type 4), • OI, moderate form (Sillence type 4), ## Prevalence Considering all types, OI has a prevalence of approximately 6-7:100,000. ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders AD = autosomal dominant; AR = autosomal recessive; cEDS = classic EDS; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance; OI = osteogenesis imperfecta ## Differential Diagnosis The primary differential diagnoses for individuals with features of Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DI = dentinogenesis imperfecta; HL = hearing loss; IUGR = intrauterine growth restriction; MOI = mode of inheritance; OI = osteogenesis imperfecta; XL = X-linked The differential diagnosis of OI depends largely on the age at which the individual is assessed [ Early prenatal ultrasound examination or radiographic findings may lead to a consideration of Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; OI = osteogenesis imperfecta Based on The continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of Family history is often unrevealing. Families suspected of possible NAT often provide an unverified family history of frequent fractures; conversely, the family history of individuals with The use of molecular testing in individuals with suspected NAT and unexplained fractures continues to be controversial. However, with the decreasing cost of molecular testing, increased availability, and constrained workforces of NAT specialists and clinical geneticists, molecular testing has become more common. Determining whether molecular testing is medically necessary can be challenging. Molecular testing has been suggested when there is uncertainty of NAT, given the clinical overlap that might be seen between NAT and mild forms of OI [ Genetic disorders associated with osteoporosis-related bone fragility (rather than inherent bone fragility as in OI) are listed in Other Genetic Disorders Associated with Bone Fragility (But Not Considered Osteogenesis Imperfecta) AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked ## Other Types of Osteogenesis Imperfecta The primary differential diagnoses for individuals with features of Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DI = dentinogenesis imperfecta; HL = hearing loss; IUGR = intrauterine growth restriction; MOI = mode of inheritance; OI = osteogenesis imperfecta; XL = X-linked ## Other Disorders and Non-Accidental Trauma The differential diagnosis of OI depends largely on the age at which the individual is assessed [ Early prenatal ultrasound examination or radiographic findings may lead to a consideration of Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; OI = osteogenesis imperfecta Based on The continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of Family history is often unrevealing. Families suspected of possible NAT often provide an unverified family history of frequent fractures; conversely, the family history of individuals with The use of molecular testing in individuals with suspected NAT and unexplained fractures continues to be controversial. However, with the decreasing cost of molecular testing, increased availability, and constrained workforces of NAT specialists and clinical geneticists, molecular testing has become more common. Determining whether molecular testing is medically necessary can be challenging. Molecular testing has been suggested when there is uncertainty of NAT, given the clinical overlap that might be seen between NAT and mild forms of OI [ Genetic disorders associated with osteoporosis-related bone fragility (rather than inherent bone fragility as in OI) are listed in Other Genetic Disorders Associated with Bone Fragility (But Not Considered Osteogenesis Imperfecta) AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked ## In Utero Assessment Early prenatal ultrasound examination or radiographic findings may lead to a consideration of Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; OI = osteogenesis imperfecta Based on ## Infancy and Childhood Assessment The continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of Family history is often unrevealing. Families suspected of possible NAT often provide an unverified family history of frequent fractures; conversely, the family history of individuals with The use of molecular testing in individuals with suspected NAT and unexplained fractures continues to be controversial. However, with the decreasing cost of molecular testing, increased availability, and constrained workforces of NAT specialists and clinical geneticists, molecular testing has become more common. Determining whether molecular testing is medically necessary can be challenging. Molecular testing has been suggested when there is uncertainty of NAT, given the clinical overlap that might be seen between NAT and mild forms of OI [ ## Other Bone Fragility Disorders Genetic disorders associated with osteoporosis-related bone fragility (rather than inherent bone fragility as in OI) are listed in Other Genetic Disorders Associated with Bone Fragility (But Not Considered Osteogenesis Imperfecta) AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked ## Management No clinical practice guidelines for To establish the extent of disease and needs of an individual diagnosed with Physical exam Growth assessment (length/height, weight, & head circumference) Pain assessment To assess deformities, scoliosis, & presence of joint laxity Growth parameters should be plotted on OI growth charts (see Referral to PT & OT to assess motor development & mobility issues Referral for surgical intervention to experienced orthopedist as needed Referral to bone disease specialist Bone biomarkers (calcium, phosphorus, alkaline phosphatase, parathyroid hormone) Vitamin D level to assess for deficiency When teeth erupt in those w/DI or at risk for DI By age 2-3 yrs for all children w/OI Assessment for pulmonary complications Referral to pulmonologist as needed Community or Social work involvement for parental support Home nursing referral DI = dentinogenesis imperfecta; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OI = osteogenesis imperfecta; OT = occupational therapist; PT = physical therapist There is no universal agreement on when screening for basilar impression should be performed. A positive Lhermitte sign (tingling in fingers with neck flexion) should prompt neurosurgical referral. Surgery is typically undertaken before persistent/permanent neurologic features are present. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Management focuses on supportive therapy to minimize fractures and disability, maximize function, foster independence and participation, and maintain overall health. A multidisciplinary approach to management is most beneficial, with care centered on maximizing quality of life [ Supportive therapy is individualized depending on the severity, degree of impairment, and age of the affected individual. Considerable support from medical personnel is generally required by parents caring for infants with perinatally lethal Physical rehabilitation of infants with OI includes assessment, therapy, and caregiver education. Therapists educate caregivers on optimal and safe positioning and handling that facilitates nurturing and development while minimizing risk of fractures and deformities. Despite the most careful handling, infants and children with OI continue to fracture during infancy. Therapists and caregivers should use wide hand support, slow and gentle movements, and avoid twisting the limbs to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck, and lower body; avoid increased pressure on a single point on any long bone; when assisting to stand, do not pull excessively on an extended arm but bend down and brace a greater surface area (e.g., placing a hand behind the back and pulling gently from the front – using the arm – while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. Alternating positions (supine, prone, side-lying) can minimize skull and limb deformities. It is important to initiate upright sitting only once the infant has adequate head and trunk control. Physical and occupational therapy should be initiated to increase bone stability, improve mobility, prevent contractures and head and spinal deformity, and improve aerobic fitness and muscle strength. Physical activity provides gravitational stressors required for bone growth and remodeling. Optimal muscle function can contribute to improving motor development, mobility, functional independence, and participation. The muscles' supporting joints are strengthened by activity, and as an overall benefit, improved joint stability aids in overall well-being as pain levels are reduced and mobility is increased. Strengthening trunk muscles and extremities may decrease back pain and improve breathing capacity and trunk stability. Children with OI should have access to a range of mobility aids to promote participation and independence, such as orthotics for ankle instability to maximize mobility, optimize muscle function, and minimize pain and fatigue. Wheelchairs should be adjusted to meet the child's participation needs and should not replace standing and walking activities. Wheelchairs should be chosen carefully to match the size of the child. Modified automobiles for adults should be considered. The period of immobility in children with Casts should be small and lightweight. Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. Results from a multicenter study that used data from the Osteogenesis Imperfecta Foundation's linked clinical research centers (LCRCs) on 466 individuals with different forms of OI showed increased lumbar vertebral body density and reduced probability of fracture and scoliosis in individuals treated with bisphosphonates compared to those untreated [ Nitrogenous bisphosphonates (e.g., alendronate, pamidronate, zoledronic acid, and neridronate) are the most frequently used. Bisphosphonates can be administered either orally or intravenously and are generally well tolerated. The most common side effects include gastrointestinal problems when taken orally and flu-like symptoms that typically occur during the first infusion. Transient hypocalcemia may also occur. Osteonecrosis of the jaw is a rare side effect in adults but has never been reported in children. Long-term safety of bisphosphonates is under investigation but may include delayed bone union after fracture or osteotomy. A randomized controlled clinical trial found that treatment with oral alendronate for two years in children with OI significantly decreased bone turnover and increased spine areal bone mineral density (BMD; bone mineral content measured by DXA divided by bone area in square centimeters) but was not associated with improved fracture outcomes [ Although there is no clear guideline, experts in OI dental health recommend treatments for damaged or decayed teeth in the primary dentition, such as full-coverage restorations, including stainless steel or zirconia crowns. Full-coverage restorations are recommended for the permanent dentition. Intracoronal restorations should be avoided, as they promote structural tooth loss. Simple extractions can be performed but should not be done immediately before or after intravenous bisphosphonate infusions. Individuals with OI who are taking bisphosphonates should be closely monitored by a dentist. When possible, required dental surgery should be scheduled before starting bisphosphonate treatment or after the treatment has finished. Bisphosphonate treatment should not be resumed until the surgical area has healed. In severe OI types, orthognathic surgery is discouraged, despite the significant skeletal dysplasia present. If warranted, orthodontic treatment can be initiated, but care must be taken with the use of orthodontic appliances due to the brittleness of the teeth. Clear aligners are a promising option for orthodontic treatment [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, a multidisciplinary approach is recommended (see Every 3 mos until age 1 yr Every 6 mos from age 1-3 yrs Then annually or w/any new fractures or other musculoskeletal concerns (e.g., long bone deformity, flat feet, leg discrepancy, osteoarthritis) Eval by bone disease specialist Vitamin D level to assess for deficiency If initial DXA scan in childhood is normal, repeat in 5 yrs In initial DXA scan is abnormal, repeat no more than annually; consider every 2-3 yrs Persons on bisphosphonates require more frequent DXA scans Every 6 mos for those w/DI or at risk for DI beginning in infancy Annually in those w/o DI. Every 3 yrs starting at age 5 yrs in those w/normal hearing Frequency as indicated based on nature & degree of HL & assoc interventions in those w/HL At least every 2-3 yrs in adults More frequently as needed based on eye findings & risk assessment by ophthalmologist Clinical assessment for symptoms of cardiovascular disease Referral to cardiologist for further eval in those w/unexplained symptoms (e.g., chest pain, back pain, dyspnea) Eval by therapists, social workers, & psychologist (might help develop skills to manage stress) Evaluate for presence of mood disorders. DI = dentinogenesis imperfecta; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HL = hearing loss; MOI = mode of inheritance; OI = osteogenesis imperfecta If possible, DXA scan should be done using the same machine each year to avoid variations in test results caused by different equipment [ DXA scans prior to age five years often require sedation, and data regarding normal values is limited. There is limited consensus regarding frequency of DXA scans in children. The minimum time between DXA scans should be six to 12 months. Consider annual DXA scan in those receiving bisphosphonates. Otherwise, consider DXA scan every two to three years or every five years, depending on severity of OI, results of initial DXA scan, and pharmacologic treatment status. In young children, avoid sudden acceleration/deceleration movements; avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. Contact sports or activities with increased fall or high-impact collision risk should be avoided. Avoid smoking and secondhand smoke to decrease risk of pulmonary disease; avoid excessive alcohol and caffeine consumption. Consider avoiding or limiting any substance or medication that may affect bone health (e.g., steroids). It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from spine examination and ophthalmic, dental, and audiology evaluations. See Fertility is normal in individuals with OI. Maternal hospitalization and cesarean rates were higher in individuals with moderate or severe OI compared to women who reported mild OI. Neonates born to women with OI had a higher risk of being low birth weight and a higher rate of neonatal intensive care unit admissions. In addition, higher neonatal mortality at 28 days of life has been reported, regardless of neonatal OI status [ Cesarean section compared to vaginal delivery was not associated with decreased fracture rate in individuals with OI; strong predictors for choosing cesarean section were in utero fracture, maternal history of OI, and breech presentation [ A retrospective multicenter study concluded that both the state of pregnancy and breastfeeding increased the risk of fracture in individuals with OI in addition to a reduction in BMD [ Women with OI and significant skeletal deformities and short stature should be followed closely during pregnancy at a high-risk prenatal care center. Most data support that women with OI have successful pregnancies but are at increased risk for complications. Awareness of these complications allows for adequate preconception counseling and proactive measures to reduce potential harm, as well as to recognize modifiable risk factors related to pregnancy and the postpartum period [ Several medications are being investigated for use in OI (see Search • Physical exam • Growth assessment (length/height, weight, & head circumference) • Pain assessment • To assess deformities, scoliosis, & presence of joint laxity • Growth parameters should be plotted on OI growth charts (see • Referral to PT & OT to assess motor development & mobility issues • Referral for surgical intervention to experienced orthopedist as needed • Referral to bone disease specialist • Bone biomarkers (calcium, phosphorus, alkaline phosphatase, parathyroid hormone) • Vitamin D level to assess for deficiency • When teeth erupt in those w/DI or at risk for DI • By age 2-3 yrs for all children w/OI • Assessment for pulmonary complications • Referral to pulmonologist as needed • Community or • Social work involvement for parental support • Home nursing referral • Physical rehabilitation of infants with OI includes assessment, therapy, and caregiver education. Therapists educate caregivers on optimal and safe positioning and handling that facilitates nurturing and development while minimizing risk of fractures and deformities. Despite the most careful handling, infants and children with OI continue to fracture during infancy. Therapists and caregivers should use wide hand support, slow and gentle movements, and avoid twisting the limbs to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck, and lower body; avoid increased pressure on a single point on any long bone; when assisting to stand, do not pull excessively on an extended arm but bend down and brace a greater surface area (e.g., placing a hand behind the back and pulling gently from the front – using the arm – while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. • Alternating positions (supine, prone, side-lying) can minimize skull and limb deformities. It is important to initiate upright sitting only once the infant has adequate head and trunk control. • Physical and occupational therapy should be initiated to increase bone stability, improve mobility, prevent contractures and head and spinal deformity, and improve aerobic fitness and muscle strength. Physical activity provides gravitational stressors required for bone growth and remodeling. Optimal muscle function can contribute to improving motor development, mobility, functional independence, and participation. The muscles' supporting joints are strengthened by activity, and as an overall benefit, improved joint stability aids in overall well-being as pain levels are reduced and mobility is increased. Strengthening trunk muscles and extremities may decrease back pain and improve breathing capacity and trunk stability. • Children with OI should have access to a range of mobility aids to promote participation and independence, such as orthotics for ankle instability to maximize mobility, optimize muscle function, and minimize pain and fatigue. Wheelchairs should be adjusted to meet the child's participation needs and should not replace standing and walking activities. Wheelchairs should be chosen carefully to match the size of the child. Modified automobiles for adults should be considered. • The period of immobility in children with • Casts should be small and lightweight. • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. • The period of immobility in children with • Casts should be small and lightweight. • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. • The period of immobility in children with • Casts should be small and lightweight. • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. • Every 3 mos until age 1 yr • Every 6 mos from age 1-3 yrs • Then annually or w/any new fractures or other musculoskeletal concerns (e.g., long bone deformity, flat feet, leg discrepancy, osteoarthritis) • Eval by bone disease specialist • Vitamin D level to assess for deficiency • If initial DXA scan in childhood is normal, repeat in 5 yrs • In initial DXA scan is abnormal, repeat no more than annually; consider every 2-3 yrs • Persons on bisphosphonates require more frequent DXA scans • Every 6 mos for those w/DI or at risk for DI beginning in infancy • Annually in those w/o DI. • Every 3 yrs starting at age 5 yrs in those w/normal hearing • Frequency as indicated based on nature & degree of HL & assoc interventions in those w/HL • At least every 2-3 yrs in adults • More frequently as needed based on eye findings & risk assessment by ophthalmologist • Clinical assessment for symptoms of cardiovascular disease • Referral to cardiologist for further eval in those w/unexplained symptoms (e.g., chest pain, back pain, dyspnea) • Eval by therapists, social workers, & psychologist (might help develop skills to manage stress) • Evaluate for presence of mood disorders. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Physical exam Growth assessment (length/height, weight, & head circumference) Pain assessment To assess deformities, scoliosis, & presence of joint laxity Growth parameters should be plotted on OI growth charts (see Referral to PT & OT to assess motor development & mobility issues Referral for surgical intervention to experienced orthopedist as needed Referral to bone disease specialist Bone biomarkers (calcium, phosphorus, alkaline phosphatase, parathyroid hormone) Vitamin D level to assess for deficiency When teeth erupt in those w/DI or at risk for DI By age 2-3 yrs for all children w/OI Assessment for pulmonary complications Referral to pulmonologist as needed Community or Social work involvement for parental support Home nursing referral DI = dentinogenesis imperfecta; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OI = osteogenesis imperfecta; OT = occupational therapist; PT = physical therapist There is no universal agreement on when screening for basilar impression should be performed. A positive Lhermitte sign (tingling in fingers with neck flexion) should prompt neurosurgical referral. Surgery is typically undertaken before persistent/permanent neurologic features are present. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Physical exam • Growth assessment (length/height, weight, & head circumference) • Pain assessment • To assess deformities, scoliosis, & presence of joint laxity • Growth parameters should be plotted on OI growth charts (see • Referral to PT & OT to assess motor development & mobility issues • Referral for surgical intervention to experienced orthopedist as needed • Referral to bone disease specialist • Bone biomarkers (calcium, phosphorus, alkaline phosphatase, parathyroid hormone) • Vitamin D level to assess for deficiency • When teeth erupt in those w/DI or at risk for DI • By age 2-3 yrs for all children w/OI • Assessment for pulmonary complications • Referral to pulmonologist as needed • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Management focuses on supportive therapy to minimize fractures and disability, maximize function, foster independence and participation, and maintain overall health. A multidisciplinary approach to management is most beneficial, with care centered on maximizing quality of life [ Supportive therapy is individualized depending on the severity, degree of impairment, and age of the affected individual. Considerable support from medical personnel is generally required by parents caring for infants with perinatally lethal Physical rehabilitation of infants with OI includes assessment, therapy, and caregiver education. Therapists educate caregivers on optimal and safe positioning and handling that facilitates nurturing and development while minimizing risk of fractures and deformities. Despite the most careful handling, infants and children with OI continue to fracture during infancy. Therapists and caregivers should use wide hand support, slow and gentle movements, and avoid twisting the limbs to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck, and lower body; avoid increased pressure on a single point on any long bone; when assisting to stand, do not pull excessively on an extended arm but bend down and brace a greater surface area (e.g., placing a hand behind the back and pulling gently from the front – using the arm – while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. Alternating positions (supine, prone, side-lying) can minimize skull and limb deformities. It is important to initiate upright sitting only once the infant has adequate head and trunk control. Physical and occupational therapy should be initiated to increase bone stability, improve mobility, prevent contractures and head and spinal deformity, and improve aerobic fitness and muscle strength. Physical activity provides gravitational stressors required for bone growth and remodeling. Optimal muscle function can contribute to improving motor development, mobility, functional independence, and participation. The muscles' supporting joints are strengthened by activity, and as an overall benefit, improved joint stability aids in overall well-being as pain levels are reduced and mobility is increased. Strengthening trunk muscles and extremities may decrease back pain and improve breathing capacity and trunk stability. Children with OI should have access to a range of mobility aids to promote participation and independence, such as orthotics for ankle instability to maximize mobility, optimize muscle function, and minimize pain and fatigue. Wheelchairs should be adjusted to meet the child's participation needs and should not replace standing and walking activities. Wheelchairs should be chosen carefully to match the size of the child. Modified automobiles for adults should be considered. The period of immobility in children with Casts should be small and lightweight. Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. Results from a multicenter study that used data from the Osteogenesis Imperfecta Foundation's linked clinical research centers (LCRCs) on 466 individuals with different forms of OI showed increased lumbar vertebral body density and reduced probability of fracture and scoliosis in individuals treated with bisphosphonates compared to those untreated [ Nitrogenous bisphosphonates (e.g., alendronate, pamidronate, zoledronic acid, and neridronate) are the most frequently used. Bisphosphonates can be administered either orally or intravenously and are generally well tolerated. The most common side effects include gastrointestinal problems when taken orally and flu-like symptoms that typically occur during the first infusion. Transient hypocalcemia may also occur. Osteonecrosis of the jaw is a rare side effect in adults but has never been reported in children. Long-term safety of bisphosphonates is under investigation but may include delayed bone union after fracture or osteotomy. A randomized controlled clinical trial found that treatment with oral alendronate for two years in children with OI significantly decreased bone turnover and increased spine areal bone mineral density (BMD; bone mineral content measured by DXA divided by bone area in square centimeters) but was not associated with improved fracture outcomes [ Although there is no clear guideline, experts in OI dental health recommend treatments for damaged or decayed teeth in the primary dentition, such as full-coverage restorations, including stainless steel or zirconia crowns. Full-coverage restorations are recommended for the permanent dentition. Intracoronal restorations should be avoided, as they promote structural tooth loss. Simple extractions can be performed but should not be done immediately before or after intravenous bisphosphonate infusions. Individuals with OI who are taking bisphosphonates should be closely monitored by a dentist. When possible, required dental surgery should be scheduled before starting bisphosphonate treatment or after the treatment has finished. Bisphosphonate treatment should not be resumed until the surgical area has healed. In severe OI types, orthognathic surgery is discouraged, despite the significant skeletal dysplasia present. If warranted, orthodontic treatment can be initiated, but care must be taken with the use of orthodontic appliances due to the brittleness of the teeth. Clear aligners are a promising option for orthodontic treatment [ • Physical rehabilitation of infants with OI includes assessment, therapy, and caregiver education. Therapists educate caregivers on optimal and safe positioning and handling that facilitates nurturing and development while minimizing risk of fractures and deformities. Despite the most careful handling, infants and children with OI continue to fracture during infancy. Therapists and caregivers should use wide hand support, slow and gentle movements, and avoid twisting the limbs to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck, and lower body; avoid increased pressure on a single point on any long bone; when assisting to stand, do not pull excessively on an extended arm but bend down and brace a greater surface area (e.g., placing a hand behind the back and pulling gently from the front – using the arm – while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. • Alternating positions (supine, prone, side-lying) can minimize skull and limb deformities. It is important to initiate upright sitting only once the infant has adequate head and trunk control. • Physical and occupational therapy should be initiated to increase bone stability, improve mobility, prevent contractures and head and spinal deformity, and improve aerobic fitness and muscle strength. Physical activity provides gravitational stressors required for bone growth and remodeling. Optimal muscle function can contribute to improving motor development, mobility, functional independence, and participation. The muscles' supporting joints are strengthened by activity, and as an overall benefit, improved joint stability aids in overall well-being as pain levels are reduced and mobility is increased. Strengthening trunk muscles and extremities may decrease back pain and improve breathing capacity and trunk stability. • Children with OI should have access to a range of mobility aids to promote participation and independence, such as orthotics for ankle instability to maximize mobility, optimize muscle function, and minimize pain and fatigue. Wheelchairs should be adjusted to meet the child's participation needs and should not replace standing and walking activities. Wheelchairs should be chosen carefully to match the size of the child. Modified automobiles for adults should be considered. • The period of immobility in children with • Casts should be small and lightweight. • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. • The period of immobility in children with • Casts should be small and lightweight. • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. • The period of immobility in children with • Casts should be small and lightweight. • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, a multidisciplinary approach is recommended (see Every 3 mos until age 1 yr Every 6 mos from age 1-3 yrs Then annually or w/any new fractures or other musculoskeletal concerns (e.g., long bone deformity, flat feet, leg discrepancy, osteoarthritis) Eval by bone disease specialist Vitamin D level to assess for deficiency If initial DXA scan in childhood is normal, repeat in 5 yrs In initial DXA scan is abnormal, repeat no more than annually; consider every 2-3 yrs Persons on bisphosphonates require more frequent DXA scans Every 6 mos for those w/DI or at risk for DI beginning in infancy Annually in those w/o DI. Every 3 yrs starting at age 5 yrs in those w/normal hearing Frequency as indicated based on nature & degree of HL & assoc interventions in those w/HL At least every 2-3 yrs in adults More frequently as needed based on eye findings & risk assessment by ophthalmologist Clinical assessment for symptoms of cardiovascular disease Referral to cardiologist for further eval in those w/unexplained symptoms (e.g., chest pain, back pain, dyspnea) Eval by therapists, social workers, & psychologist (might help develop skills to manage stress) Evaluate for presence of mood disorders. DI = dentinogenesis imperfecta; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HL = hearing loss; MOI = mode of inheritance; OI = osteogenesis imperfecta If possible, DXA scan should be done using the same machine each year to avoid variations in test results caused by different equipment [ DXA scans prior to age five years often require sedation, and data regarding normal values is limited. There is limited consensus regarding frequency of DXA scans in children. The minimum time between DXA scans should be six to 12 months. Consider annual DXA scan in those receiving bisphosphonates. Otherwise, consider DXA scan every two to three years or every five years, depending on severity of OI, results of initial DXA scan, and pharmacologic treatment status. • Every 3 mos until age 1 yr • Every 6 mos from age 1-3 yrs • Then annually or w/any new fractures or other musculoskeletal concerns (e.g., long bone deformity, flat feet, leg discrepancy, osteoarthritis) • Eval by bone disease specialist • Vitamin D level to assess for deficiency • If initial DXA scan in childhood is normal, repeat in 5 yrs • In initial DXA scan is abnormal, repeat no more than annually; consider every 2-3 yrs • Persons on bisphosphonates require more frequent DXA scans • Every 6 mos for those w/DI or at risk for DI beginning in infancy • Annually in those w/o DI. • Every 3 yrs starting at age 5 yrs in those w/normal hearing • Frequency as indicated based on nature & degree of HL & assoc interventions in those w/HL • At least every 2-3 yrs in adults • More frequently as needed based on eye findings & risk assessment by ophthalmologist • Clinical assessment for symptoms of cardiovascular disease • Referral to cardiologist for further eval in those w/unexplained symptoms (e.g., chest pain, back pain, dyspnea) • Eval by therapists, social workers, & psychologist (might help develop skills to manage stress) • Evaluate for presence of mood disorders. ## Agents/Circumstances to Avoid In young children, avoid sudden acceleration/deceleration movements; avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. Contact sports or activities with increased fall or high-impact collision risk should be avoided. Avoid smoking and secondhand smoke to decrease risk of pulmonary disease; avoid excessive alcohol and caffeine consumption. Consider avoiding or limiting any substance or medication that may affect bone health (e.g., steroids). ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from spine examination and ophthalmic, dental, and audiology evaluations. See ## Pregnancy Management Fertility is normal in individuals with OI. Maternal hospitalization and cesarean rates were higher in individuals with moderate or severe OI compared to women who reported mild OI. Neonates born to women with OI had a higher risk of being low birth weight and a higher rate of neonatal intensive care unit admissions. In addition, higher neonatal mortality at 28 days of life has been reported, regardless of neonatal OI status [ Cesarean section compared to vaginal delivery was not associated with decreased fracture rate in individuals with OI; strong predictors for choosing cesarean section were in utero fracture, maternal history of OI, and breech presentation [ A retrospective multicenter study concluded that both the state of pregnancy and breastfeeding increased the risk of fracture in individuals with OI in addition to a reduction in BMD [ Women with OI and significant skeletal deformities and short stature should be followed closely during pregnancy at a high-risk prenatal care center. Most data support that women with OI have successful pregnancies but are at increased risk for complications. Awareness of these complications allows for adequate preconception counseling and proactive measures to reduce potential harm, as well as to recognize modifiable risk factors related to pregnancy and the postpartum period [ ## Therapies Under Investigation Several medications are being investigated for use in OI (see Search ## Genetic Counseling Many individuals diagnosed with the milder forms of The proportion of individuals with Approximately 60% of probands with mild OI represent simplex cases. Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. A proband who appears to be the only affected family member may have If the proband appears to be the only affected family member, clinical examination for features suggestive of If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic and gonadal mosaicism for a If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. If a parent of the proband is known to be mosaic for the pathogenic variant, the risk to the sibs is up to 50%. The penetrance in individuals heterozygous for an OI-related If the proband represents a simplex case and the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Many individuals diagnosed with the milder forms of • The proportion of individuals with • Approximately 60% of probands with mild OI represent simplex cases. • Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. • Approximately 60% of probands with mild OI represent simplex cases. • Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. • A proband who appears to be the only affected family member may have • If the proband appears to be the only affected family member, clinical examination for features suggestive of • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for a • Approximately 60% of probands with mild OI represent simplex cases. • Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for a • If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. If a parent of the proband is known to be mosaic for the pathogenic variant, the risk to the sibs is up to 50%. The penetrance in individuals heterozygous for an OI-related • If the proband represents a simplex case and the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Many individuals diagnosed with the milder forms of The proportion of individuals with Approximately 60% of probands with mild OI represent simplex cases. Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. A proband who appears to be the only affected family member may have If the proband appears to be the only affected family member, clinical examination for features suggestive of If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic and gonadal mosaicism for a If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. If a parent of the proband is known to be mosaic for the pathogenic variant, the risk to the sibs is up to 50%. The penetrance in individuals heterozygous for an OI-related If the proband represents a simplex case and the If the parents have not been tested for the • Many individuals diagnosed with the milder forms of • The proportion of individuals with • Approximately 60% of probands with mild OI represent simplex cases. • Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. • Approximately 60% of probands with mild OI represent simplex cases. • Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. • A proband who appears to be the only affected family member may have • If the proband appears to be the only affected family member, clinical examination for features suggestive of • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for a • Approximately 60% of probands with mild OI represent simplex cases. • Virtually 100% of probands with progressively deforming OI or perinatally lethal OI represent simplex cases. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and gonadal mosaicism for a • If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. If a parent of the proband is known to be mosaic for the pathogenic variant, the risk to the sibs is up to 50%. The penetrance in individuals heterozygous for an OI-related • If the proband represents a simplex case and the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • • • ## Molecular Genetics COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for COL1A1- and COL1A2-Related Osteogenesis Imperfecta ( Collagen type I contains a triple-helical segment of 1,014 amino acids in which glycine is in every third position and prolines preceding glycine residues are generally hydroxylated, as are some lysyl residues in the Y-position of the Gly-X-Y triplet. Glycine, the smallest amino acid, must be in the third position to allow proper chain folding. The pathogenic variants in most families are unique; only a few recurrent variants (mostly CpG dinucleotides) are seen in more than one family. Classic non-deforming osteogenesis imperfecta (OI; quantitative, loss of function): Decreased production of structurally normal type I procollagen results in a reduction in the amount of bone that can be made, leading to brittle bones. The vast majority of disease-causing variants are premature termination codons (e.g., frameshift, nonsense, splice site variants) that result in the reduction of Perinatally lethal OI, progressively deforming OI, and common variable OI (qualitative, gain of function): Substitutions for glycine within the triple-helical domain of the pro-α chain delay triple helix formation, resulting in additional post-translation modification that prevents secretion of the assembled trimers. Small in-frame deletions or duplications of single amino acids or Gly-X-Y triplets and exon-skipping events may disrupt trimer assembly. Diminished amount of type I procollagen is secreted. Some of the protein in the matrix has an abnormal structure. Clinical consequence is influenced by the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid. Pathogenic variants closer to the 5' end of the protein are likely to result in milder clinical phenotypes due to chain association occurring at the C-terminal end of the chain. • Decreased production of structurally normal type I procollagen results in a reduction in the amount of bone that can be made, leading to brittle bones. • The vast majority of disease-causing variants are premature termination codons (e.g., frameshift, nonsense, splice site variants) that result in the reduction of • Substitutions for glycine within the triple-helical domain of the pro-α chain delay triple helix formation, resulting in additional post-translation modification that prevents secretion of the assembled trimers. • Small in-frame deletions or duplications of single amino acids or Gly-X-Y triplets and exon-skipping events may disrupt trimer assembly. • Diminished amount of type I procollagen is secreted. • Some of the protein in the matrix has an abnormal structure. • Clinical consequence is influenced by the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid. • Pathogenic variants closer to the 5' end of the protein are likely to result in milder clinical phenotypes due to chain association occurring at the C-terminal end of the chain. ## Molecular Pathogenesis Collagen type I contains a triple-helical segment of 1,014 amino acids in which glycine is in every third position and prolines preceding glycine residues are generally hydroxylated, as are some lysyl residues in the Y-position of the Gly-X-Y triplet. Glycine, the smallest amino acid, must be in the third position to allow proper chain folding. The pathogenic variants in most families are unique; only a few recurrent variants (mostly CpG dinucleotides) are seen in more than one family. Classic non-deforming osteogenesis imperfecta (OI; quantitative, loss of function): Decreased production of structurally normal type I procollagen results in a reduction in the amount of bone that can be made, leading to brittle bones. The vast majority of disease-causing variants are premature termination codons (e.g., frameshift, nonsense, splice site variants) that result in the reduction of Perinatally lethal OI, progressively deforming OI, and common variable OI (qualitative, gain of function): Substitutions for glycine within the triple-helical domain of the pro-α chain delay triple helix formation, resulting in additional post-translation modification that prevents secretion of the assembled trimers. Small in-frame deletions or duplications of single amino acids or Gly-X-Y triplets and exon-skipping events may disrupt trimer assembly. Diminished amount of type I procollagen is secreted. Some of the protein in the matrix has an abnormal structure. Clinical consequence is influenced by the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid. Pathogenic variants closer to the 5' end of the protein are likely to result in milder clinical phenotypes due to chain association occurring at the C-terminal end of the chain. • Decreased production of structurally normal type I procollagen results in a reduction in the amount of bone that can be made, leading to brittle bones. • The vast majority of disease-causing variants are premature termination codons (e.g., frameshift, nonsense, splice site variants) that result in the reduction of • Substitutions for glycine within the triple-helical domain of the pro-α chain delay triple helix formation, resulting in additional post-translation modification that prevents secretion of the assembled trimers. • Small in-frame deletions or duplications of single amino acids or Gly-X-Y triplets and exon-skipping events may disrupt trimer assembly. • Diminished amount of type I procollagen is secreted. • Some of the protein in the matrix has an abnormal structure. • Clinical consequence is influenced by the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid. • Pathogenic variants closer to the 5' end of the protein are likely to result in milder clinical phenotypes due to chain association occurring at the C-terminal end of the chain. ## Chapter Notes Dr Rodriguez Celin is a pediatrician currently completing her training in Medical Genetics and Genomics at Medical College of Wisconsin. Prior, she served as an attending physician at the Skeletal Dysplasia Clinic at Garrahan Pediatric Referral Hospital in Buenos Aires and worked as a clinician-researcher at Shriners Hospital for Children, Chicago. Over the last 15 years she has been working and collaborating on several projects trying to address how osteogenesis imperfecta (OI) affects function, mobility, and quality of life. She has a special interest in pain in individuals with OI and how to address and improve management. Dr Steiner is a pediatrician, clinical geneticist, and clinical biochemical geneticist. He trained under Dr Peter Byers at the University of Washington. Dr Steiner specializes in general genetics, inherited metabolic diseases, metabolic bone diseases, and OI. He participates in a Dr Basel is the Medical Director for the Clinical Genetics services for Children's Wisconsin. He is a Professor at the Medical College of Wisconsin and Chief of the Division of Genetics within the Department of Pediatrics. He is the Associate Director for the Undiagnosed and Rare Disease Program within the Mellowes Center for Genome Sciences and Precision Medicine Center. He trained under Peter Beighton at the University of Cape Town and worked as a research fellow at University of Connecticut Health Center, studying connective tissue disorders with a focus on fibrillin and type I collagen disorders. Dr Steiner participates in a clinical trial funded by Utragenyx. He acknowledges the outstanding work of Drs Neil Paloian, Blaise Nemeth, and Lindsey Boyke and genetic counselor Peggy Modaff in the UW/AFCH OI Clinic. Dr Rodriguez Celin appreciates the critical review of the information regarding spine surgical treatment by Dr Peter A Smith from Shriners Hospital for Children, Chicago, and the valuable review of the recommended surveillance table by Drs Fano Virginia and Ramos Mejía Rosario from Garrahan Pediatric Hospital, Buenos Aires. Jessica Adsit, MS, CGC; Legacy Center for Maternal Fetal Medicine (2013-2019)Donald Basel, MD (2013-present)Peter H Byers, MD; University of Washington Health Sciences Center (2003-2013)Melanie G Pepin, MS, CGC; University of Washington Health Sciences Center (2003-2013)Mercedes Rodriguez Celin, MD (2025-present)Robert D Steiner, MD (2003-present) 29 May 2025 (sw) Comprehensive update posted live 19 September 2019 (sw) Comprehensive update posted live 14 February 2013 (me) Comprehensive update posted live 28 January 2005 (me) Review posted live 14 June 2003 (rs) Original submission • 29 May 2025 (sw) Comprehensive update posted live • 19 September 2019 (sw) Comprehensive update posted live • 14 February 2013 (me) Comprehensive update posted live • 28 January 2005 (me) Review posted live • 14 June 2003 (rs) Original submission ## Author Notes Dr Rodriguez Celin is a pediatrician currently completing her training in Medical Genetics and Genomics at Medical College of Wisconsin. Prior, she served as an attending physician at the Skeletal Dysplasia Clinic at Garrahan Pediatric Referral Hospital in Buenos Aires and worked as a clinician-researcher at Shriners Hospital for Children, Chicago. Over the last 15 years she has been working and collaborating on several projects trying to address how osteogenesis imperfecta (OI) affects function, mobility, and quality of life. She has a special interest in pain in individuals with OI and how to address and improve management. Dr Steiner is a pediatrician, clinical geneticist, and clinical biochemical geneticist. He trained under Dr Peter Byers at the University of Washington. Dr Steiner specializes in general genetics, inherited metabolic diseases, metabolic bone diseases, and OI. He participates in a Dr Basel is the Medical Director for the Clinical Genetics services for Children's Wisconsin. He is a Professor at the Medical College of Wisconsin and Chief of the Division of Genetics within the Department of Pediatrics. He is the Associate Director for the Undiagnosed and Rare Disease Program within the Mellowes Center for Genome Sciences and Precision Medicine Center. He trained under Peter Beighton at the University of Cape Town and worked as a research fellow at University of Connecticut Health Center, studying connective tissue disorders with a focus on fibrillin and type I collagen disorders. ## Acknowledgments Dr Steiner participates in a clinical trial funded by Utragenyx. He acknowledges the outstanding work of Drs Neil Paloian, Blaise Nemeth, and Lindsey Boyke and genetic counselor Peggy Modaff in the UW/AFCH OI Clinic. Dr Rodriguez Celin appreciates the critical review of the information regarding spine surgical treatment by Dr Peter A Smith from Shriners Hospital for Children, Chicago, and the valuable review of the recommended surveillance table by Drs Fano Virginia and Ramos Mejía Rosario from Garrahan Pediatric Hospital, Buenos Aires. ## Author History Jessica Adsit, MS, CGC; Legacy Center for Maternal Fetal Medicine (2013-2019)Donald Basel, MD (2013-present)Peter H Byers, MD; University of Washington Health Sciences Center (2003-2013)Melanie G Pepin, MS, CGC; University of Washington Health Sciences Center (2003-2013)Mercedes Rodriguez Celin, MD (2025-present)Robert D Steiner, MD (2003-present) ## Revision History 29 May 2025 (sw) Comprehensive update posted live 19 September 2019 (sw) Comprehensive update posted live 14 February 2013 (me) Comprehensive update posted live 28 January 2005 (me) Review posted live 14 June 2003 (rs) Original submission • 29 May 2025 (sw) Comprehensive update posted live • 19 September 2019 (sw) Comprehensive update posted live • 14 February 2013 (me) Comprehensive update posted live • 28 January 2005 (me) Review posted live • 14 June 2003 (rs) Original submission ## References ## Literature Cited Representation of bone remodeling and the targets for therapeutic intervention. Bisphosphonates are the archetypal treatments to increase bone density by reducing osteoclastic activity. There are several new medications that target alternate physiologic pathways, but the end point remains the same: to improve bone density by reducing the effects of osteoclasts (antiresorptive effect) or by improving osteoblast (bone formation) activity. This includes medications under investigation that target cathepsin K and the hydrogen pump, V-ATPase. Denosumab, setrusumab, fresulimumab, and teriparatide all act by improving the osteoblast lineage. Modified from	[]	28/1/2005	29/5/2025	14/3/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
okur-chung	okur-chung	[ "CSNK2A1-Related Neurodevelopmental Syndrome", "CSNK2A1-Related Neurodevelopmental Syndrome", "Casein kinase II subunit alpha", "CSNK2A1", "Okur-Chung Neurodevelopmental Syndrome" ]	Okur-Chung Neurodevelopmental Syndrome	Wendy Chung, Volkan Okur	Summary Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability (typically in the mild-to-moderate range), generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. Developmental delay affects all areas of development, but language is more impaired than gross motor skills in most individuals. Intellectual disability has been reported in about three quarters of individuals. Less common findings may include kyphoscoliosis, postnatal short stature, disrupted circadian rhythm leading to sleep disturbance, seizures, and poor coordination. The diagnosis of OCNDS is established in a proband with suggestive findings and a heterozygous pathogenic variant in OCNDS disorder is expressed in an autosomal dominant manner and typically caused by a	## Diagnosis No consensus clinical diagnostic criteria for Okur-Chung neurodevelopmental syndrome (OCNDS) have been published. OCNDS Mild-to-moderate developmental delay (DD) or intellectual disability (ID) Generalized hypotonia in infancy and/or childhood Speech delay AND Any of the following features presenting in infancy or childhood: Infant feeding difficulties Seizures, ranging from a single seizure event to intractable epilepsy Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder Slow growth, failure to thrive, or difficulty gaining weight Nonspecific dysmorphic features (See The diagnosis of OCNDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Okur-Chung Neurodevelopmental Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Mild-to-moderate developmental delay (DD) or intellectual disability (ID) • Generalized hypotonia in infancy and/or childhood • Speech delay • Any of the following features presenting in infancy or childhood: • Infant feeding difficulties • Seizures, ranging from a single seizure event to intractable epilepsy • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder • Slow growth, failure to thrive, or difficulty gaining weight • Nonspecific dysmorphic features (See • Infant feeding difficulties • Seizures, ranging from a single seizure event to intractable epilepsy • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder • Slow growth, failure to thrive, or difficulty gaining weight • Nonspecific dysmorphic features (See • Infant feeding difficulties • Seizures, ranging from a single seizure event to intractable epilepsy • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder • Slow growth, failure to thrive, or difficulty gaining weight • Nonspecific dysmorphic features (See • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings OCNDS Mild-to-moderate developmental delay (DD) or intellectual disability (ID) Generalized hypotonia in infancy and/or childhood Speech delay AND Any of the following features presenting in infancy or childhood: Infant feeding difficulties Seizures, ranging from a single seizure event to intractable epilepsy Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder Slow growth, failure to thrive, or difficulty gaining weight Nonspecific dysmorphic features (See • Mild-to-moderate developmental delay (DD) or intellectual disability (ID) • Generalized hypotonia in infancy and/or childhood • Speech delay • Any of the following features presenting in infancy or childhood: • Infant feeding difficulties • Seizures, ranging from a single seizure event to intractable epilepsy • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder • Slow growth, failure to thrive, or difficulty gaining weight • Nonspecific dysmorphic features (See • Infant feeding difficulties • Seizures, ranging from a single seizure event to intractable epilepsy • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder • Slow growth, failure to thrive, or difficulty gaining weight • Nonspecific dysmorphic features (See • Infant feeding difficulties • Seizures, ranging from a single seizure event to intractable epilepsy • Behavioral findings including stereotypic movements, autism spectrum disorder, aggressiveness and tantrums, and attention-deficit/hyperactivity disorder • Slow growth, failure to thrive, or difficulty gaining weight • Nonspecific dysmorphic features (See ## Establishing the Diagnosis The diagnosis of OCNDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Okur-Chung Neurodevelopmental Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability, generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. To date, 51 individuals have been identified with a pathogenic variant in Select Features of Okur-Chung Neurodevelopmental Syndrome SD = standard deviation(s) One individual was too young for assessment [ 2 The number of individuals reported to have had brain MRI performed Sitting: 11 months (n=20) Walking: 28.8 months (n=25) First meaningful words: 38.3 months (n=18) Stereotypic movements (~1/3 of affected individuals) Autism spectrum disorder (~1/4) Aggressiveness and tantrums in part related to inability to communicate needs (~1/4) Attention-deficit/hyperactivity disorder (~1/5) Intractable seizures reported in some individuals Status epilepticus reported in one individual Mild hypotonia noted from infancy was reported in about two thirds of affected individuals. Gait abnormalities and poor motor coordination were reported in about one sixth of individuals. Ataxia has also been reported in a few individuals [ Infant feeding difficulties are common and manifest as poor suck in early infancy or difficulty transitioning to solid foods later in infancy. Feeding and swallowing difficulties may require gastrostomy tube placement. Constipation is common. Only one reported individual had congenital microcephaly. Outside of the newborn period, most affected individuals have an occipitofrontal circumference that is below the mean but still within the normal range for age and sex. The majority of OCNDS is rare and the exact prevalence is unknown. Only 51 individuals have been reported in the literature; others have been diagnosed but are not yet included in publications. • Sitting: 11 months (n=20) • Walking: 28.8 months (n=25) • First meaningful words: 38.3 months (n=18) • Stereotypic movements (~1/3 of affected individuals) • Autism spectrum disorder (~1/4) • Aggressiveness and tantrums in part related to inability to communicate needs (~1/4) • Attention-deficit/hyperactivity disorder (~1/5) • Intractable seizures reported in some individuals • Status epilepticus reported in one individual • Mild hypotonia noted from infancy was reported in about two thirds of affected individuals. • Gait abnormalities and poor motor coordination were reported in about one sixth of individuals. Ataxia has also been reported in a few individuals [ • Infant feeding difficulties are common and manifest as poor suck in early infancy or difficulty transitioning to solid foods later in infancy. • Feeding and swallowing difficulties may require gastrostomy tube placement. • Constipation is common. ## Clinical Description Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability, generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. To date, 51 individuals have been identified with a pathogenic variant in Select Features of Okur-Chung Neurodevelopmental Syndrome SD = standard deviation(s) One individual was too young for assessment [ 2 The number of individuals reported to have had brain MRI performed Sitting: 11 months (n=20) Walking: 28.8 months (n=25) First meaningful words: 38.3 months (n=18) Stereotypic movements (~1/3 of affected individuals) Autism spectrum disorder (~1/4) Aggressiveness and tantrums in part related to inability to communicate needs (~1/4) Attention-deficit/hyperactivity disorder (~1/5) Intractable seizures reported in some individuals Status epilepticus reported in one individual Mild hypotonia noted from infancy was reported in about two thirds of affected individuals. Gait abnormalities and poor motor coordination were reported in about one sixth of individuals. Ataxia has also been reported in a few individuals [ Infant feeding difficulties are common and manifest as poor suck in early infancy or difficulty transitioning to solid foods later in infancy. Feeding and swallowing difficulties may require gastrostomy tube placement. Constipation is common. Only one reported individual had congenital microcephaly. Outside of the newborn period, most affected individuals have an occipitofrontal circumference that is below the mean but still within the normal range for age and sex. • Sitting: 11 months (n=20) • Walking: 28.8 months (n=25) • First meaningful words: 38.3 months (n=18) • Stereotypic movements (~1/3 of affected individuals) • Autism spectrum disorder (~1/4) • Aggressiveness and tantrums in part related to inability to communicate needs (~1/4) • Attention-deficit/hyperactivity disorder (~1/5) • Intractable seizures reported in some individuals • Status epilepticus reported in one individual • Mild hypotonia noted from infancy was reported in about two thirds of affected individuals. • Gait abnormalities and poor motor coordination were reported in about one sixth of individuals. Ataxia has also been reported in a few individuals [ • Infant feeding difficulties are common and manifest as poor suck in early infancy or difficulty transitioning to solid foods later in infancy. • Feeding and swallowing difficulties may require gastrostomy tube placement. • Constipation is common. ## Genotype-Phenotype Correlations The majority of ## Prevalence OCNDS is rare and the exact prevalence is unknown. Only 51 individuals have been reported in the literature; others have been diagnosed but are not yet included in publications. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because the phenotypic features associated with Okur-Chung neurodevelopmental syndrome (OCNDS) are not sufficient to diagnose this condition, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM ## Management No clinical practice guidelines for Okur-Chung neurodevelopmental syndrome (OCNDS) have been published. To establish the extent of disease and needs in an individual diagnosed with OCNDS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Okur-Chung Neurodevelopmental Syndrome Consider EEG & possible head MRI if seizures are a concern. Assess gait & coordination. Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl eval of oromotor function, aspiration risk, & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OCNDS = Okur-Chung neurodevelopmental syndrome; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Okur-Chung Neurodevelopmental Syndrome Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; IVIG = Intravenous immune globulin; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic problems. Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Okur-Chung Neurodevelopmental Syndrome Measure growth parameters & growth velocity. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & poor coordination. OT = occupational therapy; PT = physical therapy Low threshold for evaluation for growth hormone deficiency in those with a poor growth velocity Consider assessment of quantitative immunoglobulins and referral to immunologist, if present. See Search • Consider EEG & possible head MRI if seizures are a concern. • Assess gait & coordination. • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl eval of oromotor function, aspiration risk, & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic problems. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Measure growth parameters & growth velocity. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & poor coordination. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with OCNDS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Okur-Chung Neurodevelopmental Syndrome Consider EEG & possible head MRI if seizures are a concern. Assess gait & coordination. Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl eval of oromotor function, aspiration risk, & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OCNDS = Okur-Chung neurodevelopmental syndrome; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Consider EEG & possible head MRI if seizures are a concern. • Assess gait & coordination. • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl eval of oromotor function, aspiration risk, & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Okur-Chung Neurodevelopmental Syndrome Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; IVIG = Intravenous immune globulin; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic problems. Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic problems. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic problems. Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic problems. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Okur-Chung Neurodevelopmental Syndrome Measure growth parameters & growth velocity. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & poor coordination. OT = occupational therapy; PT = physical therapy Low threshold for evaluation for growth hormone deficiency in those with a poor growth velocity Consider assessment of quantitative immunoglobulins and referral to immunologist, if present. • Measure growth parameters & growth velocity. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, mvmt disorders, & poor coordination. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Okur-Chung neurodevelopmental syndrome (OCNDS) is an autosomal dominant disorder typically caused by a Most probands reported to date with OCNDS whose parents have undergone molecular genetic testing have the disorder as a result of a Rarely, individuals diagnosed with OCNDS have the disorder as the result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the If a parent of the proband is known to have the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with OCNDS whose parents have undergone molecular genetic testing have the disorder as a result of a • Rarely, individuals diagnosed with OCNDS have the disorder as the result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If the • If a parent of the proband is known to have the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance Okur-Chung neurodevelopmental syndrome (OCNDS) is an autosomal dominant disorder typically caused by a ## Risk to Family Members Most probands reported to date with OCNDS whose parents have undergone molecular genetic testing have the disorder as a result of a Rarely, individuals diagnosed with OCNDS have the disorder as the result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the If a parent of the proband is known to have the • Most probands reported to date with OCNDS whose parents have undergone molecular genetic testing have the disorder as a result of a • Rarely, individuals diagnosed with OCNDS have the disorder as the result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Author, unpublished data]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If the • If a parent of the proband is known to have the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Okur-Chung Neurodevelopmental Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Okur-Chung Neurodevelopmental Syndrome ( CSNK2A1 regulates the downstream expression of more than 500 genes as a member of the serine/threonine kinase family of proteins [ Notable Variants listed in the table have been provided by the authors. Author, unpublished data ## Molecular Pathogenesis CSNK2A1 regulates the downstream expression of more than 500 genes as a member of the serine/threonine kinase family of proteins [ Notable Variants listed in the table have been provided by the authors. Author, unpublished data ## Chapter Notes We would like to thank the families of individuals with Okur-Chung neurodevelopmental syndrome for their participation in research studies. 9 June 2022 (ma) Review posted live 14 February 2022 (wc) Original submission • 9 June 2022 (ma) Review posted live • 14 February 2022 (wc) Original submission ## Author Notes ## Acknowledgments We would like to thank the families of individuals with Okur-Chung neurodevelopmental syndrome for their participation in research studies. ## Revision History 9 June 2022 (ma) Review posted live 14 February 2022 (wc) Original submission • 9 June 2022 (ma) Review posted live • 14 February 2022 (wc) Original submission ## References ## Literature Cited Average age at which affected individuals achieved three developmental milestones: unsupported sitting, walking, and first words. The Lollipop plot of reported pathogenic	[ "M Akahira-Azuma, Y Tsurusaki, Y Enomoto, J Mitsui, K Kurosawa. 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ondine	ondine	[ "Later-Onset Congenital Central Hypoventilation Syndrome (LO-CCHS)", "Paired mesoderm homeobox protein 2B", "PHOX2B", "Congenital Central Hypoventilation Syndrome (CCHS)" ]	Congenital Central Hypoventilation Syndrome	Debra E Weese-Mayer, Casey M Rand, Ilya Khaytin, Susan M Slattery, Kai Lee Yap, Mary L Marazita, Elizabeth M Berry-Kravis	Summary Congenital central hypoventilation syndrome (CCHS) represents the extreme manifestation of autonomic nervous system dysregulation (ANSD) with the hallmark of disordered respiratory control. The age of initial recognition of CCHS ranges from neonatal onset (i.e., in the first 30 days of life) to (less commonly) later onset (from 1 month to adulthood). The diagnosis of CCHS is established in a proband with suggestive findings and a heterozygous CCHS is typically inherited in an autosomal dominant manner (CCHS caused by biallelic reduced penetrance	## Diagnosis The 2010 American Thoracic Society Statement on congenital central hypoventilation syndrome (CCHS) presents the current consensus clinical diagnostic criteria for CCHS (neonatal-onset and LO-CCHS [later-onset CCHS]) [ CCHS Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep OR Apparent hypoventilation both while awake and while asleep Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia Absence of shortness of breath Severe typically cyanotic breath-holding spells Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors Altered perception of anxiety Esophageal dysmotility Severe constipation even in the absence of Hirschsprung disease Profuse sweating Reduced basal body temperature and peripheral skin temperature Diminished pupillary light response No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that could account for the Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age Unexplained seizures Unexplained neurocognitive delay with any history of prior cyanosis Unexplained neurocognitive impairment The diagnosis of congenital central hypoventilation syndrome (CCHS) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ The three types of Polyalanine repeat expansion mutations (PARMs) Non-polyalanine repeat expansion mutations (NPARMs) Whole-gene or exon 3 deletions (a subset of the NPARMs that will not be detected with sequence analysis) Note: The N in GCN represents any nucleotide (A/C/G/T). All four possible sequences have been observed in the complex repeat. 20 GCN repeats is most common in the population. 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ Note: Given the high frequency of the 20-GCN allele relative to other non-disease-causing repeat variants, all affected individuals with expanded alleles are said to have a 20/N genotype (e.g., genotype 20/25) unless otherwise specified. Single-gene testing is the only molecular genetic testing approach. The American Thoracic Society Statement on CCHS suggests step-wise Note: Currently no multigene panel exists for the diagnosis of CCHS. Most multigene panels are next-generation sequencing (NGS)-based assays that are unable to detect polyalanine repeat expansions, the most common disease-causing Molecular genetic testing may proceed in the following order, based on the likelihood of detecting the most common disease-causing GCN repeat expansions (PARMs), the most common type of disease-causing The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region Low-level mosaicism (see Note: Low-level mosaicism for both PARMs and NPARM deletions has been observed. A protocol to detect low-level somatic mosaicism, not detectable by routine Sanger sequencing, has been developed (see Molecular Genetic Testing Used in Congenital Central Hypoventilation Syndrome See See This polyalanine repeat comprises any one of four codon combinations – GCA, GCT, GCC, or GCG – and is referred to as GCN. See Referred to in the literature as PARMS (polyalanine repeat expansion mutations) and NPARMs (non-polyalanine repeat expansion mutations) Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene. Breakpoints of large deletions and/or deletion of adjacent genes may require special methods [ • • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • OR • Apparent hypoventilation both while awake and while asleep • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • OR • Apparent hypoventilation both while awake and while asleep • • Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep • Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia • Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia • Absence of shortness of breath • Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep • Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia • Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia • Absence of shortness of breath • Severe typically cyanotic breath-holding spells • Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors • Altered perception of anxiety • Esophageal dysmotility • Severe constipation even in the absence of Hirschsprung disease • Profuse sweating • Reduced basal body temperature and peripheral skin temperature • Diminished pupillary light response • Severe typically cyanotic breath-holding spells • Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors • Altered perception of anxiety • Esophageal dysmotility • Severe constipation even in the absence of Hirschsprung disease • Profuse sweating • Reduced basal body temperature and peripheral skin temperature • Diminished pupillary light response • No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that could account for the • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • OR • Apparent hypoventilation both while awake and while asleep • Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep • Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia • Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia • Absence of shortness of breath • Severe typically cyanotic breath-holding spells • Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors • Altered perception of anxiety • Esophageal dysmotility • Severe constipation even in the absence of Hirschsprung disease • Profuse sweating • Reduced basal body temperature and peripheral skin temperature • Diminished pupillary light response • • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) • Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator • Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness • Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) • Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator • Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness • Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age • • Unexplained seizures • Unexplained neurocognitive delay with any history of prior cyanosis • Unexplained neurocognitive impairment • Unexplained seizures • Unexplained neurocognitive delay with any history of prior cyanosis • Unexplained neurocognitive impairment • • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) • Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator • Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness • Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age • Unexplained seizures • Unexplained neurocognitive delay with any history of prior cyanosis • Unexplained neurocognitive impairment • Polyalanine repeat expansion mutations (PARMs) • Non-polyalanine repeat expansion mutations (NPARMs) • Whole-gene or exon 3 deletions (a subset of the NPARMs that will not be detected with sequence analysis) • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see • Note: Low-level mosaicism for both PARMs and NPARM deletions has been observed. A protocol to detect low-level somatic mosaicism, not detectable by routine Sanger sequencing, has been developed (see • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see ## Suggestive Findings CCHS Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep OR Apparent hypoventilation both while awake and while asleep Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia Absence of shortness of breath Severe typically cyanotic breath-holding spells Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors Altered perception of anxiety Esophageal dysmotility Severe constipation even in the absence of Hirschsprung disease Profuse sweating Reduced basal body temperature and peripheral skin temperature Diminished pupillary light response No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that could account for the Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age Unexplained seizures Unexplained neurocognitive delay with any history of prior cyanosis Unexplained neurocognitive impairment • • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • OR • Apparent hypoventilation both while awake and while asleep • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • OR • Apparent hypoventilation both while awake and while asleep • • Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep • Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia • Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia • Absence of shortness of breath • Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep • Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia • Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia • Absence of shortness of breath • Severe typically cyanotic breath-holding spells • Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors • Altered perception of anxiety • Esophageal dysmotility • Severe constipation even in the absence of Hirschsprung disease • Profuse sweating • Reduced basal body temperature and peripheral skin temperature • Diminished pupillary light response • Severe typically cyanotic breath-holding spells • Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors • Altered perception of anxiety • Esophageal dysmotility • Severe constipation even in the absence of Hirschsprung disease • Profuse sweating • Reduced basal body temperature and peripheral skin temperature • Diminished pupillary light response • No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that could account for the • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • OR • Apparent hypoventilation both while awake and while asleep • Absent or attenuated endogenous and exogenous physiologic ventilatory response to hypercarbia and/or hypoxemia when asleep or awake and asleep • Absent arousal from sleep despite physiologic compromise secondary to hypercarbia and/or hypoxemia • Absent perception or behavioral awareness of asphyxia with severe hypercarbia and/or hypoxemia • Absence of shortness of breath • Severe typically cyanotic breath-holding spells • Lack of physiologic responsiveness or behavioral perception to the challenges of exercise and environmental stressors • Altered perception of anxiety • Esophageal dysmotility • Severe constipation even in the absence of Hirschsprung disease • Profuse sweating • Reduced basal body temperature and peripheral skin temperature • Diminished pupillary light response • • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) • Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator • Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness • Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) • Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator • Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness • Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age • • Unexplained seizures • Unexplained neurocognitive delay with any history of prior cyanosis • Unexplained neurocognitive impairment • Unexplained seizures • Unexplained neurocognitive delay with any history of prior cyanosis • Unexplained neurocognitive impairment • • Generally adequate ventilation while awake and at rest, and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep • Apparent life-threatening events and cyanosis during sleep with unexplained nocturnal hypercarbia and hypoxemia • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, breath holding, severe pneumonia) • Delayed "recovery" from a severe respiratory illness or recurrent severe pulmonic infections with related hypoventilation, such that the individual without intrinsic lung disease cannot be weaned from the ventilator • Hypoventilation (unexplained marked elevation in end tidal carbon dioxide level) temporally related to antiseizure medication, sedation, anesthesia, or severe intercurrent illness • Infants and children who die suddenly and unexpectedly ("sudden infant death syndrome [SIDS]" and "sudden unexplained death of childhood [SUDC]"), especially if there is a family history of CCHS or sudden death at any age • Unexplained seizures • Unexplained neurocognitive delay with any history of prior cyanosis • Unexplained neurocognitive impairment ## Establishing the Diagnosis The diagnosis of congenital central hypoventilation syndrome (CCHS) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ The three types of Polyalanine repeat expansion mutations (PARMs) Non-polyalanine repeat expansion mutations (NPARMs) Whole-gene or exon 3 deletions (a subset of the NPARMs that will not be detected with sequence analysis) Note: The N in GCN represents any nucleotide (A/C/G/T). All four possible sequences have been observed in the complex repeat. 20 GCN repeats is most common in the population. 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ Note: Given the high frequency of the 20-GCN allele relative to other non-disease-causing repeat variants, all affected individuals with expanded alleles are said to have a 20/N genotype (e.g., genotype 20/25) unless otherwise specified. Single-gene testing is the only molecular genetic testing approach. The American Thoracic Society Statement on CCHS suggests step-wise Note: Currently no multigene panel exists for the diagnosis of CCHS. Most multigene panels are next-generation sequencing (NGS)-based assays that are unable to detect polyalanine repeat expansions, the most common disease-causing Molecular genetic testing may proceed in the following order, based on the likelihood of detecting the most common disease-causing GCN repeat expansions (PARMs), the most common type of disease-causing The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region Low-level mosaicism (see Note: Low-level mosaicism for both PARMs and NPARM deletions has been observed. A protocol to detect low-level somatic mosaicism, not detectable by routine Sanger sequencing, has been developed (see Molecular Genetic Testing Used in Congenital Central Hypoventilation Syndrome See See This polyalanine repeat comprises any one of four codon combinations – GCA, GCT, GCC, or GCG – and is referred to as GCN. See Referred to in the literature as PARMS (polyalanine repeat expansion mutations) and NPARMs (non-polyalanine repeat expansion mutations) Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene. Breakpoints of large deletions and/or deletion of adjacent genes may require special methods [ • Polyalanine repeat expansion mutations (PARMs) • Non-polyalanine repeat expansion mutations (NPARMs) • Whole-gene or exon 3 deletions (a subset of the NPARMs that will not be detected with sequence analysis) • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see • Note: Low-level mosaicism for both PARMs and NPARM deletions has been observed. A protocol to detect low-level somatic mosaicism, not detectable by routine Sanger sequencing, has been developed (see • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see The three types of Polyalanine repeat expansion mutations (PARMs) Non-polyalanine repeat expansion mutations (NPARMs) Whole-gene or exon 3 deletions (a subset of the NPARMs that will not be detected with sequence analysis) Note: The N in GCN represents any nucleotide (A/C/G/T). All four possible sequences have been observed in the complex repeat. 20 GCN repeats is most common in the population. 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ Note: Given the high frequency of the 20-GCN allele relative to other non-disease-causing repeat variants, all affected individuals with expanded alleles are said to have a 20/N genotype (e.g., genotype 20/25) unless otherwise specified. • Polyalanine repeat expansion mutations (PARMs) • Non-polyalanine repeat expansion mutations (NPARMs) • Whole-gene or exon 3 deletions (a subset of the NPARMs that will not be detected with sequence analysis) • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ • • 20 GCN repeats is most common in the population. • 9, 13, 14, and 15 GCN repeats have been reported but not associated with either neonatal-onset CCHS or LO-CCHS phenotype [ ## Molecular Genetic Testing Approach Single-gene testing is the only molecular genetic testing approach. The American Thoracic Society Statement on CCHS suggests step-wise Note: Currently no multigene panel exists for the diagnosis of CCHS. Most multigene panels are next-generation sequencing (NGS)-based assays that are unable to detect polyalanine repeat expansions, the most common disease-causing Molecular genetic testing may proceed in the following order, based on the likelihood of detecting the most common disease-causing GCN repeat expansions (PARMs), the most common type of disease-causing The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region Low-level mosaicism (see Note: Low-level mosaicism for both PARMs and NPARM deletions has been observed. A protocol to detect low-level somatic mosaicism, not detectable by routine Sanger sequencing, has been developed (see Molecular Genetic Testing Used in Congenital Central Hypoventilation Syndrome See See This polyalanine repeat comprises any one of four codon combinations – GCA, GCT, GCC, or GCG – and is referred to as GCN. See Referred to in the literature as PARMS (polyalanine repeat expansion mutations) and NPARMs (non-polyalanine repeat expansion mutations) Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene. Breakpoints of large deletions and/or deletion of adjacent genes may require special methods [ • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see • Note: Low-level mosaicism for both PARMs and NPARM deletions has been observed. A protocol to detect low-level somatic mosaicism, not detectable by routine Sanger sequencing, has been developed (see • GCN repeat expansions (PARMs), the most common type of disease-causing • The 35-bp and 38-bp NPARM recurrent out-of-frame deletions within the GCN repeat region • Low-level mosaicism (see ## Clinical Characteristics Congenital central hypoventilation syndrome (CCHS) represents the extreme manifestation of autonomic nervous system dysregulation (ANSD) with a hallmark of disordered respiratory control [ Classic CCHS is characterized by adequate ventilation when the individual is awake and apparent hypoventilation with monotonous respiratory rates and shallow breathing (diminished tidal volume) when asleep. More severely affected individuals hypoventilate both when awake and when asleep. Children who hypoventilate both when awake and when asleep typically present in the neonatal period (i.e., first 30 days of life), as do the vast majority of children who hypoventilate only when asleep. Select Features of Congenital Central Hypoventilation Syndrome by PARM vs NPARM and PARM Genotype Based on ANSD = autonomic nervous system dysregulation; NPARM = non-polyalanine repeat expansion mutation (i.e., missense, nonsense, frameshift, stop codon, splice site); PARM = polyalanine repeat expansion mutation Genotype 20/24 would be considered a susceptibility allele (needs another factor to manifest) or a low- or variable-penetrance allele with features that can be triggered by pharmacologic agents (a pharmaco-genetic phenomenon), or a gene x environment interaction (without main effects). Generally 0%; however, an infant with the 20/33 genotype had metastatic neuroblastoma [ The tumors can present at variable ages – neuroblastoma typically before age two years, ganglioneuromas and ganglioneuroblastomas later as incidental findings. Tumor-related deaths in individuals with CCHS are rare. Taken together, these results raise the concern that decreased cognitive performance is more pronounced in children with suboptimal ventilatory management and more severe phenotypic features (i.e., intermittent hypoxemia and altered cerebral autoregulation). Many individuals with CCHS are living with successful artificial ventilation into their third and fourth decades, suggesting the potential for a normal life span. The cause of death when it has occurred has been related to suboptimal ventilatory support leading to recurrent hypoxemia and hypercarbia or lack of compliance with artificial ventilation. A limited number of individuals have engaged in substance use, a lethal combination for unsupervised ventilator-dependent adolescents or young adults [ Among individuals with a prolonged R-R interval, development of asystoles is a potential cause of sudden death [ Neuropathologic and neuroimaging findings of individuals given a clinical diagnosis of CCHS (many of whom did not undergo confirmatory Congenital Central Hypoventilation Syndrome: Neuropathologic and Neuroimaging Findings (See footnote 1.) Hypothalamus (responsible for thermal drive to breathing) Posterior thalamus & midbrain (mediating O Caudal raphé & locus coeruleus (regulating serotonergic & noradrenergic systems) Lateral medulla, parabrachial pons, & cerebellum (coordinating chemoreceptor & somatic afferent activity w/breathing) Insular & cingulate cortices (mediating shortness of breath perception) Structural and functional alterations in these sites may be caused by pathogenic variants in See Until a large screening study is performed in a racially/ethnically diverse cohort, the prevalence of CCHS will remain an estimate. Investigators in France [ • The tumors can present at variable ages – neuroblastoma typically before age two years, ganglioneuromas and ganglioneuroblastomas later as incidental findings. • Tumor-related deaths in individuals with CCHS are rare. • Hypothalamus (responsible for thermal drive to breathing) • Posterior thalamus & midbrain (mediating O • Caudal raphé & locus coeruleus (regulating serotonergic & noradrenergic systems) • Lateral medulla, parabrachial pons, & cerebellum (coordinating chemoreceptor & somatic afferent activity w/breathing) • Insular & cingulate cortices (mediating shortness of breath perception) ## Clinical Description Congenital central hypoventilation syndrome (CCHS) represents the extreme manifestation of autonomic nervous system dysregulation (ANSD) with a hallmark of disordered respiratory control [ Classic CCHS is characterized by adequate ventilation when the individual is awake and apparent hypoventilation with monotonous respiratory rates and shallow breathing (diminished tidal volume) when asleep. More severely affected individuals hypoventilate both when awake and when asleep. Children who hypoventilate both when awake and when asleep typically present in the neonatal period (i.e., first 30 days of life), as do the vast majority of children who hypoventilate only when asleep. Select Features of Congenital Central Hypoventilation Syndrome by PARM vs NPARM and PARM Genotype Based on ANSD = autonomic nervous system dysregulation; NPARM = non-polyalanine repeat expansion mutation (i.e., missense, nonsense, frameshift, stop codon, splice site); PARM = polyalanine repeat expansion mutation Genotype 20/24 would be considered a susceptibility allele (needs another factor to manifest) or a low- or variable-penetrance allele with features that can be triggered by pharmacologic agents (a pharmaco-genetic phenomenon), or a gene x environment interaction (without main effects). Generally 0%; however, an infant with the 20/33 genotype had metastatic neuroblastoma [ The tumors can present at variable ages – neuroblastoma typically before age two years, ganglioneuromas and ganglioneuroblastomas later as incidental findings. Tumor-related deaths in individuals with CCHS are rare. Taken together, these results raise the concern that decreased cognitive performance is more pronounced in children with suboptimal ventilatory management and more severe phenotypic features (i.e., intermittent hypoxemia and altered cerebral autoregulation). Many individuals with CCHS are living with successful artificial ventilation into their third and fourth decades, suggesting the potential for a normal life span. The cause of death when it has occurred has been related to suboptimal ventilatory support leading to recurrent hypoxemia and hypercarbia or lack of compliance with artificial ventilation. A limited number of individuals have engaged in substance use, a lethal combination for unsupervised ventilator-dependent adolescents or young adults [ Among individuals with a prolonged R-R interval, development of asystoles is a potential cause of sudden death [ Neuropathologic and neuroimaging findings of individuals given a clinical diagnosis of CCHS (many of whom did not undergo confirmatory Congenital Central Hypoventilation Syndrome: Neuropathologic and Neuroimaging Findings (See footnote 1.) Hypothalamus (responsible for thermal drive to breathing) Posterior thalamus & midbrain (mediating O Caudal raphé & locus coeruleus (regulating serotonergic & noradrenergic systems) Lateral medulla, parabrachial pons, & cerebellum (coordinating chemoreceptor & somatic afferent activity w/breathing) Insular & cingulate cortices (mediating shortness of breath perception) Structural and functional alterations in these sites may be caused by pathogenic variants in • The tumors can present at variable ages – neuroblastoma typically before age two years, ganglioneuromas and ganglioneuroblastomas later as incidental findings. • Tumor-related deaths in individuals with CCHS are rare. • Hypothalamus (responsible for thermal drive to breathing) • Posterior thalamus & midbrain (mediating O • Caudal raphé & locus coeruleus (regulating serotonergic & noradrenergic systems) • Lateral medulla, parabrachial pons, & cerebellum (coordinating chemoreceptor & somatic afferent activity w/breathing) • Insular & cingulate cortices (mediating shortness of breath perception) ## Other Taken together, these results raise the concern that decreased cognitive performance is more pronounced in children with suboptimal ventilatory management and more severe phenotypic features (i.e., intermittent hypoxemia and altered cerebral autoregulation). ## Prognosis Many individuals with CCHS are living with successful artificial ventilation into their third and fourth decades, suggesting the potential for a normal life span. The cause of death when it has occurred has been related to suboptimal ventilatory support leading to recurrent hypoxemia and hypercarbia or lack of compliance with artificial ventilation. A limited number of individuals have engaged in substance use, a lethal combination for unsupervised ventilator-dependent adolescents or young adults [ Among individuals with a prolonged R-R interval, development of asystoles is a potential cause of sudden death [ ## Neuropathologic and Neuroimaging Findings Neuropathologic and neuroimaging findings of individuals given a clinical diagnosis of CCHS (many of whom did not undergo confirmatory Congenital Central Hypoventilation Syndrome: Neuropathologic and Neuroimaging Findings (See footnote 1.) Hypothalamus (responsible for thermal drive to breathing) Posterior thalamus & midbrain (mediating O Caudal raphé & locus coeruleus (regulating serotonergic & noradrenergic systems) Lateral medulla, parabrachial pons, & cerebellum (coordinating chemoreceptor & somatic afferent activity w/breathing) Insular & cingulate cortices (mediating shortness of breath perception) Structural and functional alterations in these sites may be caused by pathogenic variants in • Hypothalamus (responsible for thermal drive to breathing) • Posterior thalamus & midbrain (mediating O • Caudal raphé & locus coeruleus (regulating serotonergic & noradrenergic systems) • Lateral medulla, parabrachial pons, & cerebellum (coordinating chemoreceptor & somatic afferent activity w/breathing) • Insular & cingulate cortices (mediating shortness of breath perception) ## Genotype-Phenotype Correlations See ## Nomenclature ## Prevalence Until a large screening study is performed in a racially/ethnically diverse cohort, the prevalence of CCHS will remain an estimate. Investigators in France [ ## Genetically Related (Allelic) disorders No phenotypes other than those discussed in this ## Differential Diagnosis Primary neuromuscular, pulmonary, or cardiac disease or an identifiable brain stem lesion that could account for the full constellation of CCHS findings, including the autonomic nervous system dysregulation (ANSD) [ Hypoxic ischemic encephalopathy, asphyxia, infarction, infection; Severe prematurity [ Hypothalamic dysfunction (altered water balance, hyperprolactinemia, hypothyroidism, altered onset of puberty, growth hormone deficiency, and ACTH insufficiency) [ Central alveolar hypoventilation (often preceded by obstructive sleep apnea) asleep and later awake and asleep; and ANSD (altered thermoregulation, diaphoresis, pupillary light response, peripheral vasomotor function, and bradycardia). Affected children can also have mild-to-severe behavioral problems if ventilatory support is inadequate; about 40% of the children have tumors including ganglioneuromas and ganglioneuroblastomas (rarely neuroblastomas). The ROHHAD phenotype "unfolds" with advancing age as additional features of the phenotype become apparent. With pristine management, awake spontaneous breathing has recovered [Author, personal observation]. Although a genetic cause is suspected, candidate gene investigations have not yet identified a molecular cause of ROHHAD [ • Primary neuromuscular, pulmonary, or cardiac disease or an identifiable brain stem lesion that could account for the full constellation of CCHS findings, including the autonomic nervous system dysregulation (ANSD) [ • Hypoxic ischemic encephalopathy, asphyxia, infarction, infection; • Severe prematurity [ • Hypothalamic dysfunction (altered water balance, hyperprolactinemia, hypothyroidism, altered onset of puberty, growth hormone deficiency, and ACTH insufficiency) [ • Central alveolar hypoventilation (often preceded by obstructive sleep apnea) asleep and later awake and asleep; and • ANSD (altered thermoregulation, diaphoresis, pupillary light response, peripheral vasomotor function, and bradycardia). ## Management Clinical practice guidelines for congenital central hypoventilation syndrome (CCHS) have been published in the ATS Statement on CCHS [ To establish the extent of disease and needs in an individual diagnosed with CCHS, the evaluations by phenotype summarized in Congenital Central Hypoventilation Syndrome: Recommended Evaluations by Genotype Following Initial Diagnosis Adapted from NPARM = non-polyalanine repeat expansion mutation (i.e., missense, nonsense, frameshift, stop codon, splice site); PARM = polyalanine repeat expansion mutation with number of repeats on each allele (i.e., 20/24-20/33) Evaluations asleep and awake during age-appropriate activities of daily living with exogenous and endogenous ventilatory challenges and autonomic testing Evaluation as per standard protocols A punch biopsy in the neonatal period or a full thickness biopsy later should be considered based on symptoms and Chest and abdominal imaging to detect ganglioneuroblastomas and ganglioneuroma; chest and abdominal imaging and urine catecholamines to detect neuroblastomas Exon or whole-gene deletion or duplication Evaluations should also include Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, electrocardiogram, blood pressure, cerebral regional blood flow/oxygenation, and appropriate sleep-state staging measures Evaluation of the awake and asleep physiologic responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living Venous or arterial blood gas or serum bicarbonate level to look for elevated carbon dioxide content at the time of presentation Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia 72-hour Holter recording to assess for abrupt, prolonged asystoles Echocardiogram to assess for changes consistent with right ventricular hypertrophy and Neurocognitive assessment to determine baseline function Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing Management by multidisciplinary specialists including pediatric pulmonology, sleep medicine, cardiology, oncology, ophthalmology, gastroenterology, neurodevelopmental psychology, and neurology is recommended. Because individuals with CCHS may experience severe hypoventilation or complete respiratory arrest and, thus, the sequelae of hypoxemia, they require monitoring of objective measures of oxygenation (i.e., peripheral pulse oximeter SpO For each of the options listed below, the goal is to provide the affected individual with the technology optimal for the individual's lifestyle needs. Typically, the infant needing ventilatory support 24 hours/day is most safely and effectively supported via tracheostomy and use of a home mechanical ventilator. Tracheostomy is also recommended for children and adults who require artificial ventilation during sleep only, though transition to mask ventilation is a consideration in a subset of individuals after maturation of the facial configuration. As toddlers who require continuous ventilatory support become ambulatory, diaphragm pacing by phrenic nerve stimulation can be considered to allow for increased mobility and improved quality of life. Diaphragm pacing is not typically recommended for the young child who requires only nighttime ventilatory support because the benefits do not outweigh the risks; however, for a subset of older adolescents and young adults, this could be an appropriate consideration. Tracheal decannulation is not assured in affected individuals who use diaphragm pacing during sleep, especially young children [ Diaphragm pacers for the active child with CCHS should be implanted at each phrenic nerve in the chest, ideally by thoracoscopic technique by highly experienced surgeons and phrenic nerve-diaphragm pacer teams [ Older infants, toddlers, and children with diaphragm pacers should be assessed for use of a speaking valve (Tracoe or Passy-Muir one-way speaking valve) while awake, allowing for vocalization and use of the upper airway on exhalation. Children with diaphragm pacers may be assessed for capping of the tracheostomy tube while awake and paced, thereby allowing for inspiration and exhalation via the upper airway; tracheostomy is typically still required for mechanical ventilation during sleep to avoid upper-airway obstruction and physiologic compromise. Although not yet accomplished, the older child with an entirely normal airway may be able to eliminate the need for a tracheostomy by relying on diaphragm pacing while awake and on mask ventilation while asleep; however, such a child may require interim endotracheal intubation to allow for optimal oxygenation and ventilation during acute illness that requires more aggressive ventilatory management. Cooperative older children who consistently require ventilatory support only while sleeping may be candidates for noninvasive support with either mask ventilation or negative-pressure ventilation; however, this must be done with careful consideration of the individual child's needs. If successful, tracheal decannulation can be considered (with the caveat that in the event of severe illness, interim endotracheal intubation may be required in a pediatric intensive care unit). The child who normally requires ventilatory support during sleep only may, during an intercurrent illness, also require artificial ventilation both awake and asleep. Note: While Because individuals with CCHS may receive medications expected to alter pupillary light response or because of potential use of illicit drugs, it is essential that medical personnel appreciate the innate abnormalities of pupillary reactivity to light. Use of pupillometry at the time of each clinical evaluation allows reliable objective documentation of the individual's signature pupillary light response relative to an established clinical baseline and published norms Every six months for the first three years, then annually thereafter, assessment of the following in a pediatric respiratory physiology laboratory experienced in the diagnosis and care of individuals with CCHS is recommended: Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, blood pressure, cerebral regional blood flow/oxygenation, and electrocardiogram, and appropriate sleep state staging measures Evaluation of the awake and asleep responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia 72-hour Holter recording to assess for abrupt, prolonged asystoles Echocardiogram to assess for changes consistent with right ventricular hypertrophy and Neurocognitive assessment/educational needs Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing Ideally, children with CCHS should not go swimming. If they do, they should be carefully supervised, regardless of the presence or absence of a tracheostomy. Children with CCHS should not compete in underwater swimming contests as they cannot perceive the asphyxia that occurs with drowning and breath-holding and, therefore, are likely to swim longer and farther than children without CCHS, thereby increasing the risk of drowning. Breath-holding contests may lead to asphyxia and/or death. Alcohol (respiratory depression), recreational drugs (varied effects), and prescribed as well as non-prescribed medications/sedatives/anesthetics that could induce respiratory depression should be avoided [ The parents , sibs, and offspring of an affected individual are at risk for CCHS. It is appropriate to clarify the genetic status of these individuals in order to identify as early as possible family members who would benefit from prompt initiation of treatment (see Evaluation of the parents of a child with CCHS should include testing capable of detecting low-level somatic mosaicism (see See Though not prospectively evaluated, the ventilatory needs of a pregnant woman with CCHS warrant careful consideration by the obstetrician. Search • Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, electrocardiogram, blood pressure, cerebral regional blood flow/oxygenation, and appropriate sleep-state staging measures • Evaluation of the awake and asleep physiologic responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living • Venous or arterial blood gas or serum bicarbonate level to look for elevated carbon dioxide content at the time of presentation • Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia • 72-hour Holter recording to assess for abrupt, prolonged asystoles • Echocardiogram to assess for changes consistent with right ventricular hypertrophy and • Neurocognitive assessment to determine baseline function • Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing • Diaphragm pacers for the active child with CCHS should be implanted at each phrenic nerve in the chest, ideally by thoracoscopic technique by highly experienced surgeons and phrenic nerve-diaphragm pacer teams [ • Older infants, toddlers, and children with diaphragm pacers should be assessed for use of a speaking valve (Tracoe or Passy-Muir one-way speaking valve) while awake, allowing for vocalization and use of the upper airway on exhalation. • Children with diaphragm pacers may be assessed for capping of the tracheostomy tube while awake and paced, thereby allowing for inspiration and exhalation via the upper airway; tracheostomy is typically still required for mechanical ventilation during sleep to avoid upper-airway obstruction and physiologic compromise. • Although not yet accomplished, the older child with an entirely normal airway may be able to eliminate the need for a tracheostomy by relying on diaphragm pacing while awake and on mask ventilation while asleep; however, such a child may require interim endotracheal intubation to allow for optimal oxygenation and ventilation during acute illness that requires more aggressive ventilatory management. • Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, blood pressure, cerebral regional blood flow/oxygenation, and electrocardiogram, and appropriate sleep state staging measures • Evaluation of the awake and asleep responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living • Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia • 72-hour Holter recording to assess for abrupt, prolonged asystoles • Echocardiogram to assess for changes consistent with right ventricular hypertrophy and • Neurocognitive assessment/educational needs • Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CCHS, the evaluations by phenotype summarized in Congenital Central Hypoventilation Syndrome: Recommended Evaluations by Genotype Following Initial Diagnosis Adapted from NPARM = non-polyalanine repeat expansion mutation (i.e., missense, nonsense, frameshift, stop codon, splice site); PARM = polyalanine repeat expansion mutation with number of repeats on each allele (i.e., 20/24-20/33) Evaluations asleep and awake during age-appropriate activities of daily living with exogenous and endogenous ventilatory challenges and autonomic testing Evaluation as per standard protocols A punch biopsy in the neonatal period or a full thickness biopsy later should be considered based on symptoms and Chest and abdominal imaging to detect ganglioneuroblastomas and ganglioneuroma; chest and abdominal imaging and urine catecholamines to detect neuroblastomas Exon or whole-gene deletion or duplication Evaluations should also include Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, electrocardiogram, blood pressure, cerebral regional blood flow/oxygenation, and appropriate sleep-state staging measures Evaluation of the awake and asleep physiologic responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living Venous or arterial blood gas or serum bicarbonate level to look for elevated carbon dioxide content at the time of presentation Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia 72-hour Holter recording to assess for abrupt, prolonged asystoles Echocardiogram to assess for changes consistent with right ventricular hypertrophy and Neurocognitive assessment to determine baseline function Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing • Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, electrocardiogram, blood pressure, cerebral regional blood flow/oxygenation, and appropriate sleep-state staging measures • Evaluation of the awake and asleep physiologic responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living • Venous or arterial blood gas or serum bicarbonate level to look for elevated carbon dioxide content at the time of presentation • Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia • 72-hour Holter recording to assess for abrupt, prolonged asystoles • Echocardiogram to assess for changes consistent with right ventricular hypertrophy and • Neurocognitive assessment to determine baseline function • Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing ## Treatment of Manifestations Management by multidisciplinary specialists including pediatric pulmonology, sleep medicine, cardiology, oncology, ophthalmology, gastroenterology, neurodevelopmental psychology, and neurology is recommended. Because individuals with CCHS may experience severe hypoventilation or complete respiratory arrest and, thus, the sequelae of hypoxemia, they require monitoring of objective measures of oxygenation (i.e., peripheral pulse oximeter SpO For each of the options listed below, the goal is to provide the affected individual with the technology optimal for the individual's lifestyle needs. Typically, the infant needing ventilatory support 24 hours/day is most safely and effectively supported via tracheostomy and use of a home mechanical ventilator. Tracheostomy is also recommended for children and adults who require artificial ventilation during sleep only, though transition to mask ventilation is a consideration in a subset of individuals after maturation of the facial configuration. As toddlers who require continuous ventilatory support become ambulatory, diaphragm pacing by phrenic nerve stimulation can be considered to allow for increased mobility and improved quality of life. Diaphragm pacing is not typically recommended for the young child who requires only nighttime ventilatory support because the benefits do not outweigh the risks; however, for a subset of older adolescents and young adults, this could be an appropriate consideration. Tracheal decannulation is not assured in affected individuals who use diaphragm pacing during sleep, especially young children [ Diaphragm pacers for the active child with CCHS should be implanted at each phrenic nerve in the chest, ideally by thoracoscopic technique by highly experienced surgeons and phrenic nerve-diaphragm pacer teams [ Older infants, toddlers, and children with diaphragm pacers should be assessed for use of a speaking valve (Tracoe or Passy-Muir one-way speaking valve) while awake, allowing for vocalization and use of the upper airway on exhalation. Children with diaphragm pacers may be assessed for capping of the tracheostomy tube while awake and paced, thereby allowing for inspiration and exhalation via the upper airway; tracheostomy is typically still required for mechanical ventilation during sleep to avoid upper-airway obstruction and physiologic compromise. Although not yet accomplished, the older child with an entirely normal airway may be able to eliminate the need for a tracheostomy by relying on diaphragm pacing while awake and on mask ventilation while asleep; however, such a child may require interim endotracheal intubation to allow for optimal oxygenation and ventilation during acute illness that requires more aggressive ventilatory management. Cooperative older children who consistently require ventilatory support only while sleeping may be candidates for noninvasive support with either mask ventilation or negative-pressure ventilation; however, this must be done with careful consideration of the individual child's needs. If successful, tracheal decannulation can be considered (with the caveat that in the event of severe illness, interim endotracheal intubation may be required in a pediatric intensive care unit). The child who normally requires ventilatory support during sleep only may, during an intercurrent illness, also require artificial ventilation both awake and asleep. Note: While Because individuals with CCHS may receive medications expected to alter pupillary light response or because of potential use of illicit drugs, it is essential that medical personnel appreciate the innate abnormalities of pupillary reactivity to light. Use of pupillometry at the time of each clinical evaluation allows reliable objective documentation of the individual's signature pupillary light response relative to an established clinical baseline and published norms • Diaphragm pacers for the active child with CCHS should be implanted at each phrenic nerve in the chest, ideally by thoracoscopic technique by highly experienced surgeons and phrenic nerve-diaphragm pacer teams [ • Older infants, toddlers, and children with diaphragm pacers should be assessed for use of a speaking valve (Tracoe or Passy-Muir one-way speaking valve) while awake, allowing for vocalization and use of the upper airway on exhalation. • Children with diaphragm pacers may be assessed for capping of the tracheostomy tube while awake and paced, thereby allowing for inspiration and exhalation via the upper airway; tracheostomy is typically still required for mechanical ventilation during sleep to avoid upper-airway obstruction and physiologic compromise. • Although not yet accomplished, the older child with an entirely normal airway may be able to eliminate the need for a tracheostomy by relying on diaphragm pacing while awake and on mask ventilation while asleep; however, such a child may require interim endotracheal intubation to allow for optimal oxygenation and ventilation during acute illness that requires more aggressive ventilatory management. ## Surveillance Every six months for the first three years, then annually thereafter, assessment of the following in a pediatric respiratory physiology laboratory experienced in the diagnosis and care of individuals with CCHS is recommended: Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, blood pressure, cerebral regional blood flow/oxygenation, and electrocardiogram, and appropriate sleep state staging measures Evaluation of the awake and asleep responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia 72-hour Holter recording to assess for abrupt, prolonged asystoles Echocardiogram to assess for changes consistent with right ventricular hypertrophy and Neurocognitive assessment/educational needs Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing • Clinical study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, blood pressure, cerebral regional blood flow/oxygenation, and electrocardiogram, and appropriate sleep state staging measures • Evaluation of the awake and asleep responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia in varied age-appropriate activities of daily living • Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia • 72-hour Holter recording to assess for abrupt, prolonged asystoles • Echocardiogram to assess for changes consistent with right ventricular hypertrophy and • Neurocognitive assessment/educational needs • Comprehensive autonomic testing of all organ systems regulated by the autonomic nervous system, including but not limited to pupillometry, head up-tilt testing, thermoregulatory chamber sweat testing, Q-Sweat testing, heart rate deep breathing, Valsalva maneuver, and measures of cerebral regional blood flow and blood pressure in activities of daily living as well as orthostatic testing ## Agents/Circumstances to Avoid Ideally, children with CCHS should not go swimming. If they do, they should be carefully supervised, regardless of the presence or absence of a tracheostomy. Children with CCHS should not compete in underwater swimming contests as they cannot perceive the asphyxia that occurs with drowning and breath-holding and, therefore, are likely to swim longer and farther than children without CCHS, thereby increasing the risk of drowning. Breath-holding contests may lead to asphyxia and/or death. Alcohol (respiratory depression), recreational drugs (varied effects), and prescribed as well as non-prescribed medications/sedatives/anesthetics that could induce respiratory depression should be avoided [ ## Evaluation of Relatives at Risk The parents , sibs, and offspring of an affected individual are at risk for CCHS. It is appropriate to clarify the genetic status of these individuals in order to identify as early as possible family members who would benefit from prompt initiation of treatment (see Evaluation of the parents of a child with CCHS should include testing capable of detecting low-level somatic mosaicism (see See ## Pregnancy Management Though not prospectively evaluated, the ventilatory needs of a pregnant woman with CCHS warrant careful consideration by the obstetrician. ## Therapies Under Investigation Search ## Genetic Counseling Congenital central hypoventilation syndrome (CCHS), i.e., neonatal-onset CCHS and later-onset CCHS (LO-CCHS), are typically inherited in an autosomal dominant manner. CCHS caused by biallelic reduced penetrance The majority of individuals diagnosed with CCHS have the disorder as the result of a Some individuals diagnosed with CCHS have an affected parent [ Molecular genetic testing for the Germline mosaicism ( Germline mosaicism The family history of some individuals diagnosed with CCHS or LO-CCHS may appear to be negative because of reduced penetrance or variable expressivity in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless the appropriate molecular genetic testing (see If a parent of the proband is affected and/or is known to be heterozygous for the If a parent of the proband has mosaicism for the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Delivery of a fetus known to have a CCHS-causing pathogenic variant should be managed by a high-risk obstetrician. A neonatology team should be present at delivery, and delivery should occur in a quaternary care medical center so that the newborn's transition to extrauterine life, prompt intubation, and mechanical ventilation can be smoothly achieved and transfer to the neonatal intensive care unit can be expedited. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The majority of individuals diagnosed with CCHS have the disorder as the result of a • Some individuals diagnosed with CCHS have an affected parent [ • Molecular genetic testing for the • Germline mosaicism ( • Germline mosaicism • The family history of some individuals diagnosed with CCHS or LO-CCHS may appear to be negative because of reduced penetrance or variable expressivity in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless the appropriate molecular genetic testing (see • If a parent of the proband is affected and/or is known to be heterozygous for the • If a parent of the proband has mosaicism for the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Congenital central hypoventilation syndrome (CCHS), i.e., neonatal-onset CCHS and later-onset CCHS (LO-CCHS), are typically inherited in an autosomal dominant manner. CCHS caused by biallelic reduced penetrance ## Risk to Family Members (Autosomal Dominant Inheritance) The majority of individuals diagnosed with CCHS have the disorder as the result of a Some individuals diagnosed with CCHS have an affected parent [ Molecular genetic testing for the Germline mosaicism ( Germline mosaicism The family history of some individuals diagnosed with CCHS or LO-CCHS may appear to be negative because of reduced penetrance or variable expressivity in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless the appropriate molecular genetic testing (see If a parent of the proband is affected and/or is known to be heterozygous for the If a parent of the proband has mosaicism for the If the parents have not been tested for the • The majority of individuals diagnosed with CCHS have the disorder as the result of a • Some individuals diagnosed with CCHS have an affected parent [ • Molecular genetic testing for the • Germline mosaicism ( • Germline mosaicism • The family history of some individuals diagnosed with CCHS or LO-CCHS may appear to be negative because of reduced penetrance or variable expressivity in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless the appropriate molecular genetic testing (see • If a parent of the proband is affected and/or is known to be heterozygous for the • If a parent of the proband has mosaicism for the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Delivery of a fetus known to have a CCHS-causing pathogenic variant should be managed by a high-risk obstetrician. A neonatology team should be present at delivery, and delivery should occur in a quaternary care medical center so that the newborn's transition to extrauterine life, prompt intubation, and mechanical ventilation can be smoothly achieved and transfer to the neonatal intensive care unit can be expedited. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 11A Lomond Crescent Scotland G83 0RJ United Kingdom Rimière Street 22 Neupre Belgium 3 Surrey Lane Hempstead NY 11550 International CCHS Registry International ROHHAD Registry • • • • 11A Lomond Crescent • Scotland G83 0RJ • United Kingdom • • Rimière Street 22 • Neupre • Belgium • • • • • • • • 3 Surrey Lane • Hempstead NY 11550 • • • International CCHS Registry • • • International ROHHAD Registry • ## Molecular Genetics Congenital Central Hypoventilation Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Congenital Central Hypoventilation Syndrome ( A 20-GCN repeat is the most common normal allele. Normal alleles with 7, 13, 14, and 15 repeats have been reported [ Polyalanine repeat expansion mutations (PARMs) and non-polyalanine repeat expansion mutations (NPARMs) cause congenital central hypoventilation syndrome. NPARMs, including frameshift variants within the polyalanine repeat, are typically small out-of-frame deletions or duplications [ Further study is necessary to elucidate the relationship between Several lines of evidence support a possible dominant-negative mechanism for All individuals with CCHS have pathogenic variants that alter the protein downstream from the homeodomain, potentially producing altered proteins [ For other technical considerations see Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis A 20-GCN repeat is the most common normal allele. Normal alleles with 7, 13, 14, and 15 repeats have been reported [ Polyalanine repeat expansion mutations (PARMs) and non-polyalanine repeat expansion mutations (NPARMs) cause congenital central hypoventilation syndrome. NPARMs, including frameshift variants within the polyalanine repeat, are typically small out-of-frame deletions or duplications [ Further study is necessary to elucidate the relationship between Several lines of evidence support a possible dominant-negative mechanism for All individuals with CCHS have pathogenic variants that alter the protein downstream from the homeodomain, potentially producing altered proteins [ For other technical considerations see Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Elizabeth M Berry-Kravis, MD, PhD (2003-present)Ilya Khaytin, MD, PhD (2021-present)Mary L Marazita, PhD, FACMG (2003-present)Pallavi P Patwari, MD; Children's Memorial Hospital, Chicago (2010-2014)Casey M Rand, BS (2014-present)Susan M Slattery, MD, MS (2021-present)Debra E Weese-Mayer, MD (2003-present)Kai Lee Yap, PhD (2021-present) 28 January 2021 (bp) Comprehensive update posted live 30 January 2014 (me) Comprehensive update posted live 10 November 2011 (me) Comprehensive update posted live 24 July 2008 (cd) Revision: Testing Strategy 23 February 2007 (me) Comprehensive update posted live 17 December 2004 (me) Comprehensive update posted live 28 January 2004 (me) Review posted live 12 August 2003 (mm) Original submission • 28 January 2021 (bp) Comprehensive update posted live • 30 January 2014 (me) Comprehensive update posted live • 10 November 2011 (me) Comprehensive update posted live • 24 July 2008 (cd) Revision: Testing Strategy • 23 February 2007 (me) Comprehensive update posted live • 17 December 2004 (me) Comprehensive update posted live • 28 January 2004 (me) Review posted live • 12 August 2003 (mm) Original submission ## Author Notes ## Author History Elizabeth M Berry-Kravis, MD, PhD (2003-present)Ilya Khaytin, MD, PhD (2021-present)Mary L Marazita, PhD, FACMG (2003-present)Pallavi P Patwari, MD; Children's Memorial Hospital, Chicago (2010-2014)Casey M Rand, BS (2014-present)Susan M Slattery, MD, MS (2021-present)Debra E Weese-Mayer, MD (2003-present)Kai Lee Yap, PhD (2021-present) ## Revision History 28 January 2021 (bp) Comprehensive update posted live 30 January 2014 (me) Comprehensive update posted live 10 November 2011 (me) Comprehensive update posted live 24 July 2008 (cd) Revision: Testing Strategy 23 February 2007 (me) Comprehensive update posted live 17 December 2004 (me) Comprehensive update posted live 28 January 2004 (me) Review posted live 12 August 2003 (mm) Original submission • 28 January 2021 (bp) Comprehensive update posted live • 30 January 2014 (me) Comprehensive update posted live • 10 November 2011 (me) Comprehensive update posted live • 24 July 2008 (cd) Revision: Testing Strategy • 23 February 2007 (me) Comprehensive update posted live • 17 December 2004 (me) Comprehensive update posted live • 28 January 2004 (me) Review posted live • 12 August 2003 (mm) Original submission ## References Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, on behalf of the ATS Congenital Central Hypoventilation Syndrome Subcommittee. An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Available • Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, on behalf of the ATS Congenital Central Hypoventilation Syndrome Subcommittee. An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Available ## Published Guidelines / Consensus Statements Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, on behalf of the ATS Congenital Central Hypoventilation Syndrome Subcommittee. An official ATS clinical policy statement: congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Available • Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, on behalf of the ATS Congenital Central Hypoventilation Syndrome Subcommittee. 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Diaphragm pacing with a quadripolar phrenic nerve electrode: an international study.. Pacing Clin Electrophysiol 1996;19:1311-9", "MA Woo, PM Macey, KE Macey, TG Keens, MS Woo, RK Harper, RM Harper. FMRI responses to hyperoxia in congenital central hypoventilation syndrome.. Pediatr Res 2005;57:510-8", "MS Woo, MA Woo, D Gozal, MT Jansen, TG Keens, RM Harper. Heart rate variability in congenital central hypoventilation syndrome.. Pediatr Res 1992;31:291-6", "FA Zelko, MN Nelson, SE Leurgans, EM Berry-Kravis, DE Weese-Mayer. Congenital central hypoventilation syndrome: neurocognitive functioning in school age children.. Pediatr Pulmonol 2010;45:92-8", "FA Zelko, TM Stewart, CD Brogadir, CM Rand, DE Weese-Mayer. Congenital central hypoventilation syndrome (CCHS): broader cognitive deficits revealed by parent controls.. Pediatr Pulmonol 2018;53:492-7" ]	28/1/2004	28/1/2021	24/7/2008	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
opa	opa	[ "Dynamin-like 120 kDa protein, mitochondrial", "OPA1", "Optic Atrophy Type 1" ]	Optic Atrophy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Cécile Delettre-Cribaillet, Christian P Hamel, Guy Lenaers	Summary Optic atrophy type 1 (OPA1, or Kjer type optic atrophy) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity (usually between ages 4 and 6 years), visual field defects, and color vision defects. Visual impairment is usually moderate (6/10 to 2/10), but ranges from mild or even insignificant to severe (legal blindness with acuity <1/20). The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Other findings can include auditory neuropathy resulting in sensorineural hearing loss that ranges from severe and congenital to subclinical (i.e., identified by specific audiologic testing only). Visual evoked potentials are typically absent or delayed; pattern electroretinogram shows an abnormal N95:P50 ratio. Tritanopia is the classic feature of color vision defect, but more diffuse nonspecific dyschromatopsia is not uncommon. Ophthalmoscopic examination discloses temporal or diffuse pallor of the optic discs, sometimes associated with optic disc excavation. The neuroretinal rim shows some pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. The diagnosis of OPA1 is made based on a combination of clinical findings, electrophysiologic studies, and family history and/or by the identification of a heterozygous pathogenic variant in OPA1 is inherited in an autosomal dominant manner. Most individuals diagnosed with OPA1 have an affected parent; however,	## Diagnosis Optic atrophy type 1 (OPA1 or Kjer type optic atrophy) Childhood onset Bilateral vision loss that is usually symmetric Visual field defect that is typically centrocecal, central, or paracentral Peripheral field that is usually normal, although inversion of red and blue isopters may occur. Note: The isopters are lines joining points of equal sensitivity on a visual field chart. The red isopter represents the largest/brightest stimulus; the blue isopter represents the smallest/dimmest stimulus. Persons with OPA1 have scotomas (areas of impaired visual acuity) in the central visual fields and sparing of the peripheral visual fields. Color vision defect, often described as acquired blue-yellow loss (tritanopia) Opthalmoscopic examination that demonstrates: Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ Profound papillary excavation (21% of eyes with OPA1) [ Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. Visual evoked potentials (VEPs) are typically absent or delayed, indicating a conduction defect in the optic nerve. Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform [ Note: The PERG originates from the inner retinal layers, enabling an assessment of ganglion cell function, and is increasingly used in the assessment of anterior visual pathway dysfunction. The normal PERG consists of a prominent positive peak at 50 ms (P50), and a slow, broad trough with a minimum at 95 ms (N95). The positive P50 component is invariably affected in retinal and macular dysfunction, whereas the negative N95 component is principally affected in optic nerve disease. Furthermore, the ratio between N95 and P50 has been shown to be an effective measure of retinal ganglion cell function. The diagnosis of optic atrophy type 1 (OPA1) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include Targeted analysis for the In individuals who are not of Danish ancestry or if targeted analysis does not identify a pathogenic variant, sequence analysis of If no pathogenic variant is identified, molecular genetic testing of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Optic Atrophy Type 1 See See Simplex = a single occurrence in a family Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A ~325-bp intronic insertion resulting in exon skipping has been reported [ Detects the Danish founder pathogenic Because the detection rate for pathogenic variants in • Childhood onset • Bilateral vision loss that is usually symmetric • Visual field defect that is typically centrocecal, central, or paracentral • Peripheral field that is usually normal, although inversion of red and blue isopters may occur. • Note: The isopters are lines joining points of equal sensitivity on a visual field chart. The red isopter represents the largest/brightest stimulus; the blue isopter represents the smallest/dimmest stimulus. Persons with OPA1 have scotomas (areas of impaired visual acuity) in the central visual fields and sparing of the peripheral visual fields. • Color vision defect, often described as acquired blue-yellow loss (tritanopia) • Opthalmoscopic examination that demonstrates: • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ • Profound papillary excavation (21% of eyes with OPA1) [ • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ • Profound papillary excavation (21% of eyes with OPA1) [ • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ • Profound papillary excavation (21% of eyes with OPA1) [ • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. • Visual evoked potentials (VEPs) are typically absent or delayed, indicating a conduction defect in the optic nerve. • Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform [ • Note: The PERG originates from the inner retinal layers, enabling an assessment of ganglion cell function, and is increasingly used in the assessment of anterior visual pathway dysfunction. The normal PERG consists of a prominent positive peak at 50 ms (P50), and a slow, broad trough with a minimum at 95 ms (N95). The positive P50 component is invariably affected in retinal and macular dysfunction, whereas the negative N95 component is principally affected in optic nerve disease. Furthermore, the ratio between N95 and P50 has been shown to be an effective measure of retinal ganglion cell function. • Targeted analysis for the • In individuals who are not of Danish ancestry or if targeted analysis does not identify a pathogenic variant, sequence analysis of • If no pathogenic variant is identified, molecular genetic testing of ## Suggestive Findings Optic atrophy type 1 (OPA1 or Kjer type optic atrophy) Childhood onset Bilateral vision loss that is usually symmetric Visual field defect that is typically centrocecal, central, or paracentral Peripheral field that is usually normal, although inversion of red and blue isopters may occur. Note: The isopters are lines joining points of equal sensitivity on a visual field chart. The red isopter represents the largest/brightest stimulus; the blue isopter represents the smallest/dimmest stimulus. Persons with OPA1 have scotomas (areas of impaired visual acuity) in the central visual fields and sparing of the peripheral visual fields. Color vision defect, often described as acquired blue-yellow loss (tritanopia) Opthalmoscopic examination that demonstrates: Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ Profound papillary excavation (21% of eyes with OPA1) [ Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. Visual evoked potentials (VEPs) are typically absent or delayed, indicating a conduction defect in the optic nerve. Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform [ Note: The PERG originates from the inner retinal layers, enabling an assessment of ganglion cell function, and is increasingly used in the assessment of anterior visual pathway dysfunction. The normal PERG consists of a prominent positive peak at 50 ms (P50), and a slow, broad trough with a minimum at 95 ms (N95). The positive P50 component is invariably affected in retinal and macular dysfunction, whereas the negative N95 component is principally affected in optic nerve disease. Furthermore, the ratio between N95 and P50 has been shown to be an effective measure of retinal ganglion cell function. • Childhood onset • Bilateral vision loss that is usually symmetric • Visual field defect that is typically centrocecal, central, or paracentral • Peripheral field that is usually normal, although inversion of red and blue isopters may occur. • Note: The isopters are lines joining points of equal sensitivity on a visual field chart. The red isopter represents the largest/brightest stimulus; the blue isopter represents the smallest/dimmest stimulus. Persons with OPA1 have scotomas (areas of impaired visual acuity) in the central visual fields and sparing of the peripheral visual fields. • Color vision defect, often described as acquired blue-yellow loss (tritanopia) • Opthalmoscopic examination that demonstrates: • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ • Profound papillary excavation (21% of eyes with OPA1) [ • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ • Profound papillary excavation (21% of eyes with OPA1) [ • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. • Optic nerve pallor (the cardinal sign) that is most often bilateral and symmetric, but may be temporal (50% of individuals) and global (50%) [ • Profound papillary excavation (21% of eyes with OPA1) [ • Neuroretinal rim pallor in most cases, sometimes associated with a temporal pigmentary gray crescent. • Visual evoked potentials (VEPs) are typically absent or delayed, indicating a conduction defect in the optic nerve. • Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform [ • Note: The PERG originates from the inner retinal layers, enabling an assessment of ganglion cell function, and is increasingly used in the assessment of anterior visual pathway dysfunction. The normal PERG consists of a prominent positive peak at 50 ms (P50), and a slow, broad trough with a minimum at 95 ms (N95). The positive P50 component is invariably affected in retinal and macular dysfunction, whereas the negative N95 component is principally affected in optic nerve disease. Furthermore, the ratio between N95 and P50 has been shown to be an effective measure of retinal ganglion cell function. ## Establishing the Diagnosis The diagnosis of optic atrophy type 1 (OPA1) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include Targeted analysis for the In individuals who are not of Danish ancestry or if targeted analysis does not identify a pathogenic variant, sequence analysis of If no pathogenic variant is identified, molecular genetic testing of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Optic Atrophy Type 1 See See Simplex = a single occurrence in a family Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A ~325-bp intronic insertion resulting in exon skipping has been reported [ Detects the Danish founder pathogenic Because the detection rate for pathogenic variants in • Targeted analysis for the • In individuals who are not of Danish ancestry or if targeted analysis does not identify a pathogenic variant, sequence analysis of • If no pathogenic variant is identified, molecular genetic testing of ## Clinical Characteristics The visual impairment is usually moderate (6/10 to 2/10), but ranges from severe (legal blindness with acuity <1/20) to mild or even insignificant, and consequently can be underestimated. The vision loss is occasionally asymmetric. The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Typical OPA1 is associated with a progressive and irreversible loss of vision. However, Muscle biopsy revealed features diagnostic of mitochondrial myopathy. In these individuals approximately 10% of all fibers were deficient in histochemical COX activity and several fibers showed evidence of subsarcolemmal accumulation of abnormal mitochondria. The cardinal sign of OPA1 is optic atrophy that appears as bilateral and generally symmetric temporal pallor of the optic disc, implying the loss of central retinal ganglion cells. Histopathology shows a normal outer retina and loss of retinal ganglion cells, primarily in the macula and in the papillo-macular bundle of the optic nerve. No correlation has been observed between the degree of visual impairment and the location or type of pathogenic variant [ Complete deletion of In an individual with the In contrast, the The estimated penetrance of 98% in OPA1 has been revised in the light of molecular genetic studies. Penetrance varies from family to family and pathogenic variant to pathogenic variant. It has been reported as high as 100% (variant Optic atrophy type 1 was formerly known as Kjer type optic atrophy. OPA1 is believed to be the most common of the hereditary optic neuropathies. The estimated prevalence of OPA1 is 1:50,000 in most populations, or as high as 1:10,000 in Denmark. The relatively high frequency of OPA1 in Denmark may be attributable to a founder effect [ • The cardinal sign of OPA1 is optic atrophy that appears as bilateral and generally symmetric temporal pallor of the optic disc, implying the loss of central retinal ganglion cells. • Histopathology shows a normal outer retina and loss of retinal ganglion cells, primarily in the macula and in the papillo-macular bundle of the optic nerve. • In an individual with the • In contrast, the ## Clinical Description The visual impairment is usually moderate (6/10 to 2/10), but ranges from severe (legal blindness with acuity <1/20) to mild or even insignificant, and consequently can be underestimated. The vision loss is occasionally asymmetric. The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Typical OPA1 is associated with a progressive and irreversible loss of vision. However, Muscle biopsy revealed features diagnostic of mitochondrial myopathy. In these individuals approximately 10% of all fibers were deficient in histochemical COX activity and several fibers showed evidence of subsarcolemmal accumulation of abnormal mitochondria. The cardinal sign of OPA1 is optic atrophy that appears as bilateral and generally symmetric temporal pallor of the optic disc, implying the loss of central retinal ganglion cells. Histopathology shows a normal outer retina and loss of retinal ganglion cells, primarily in the macula and in the papillo-macular bundle of the optic nerve. • The cardinal sign of OPA1 is optic atrophy that appears as bilateral and generally symmetric temporal pallor of the optic disc, implying the loss of central retinal ganglion cells. • Histopathology shows a normal outer retina and loss of retinal ganglion cells, primarily in the macula and in the papillo-macular bundle of the optic nerve. ## Genotype-Phenotype Correlations No correlation has been observed between the degree of visual impairment and the location or type of pathogenic variant [ Complete deletion of In an individual with the In contrast, the • In an individual with the • In contrast, the ## Penetrance The estimated penetrance of 98% in OPA1 has been revised in the light of molecular genetic studies. Penetrance varies from family to family and pathogenic variant to pathogenic variant. It has been reported as high as 100% (variant ## Nomenclature Optic atrophy type 1 was formerly known as Kjer type optic atrophy. ## Prevalence OPA1 is believed to be the most common of the hereditary optic neuropathies. The estimated prevalence of OPA1 is 1:50,000 in most populations, or as high as 1:10,000 in Denmark. The relatively high frequency of OPA1 in Denmark may be attributable to a founder effect [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis LHON is transmitted by maternal inheritance. In one large study, 90% of individuals with LHON were found to have one of three pathogenic variants in mtDNA: m.11778G>A, m.14484T>C, m.3460G>A. OPA4 (OMIM OPA5 (OMIM The phenotype of the three families with OPA4 or OPA5 is comparable to the phenotype seen in OPA1: optic nerve pallor, decreased visual acuity, color vision defects, impaired VEP, and normal ERG. No extraocular findings were described in these families. Another OPA locus for autosomal dominant optic atrophy (OPA8) was mapped to 16q21-q22 in one Italian family with extraophthalmologic features extending to the auditory system [ Inheritance is X-linked. The DDON syndrome occurs as either a single-gene disorder resulting from pathogenic variants in Nutritional deficiencies of protein, or of the B vitamins and folate, associated with starvation, malabsorption, or alcoholism Toxic exposures. The most common is "tobacco-alcohol amblyopia," thought to be caused by exposure to cyanide from tobacco smoking, and by low levels of vitamin B Certain medications See • OPA4 (OMIM • OPA5 (OMIM • Nutritional deficiencies of protein, or of the B vitamins and folate, associated with starvation, malabsorption, or alcoholism • Toxic exposures. The most common is "tobacco-alcohol amblyopia," thought to be caused by exposure to cyanide from tobacco smoking, and by low levels of vitamin B • Certain medications ## Management To establish the extent of disease and needs in an individual with optic atrophy type 1 (OPA1), the following evaluations are recommended: Assessment of visual acuity, color vision, and visual fields Assessment of extraocular muscles (the affected individual is asked to follow the ophthalmoscope with the eyes without moving the head) Hearing evaluation: auditory brain stem responses (ABRs), auditory evoked potentials (AEPs), and evoked otoacoustic emissions Oral glucose tolerance test Consultation with a clinical geneticist and/or genetic counselor No treatment for OPA1 is of proven efficacy. Treatment of decreased visual acuity is symptomatic (e.g., low-vision aids). For treatment of sensorineural hearing loss, see For treatment of ataxia, see Appropriate surveillance includes: Annual ophthalmologic examination, including measurement of visual acuity and visual fields and optical coherence tomography (OCT); Annual hearing evaluation. Individuals with an Not to smoke; To moderate their alcohol intake; To use sunglasses to limit UV exposure; Note: While limiting UV exposure is a good practice, no evidence for its effectiveness exists. To avoid medications (antibiotics, antivirals) that interfere with mitochondrial metabolism. See A study using the antioxidant EPI-743 in individuals with autosomal dominant optic atrophy (ADOA), including persons with OPA1, is in preparation in Italy (Dr. Valerio Carelli, University of Bologna). Search • Assessment of visual acuity, color vision, and visual fields • Assessment of extraocular muscles (the affected individual is asked to follow the ophthalmoscope with the eyes without moving the head) • Hearing evaluation: auditory brain stem responses (ABRs), auditory evoked potentials (AEPs), and evoked otoacoustic emissions • Oral glucose tolerance test • Consultation with a clinical geneticist and/or genetic counselor • Annual ophthalmologic examination, including measurement of visual acuity and visual fields and optical coherence tomography (OCT); • Annual hearing evaluation. • Not to smoke; • To moderate their alcohol intake; • To use sunglasses to limit UV exposure; • Note: While limiting UV exposure is a good practice, no evidence for its effectiveness exists. • To avoid medications (antibiotics, antivirals) that interfere with mitochondrial metabolism. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual with optic atrophy type 1 (OPA1), the following evaluations are recommended: Assessment of visual acuity, color vision, and visual fields Assessment of extraocular muscles (the affected individual is asked to follow the ophthalmoscope with the eyes without moving the head) Hearing evaluation: auditory brain stem responses (ABRs), auditory evoked potentials (AEPs), and evoked otoacoustic emissions Oral glucose tolerance test Consultation with a clinical geneticist and/or genetic counselor • Assessment of visual acuity, color vision, and visual fields • Assessment of extraocular muscles (the affected individual is asked to follow the ophthalmoscope with the eyes without moving the head) • Hearing evaluation: auditory brain stem responses (ABRs), auditory evoked potentials (AEPs), and evoked otoacoustic emissions • Oral glucose tolerance test • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations No treatment for OPA1 is of proven efficacy. Treatment of decreased visual acuity is symptomatic (e.g., low-vision aids). For treatment of sensorineural hearing loss, see For treatment of ataxia, see ## Surveillance Appropriate surveillance includes: Annual ophthalmologic examination, including measurement of visual acuity and visual fields and optical coherence tomography (OCT); Annual hearing evaluation. • Annual ophthalmologic examination, including measurement of visual acuity and visual fields and optical coherence tomography (OCT); • Annual hearing evaluation. ## Agents/Circumstances to Avoid Individuals with an Not to smoke; To moderate their alcohol intake; To use sunglasses to limit UV exposure; Note: While limiting UV exposure is a good practice, no evidence for its effectiveness exists. To avoid medications (antibiotics, antivirals) that interfere with mitochondrial metabolism. • Not to smoke; • To moderate their alcohol intake; • To use sunglasses to limit UV exposure; • Note: While limiting UV exposure is a good practice, no evidence for its effectiveness exists. • To avoid medications (antibiotics, antivirals) that interfere with mitochondrial metabolism. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation A study using the antioxidant EPI-743 in individuals with autosomal dominant optic atrophy (ADOA), including persons with OPA1, is in preparation in Italy (Dr. Valerio Carelli, University of Bologna). Search ## Genetic Counseling Optic atrophy type 1 (OPA1) is inherited in an autosomal dominant manner. Most individuals diagnosed with OPA1 have an affected parent. A proband with OPA1 may have the disorder as the result of a Two instances of In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are Recommendations for the evaluation of parents of a proband with an apparent The family history of some individuals diagnosed with OPA1 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. When the parents are found on the basis of visual acuity study, color vision evaluation, fundus examination, VEP, and PERG to be clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for OPA1 because of the possibility of reduced penetrance in a parent. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has an The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with OPA1 have an affected parent. • A proband with OPA1 may have the disorder as the result of a • Two instances of • In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous • Two instances of • In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are • Recommendations for the evaluation of parents of a proband with an apparent • The family history of some individuals diagnosed with OPA1 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • Two instances of • In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous • The risk to the sibs of the proband depends on the genetic status of the proband's parents. • If a parent of the proband is affected, the risk to the sibs is 50%. • When the parents are found on the basis of visual acuity study, color vision evaluation, fundus examination, VEP, and PERG to be clinically unaffected, the risk to the sibs of a proband appears to be low. • The sibs of a proband with clinically unaffected parents are still at increased risk for OPA1 because of the possibility of reduced penetrance in a parent. • The risk to other family members depends on the status of the proband's parents. • If a parent is affected or has an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Optic atrophy type 1 (OPA1) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with OPA1 have an affected parent. A proband with OPA1 may have the disorder as the result of a Two instances of In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are Recommendations for the evaluation of parents of a proband with an apparent The family history of some individuals diagnosed with OPA1 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. When the parents are found on the basis of visual acuity study, color vision evaluation, fundus examination, VEP, and PERG to be clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for OPA1 because of the possibility of reduced penetrance in a parent. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has an • Most individuals diagnosed with OPA1 have an affected parent. • A proband with OPA1 may have the disorder as the result of a • Two instances of • In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous • Two instances of • In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are • Recommendations for the evaluation of parents of a proband with an apparent • The family history of some individuals diagnosed with OPA1 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • Two instances of • In a report of molecular genetic testing in 980 persons for suspected hereditary optic neuropathies, about half of those identified as having a heterozygous • The risk to the sibs of the proband depends on the genetic status of the proband's parents. • If a parent of the proband is affected, the risk to the sibs is 50%. • When the parents are found on the basis of visual acuity study, color vision evaluation, fundus examination, VEP, and PERG to be clinically unaffected, the risk to the sibs of a proband appears to be low. • The sibs of a proband with clinically unaffected parents are still at increased risk for OPA1 because of the possibility of reduced penetrance in a parent. • The risk to other family members depends on the status of the proband's parents. • If a parent is affected or has an ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 7168 Columbia Gateway Drive Suite 100 Columbia MD 21046 • • 7168 Columbia Gateway Drive • Suite 100 • Columbia MD 21046 • • • • • • • ## Molecular Genetics Optic Atrophy Type 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Optic Atrophy Type 1 ( Because An ~325-bp Alu-element insertion located in intron 7 of Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions In exon 5b of alternative transcript that encodes isoform 8 ( Substitution in the antepenultimate nucleotide position of exon 9, which modifies the consensus sequence of the 5' donor splice site of intron 9, resulting in an in-frame skipping of exon 9 [ OPA1 appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. Downregulation of Interestingly, evidence for a dominant-negative mechanism has been reported in all the multisystemic forms of the disease (ADOAD and "ADOA plus"). These disease forms have pathogenic missense variants affecting the GTPase domain [ ## Molecular Pathogenesis Because An ~325-bp Alu-element insertion located in intron 7 of Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions In exon 5b of alternative transcript that encodes isoform 8 ( Substitution in the antepenultimate nucleotide position of exon 9, which modifies the consensus sequence of the 5' donor splice site of intron 9, resulting in an in-frame skipping of exon 9 [ OPA1 appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. Downregulation of Interestingly, evidence for a dominant-negative mechanism has been reported in all the multisystemic forms of the disease (ADOAD and "ADOA plus"). These disease forms have pathogenic missense variants affecting the GTPase domain [ ## Chapter Notes Web: Ophthalmology Service, 1 Hôpital Guy de Chauliac 80, Avenue Augustin Fliche 34 295 Montpellier Cedex 5, France Phone: (33/0) 467 330 278 / (33/0) 467 330 279 Email: [email protected] Web: 9 May 2024 (ma) Chapter retired: outdated 12 November 2015 (me) Comprehensive update posted live 20 July 2010 (me) Comprehensive update posted live 13 July 2007 (me) Review posted live 23 October 2006 (cdc) Original submission • 9 May 2024 (ma) Chapter retired: outdated • 12 November 2015 (me) Comprehensive update posted live • 20 July 2010 (me) Comprehensive update posted live • 13 July 2007 (me) Review posted live • 23 October 2006 (cdc) Original submission ## Author Notes Web: Ophthalmology Service, 1 Hôpital Guy de Chauliac 80, Avenue Augustin Fliche 34 295 Montpellier Cedex 5, France Phone: (33/0) 467 330 278 / (33/0) 467 330 279 Email: [email protected] Web: ## Revision History 9 May 2024 (ma) Chapter retired: outdated 12 November 2015 (me) Comprehensive update posted live 20 July 2010 (me) Comprehensive update posted live 13 July 2007 (me) Review posted live 23 October 2006 (cdc) Original submission • 9 May 2024 (ma) Chapter retired: outdated • 12 November 2015 (me) Comprehensive update posted live • 20 July 2010 (me) Comprehensive update posted live • 13 July 2007 (me) Review posted live • 23 October 2006 (cdc) Original submission ## References ## Literature Cited	[]	13/7/2007	12/11/2015	24/3/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
opd	opd	[ "Otopalatodigital Spectrum Disorders (OPDSD)", "X-Linked Otopalatodigital Spectrum Disorders", "Otopalatodigital Spectrum Disorders (OPDSD)", "X-Linked Otopalatodigital Spectrum Disorders", "Otopalatodigital Syndrome Type 1 (FLNA-OPD1)", "Frontometaphyseal Dysplasia (FLNA-FMD)", "Melnick-Needles Syndrome (FLNA-MNS)", "Otopalatodigital Syndrome Type 2 (FLNA-OPD2)", "Terminal Osseous Dysplasia (FLNA-TOD)", "Filamin-A", "FLNA", "FLNA-Related Otopalatodigital Spectrum Disorders" ]		Stephen Robertson, Emma Wade	Summary The The diagnosis of an The diagnosis of an	Otopalatodigital syndrome type 1 ( Otopalatodigital syndrome type 2 ( Frontometaphyseal dysplasia ( Melnick-Needles syndrome ( Terminal osseous dysplasia ( For synonyms and outdated names see • Otopalatodigital syndrome type 1 ( • Otopalatodigital syndrome type 2 ( • Frontometaphyseal dysplasia ( • Melnick-Needles syndrome ( • Terminal osseous dysplasia ( ## Diagnosis The Otopalatodigital syndrome type 1 ( Otopalatodigital syndrome type 2 ( Frontometaphyseal dysplasia type 1 ( Melnick-Needles syndrome ( Terminal osseous dysplasia ( For the purposes of this No consensus clinical diagnostic criteria for Cleft palate Characteristic facies: prominent supraorbital ridges, downslanted palpebral fissures, hypertelorism, broad nasal bridge & nasal tip, hypodontia, oligodontia Digits: short proximally placed thumbs, hypoplastic broad distal phalanges, great toe hypoplasia, long 2nd toe, prominent sandal gap Limited joint mobility Limbs w/mild bowing Conductive HL & SNHL Normal intelligence Pierre Robin sequence Characteristic facies (more severe than OPD1) Occasional instance of cleft lip Digits: hypoplastic thumbs & great toes, absent halluces, camptodactyly Thoracic hypoplasia Delayed closure of fontanelles Bowed limbs Scoliosis Short stature Conductive HL & SNHL Cardiac: septal defects, obstructive lesions to the right ventricular outflow tract Omphalocele GU: ureteric obstruction w/hydronephrosis, hypospadias CNS: hydrocephalus, cerebellar hypoplasia Developmental delay Death in neonatal period Digits: distal phalangeal hypoplasia, progressive contractures of hands Limited joint mobility (wrists, elbows, knees, ankles) Scoliosis Bowed limbs Conductive HL & SNHL Underdevelopment of musculature (shoulder girdle, intrinsic muscles of hands) Subglottic stenosis w/congenital stridor GU: posterior urethral valves, ureteric & urethral stenosis, prune belly sequence, hydronephrosis Predisposition to keloid scarring Dysplastic cardiac valves Normal intelligence Digits: long w/mild distal phalangeal hypoplasia Thoracic hypoplasia Bowed limbs Joint subluxation Scoliosis Short stature Conductive HL & SNHL Ureteric obstruction w/hydronephrosis Coloboma Normal intelligence Digits: skin fibromata esp on fingers, camptodactyly, brachydactyly Bowed limbs Scoliosis Short stature Cardiac: septal defects, cardiomyopathy Normal intelligence CNS = central nervous system; Sclerosis of skull base Thickened calvarium Underdeveloped frontal sinuses Mastoids under-pneumatized Mild bowing Dislocation of radial heads Thumb w/short, broad metacarpal Distal phalangeal hypoplasia Accessory proximal ossification center of 2nd metacarpal Accessory carpal ossification centers Fusion of carpal & tarsal bones Contracted No iliac flaring Same as OPD1 Large fontanelles Same as OPD1 Vertebral segmentation anomalies Scoliosis Hypoplastic Thin ribs Bowed Splayed metaphyses Absent fibulae Broad, poorly modeled phalanges, metacarpals & metatarsals ± duplicated terminal phalanges Sclerosis of skull base Thickened calvarium Underdeveloped frontal sinuses Mastoids under-pneumatized Prominent supraorbital ridges Occasionally, craniosynostosis Fusion of C2-3-4 Deficiency of posterior vertebral arches Scoliosis Mild bowing Undertubulation Carpal & tarsal fusions Later erosion of carpal bones Elongation, poor modeling of phalanges, metacarpals, & metatarsals Distal phalangeal hypoplasia (thumbs & great toes) ↑ vertebral body height, esp lumbar Scoliosis Hypoplasia Ribs irregular Wavy clavicle w/expansion of proximal end Bowed, sometimes ribbon-like Cortical irregularity Supra-acetabular constriction Iliac flaring Irregular ossification Cystic lesions near epiphyses Bowed Radial head dislocation Hypoplasia, shortening, irregular ossification &/or fusions of carpals & metacarpals Irregular cortices Narrow ilia Coxa vara Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of an Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. A single instance of a multiexon gene deletion that preserved the open reading frame has been described to result in an Targeted analysis for For an introduction to multigene panels click When the diagnosis of an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in FMD = frontometaphyseal dysplasia; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; TOD = terminal osseous dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click FMD is the only OPD spectrum disorder that exhibits locus heterogeneity. 50% of individuals have a pathogenic variant in All but one reported individual with TOD have been heterozygous for the synonymous change Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions and duplications have been associated with allelic conditions such as myxomatous cardiac valvular dystrophy, periventricular nodular heterotopia, and intellectual disability (see • Otopalatodigital syndrome type 1 ( • Otopalatodigital syndrome type 2 ( • Frontometaphyseal dysplasia type 1 ( • Melnick-Needles syndrome ( • Terminal osseous dysplasia ( • Cleft palate • Characteristic facies: prominent supraorbital ridges, downslanted palpebral fissures, hypertelorism, broad nasal bridge & nasal tip, hypodontia, oligodontia • Digits: short proximally placed thumbs, hypoplastic broad distal phalanges, great toe hypoplasia, long 2nd toe, prominent sandal gap • Limited joint mobility • Limbs w/mild bowing • Conductive HL & SNHL • Normal intelligence • Pierre Robin sequence • Characteristic facies (more severe than OPD1) • Occasional instance of cleft lip • Digits: hypoplastic thumbs & great toes, absent halluces, camptodactyly • Thoracic hypoplasia • Delayed closure of fontanelles • Bowed limbs • Scoliosis • Short stature • Conductive HL & SNHL • Cardiac: septal defects, obstructive lesions to the right ventricular outflow tract • Omphalocele • GU: ureteric obstruction w/hydronephrosis, hypospadias • CNS: hydrocephalus, cerebellar hypoplasia • Developmental delay • Death in neonatal period • Digits: distal phalangeal hypoplasia, progressive contractures of hands • Limited joint mobility (wrists, elbows, knees, ankles) • Scoliosis • Bowed limbs • Conductive HL & SNHL • Underdevelopment of musculature (shoulder girdle, intrinsic muscles of hands) • Subglottic stenosis w/congenital stridor • GU: posterior urethral valves, ureteric & urethral stenosis, prune belly sequence, hydronephrosis • Predisposition to keloid scarring • Dysplastic cardiac valves • Normal intelligence • Digits: long w/mild distal phalangeal hypoplasia • Thoracic hypoplasia • Bowed limbs • Joint subluxation • Scoliosis • Short stature • Conductive HL & SNHL • Ureteric obstruction w/hydronephrosis • Coloboma • Normal intelligence • Digits: skin fibromata esp on fingers, camptodactyly, brachydactyly • Bowed limbs • Scoliosis • Short stature • Cardiac: septal defects, cardiomyopathy • Normal intelligence • Sclerosis of skull base • Thickened calvarium • Underdeveloped frontal sinuses • Mastoids under-pneumatized • Mild bowing • Dislocation of radial heads • Thumb w/short, broad metacarpal • Distal phalangeal hypoplasia • Accessory proximal ossification center of 2nd metacarpal • Accessory carpal ossification centers • Fusion of carpal & tarsal bones • Contracted • No iliac flaring • Same as OPD1 • Large fontanelles • Same as OPD1 • Vertebral segmentation anomalies • Scoliosis • Hypoplastic • Thin ribs • Bowed • Splayed metaphyses • Absent fibulae • Broad, poorly modeled phalanges, metacarpals & metatarsals • ± duplicated terminal phalanges • Sclerosis of skull base • Thickened calvarium • Underdeveloped frontal sinuses • Mastoids under-pneumatized • Prominent supraorbital ridges • Occasionally, craniosynostosis • Fusion of C2-3-4 • Deficiency of posterior vertebral arches • Scoliosis • Mild bowing • Undertubulation • Carpal & tarsal fusions • Later erosion of carpal bones • Elongation, poor modeling of phalanges, metacarpals, & metatarsals • Distal phalangeal hypoplasia (thumbs & great toes) • ↑ vertebral body height, esp lumbar • Scoliosis • Hypoplasia • Ribs irregular • Wavy clavicle w/expansion of proximal end • Bowed, sometimes ribbon-like • Cortical irregularity • Supra-acetabular constriction • Iliac flaring • Irregular ossification • Cystic lesions near epiphyses • Bowed • Radial head dislocation • Hypoplasia, shortening, irregular ossification &/or fusions of carpals & metacarpals • Irregular cortices • Narrow ilia • Coxa vara • Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. A single instance of a multiexon gene deletion that preserved the open reading frame has been described to result in an • Targeted analysis for • For an introduction to multigene panels click ## Suggestive Findings Cleft palate Characteristic facies: prominent supraorbital ridges, downslanted palpebral fissures, hypertelorism, broad nasal bridge & nasal tip, hypodontia, oligodontia Digits: short proximally placed thumbs, hypoplastic broad distal phalanges, great toe hypoplasia, long 2nd toe, prominent sandal gap Limited joint mobility Limbs w/mild bowing Conductive HL & SNHL Normal intelligence Pierre Robin sequence Characteristic facies (more severe than OPD1) Occasional instance of cleft lip Digits: hypoplastic thumbs & great toes, absent halluces, camptodactyly Thoracic hypoplasia Delayed closure of fontanelles Bowed limbs Scoliosis Short stature Conductive HL & SNHL Cardiac: septal defects, obstructive lesions to the right ventricular outflow tract Omphalocele GU: ureteric obstruction w/hydronephrosis, hypospadias CNS: hydrocephalus, cerebellar hypoplasia Developmental delay Death in neonatal period Digits: distal phalangeal hypoplasia, progressive contractures of hands Limited joint mobility (wrists, elbows, knees, ankles) Scoliosis Bowed limbs Conductive HL & SNHL Underdevelopment of musculature (shoulder girdle, intrinsic muscles of hands) Subglottic stenosis w/congenital stridor GU: posterior urethral valves, ureteric & urethral stenosis, prune belly sequence, hydronephrosis Predisposition to keloid scarring Dysplastic cardiac valves Normal intelligence Digits: long w/mild distal phalangeal hypoplasia Thoracic hypoplasia Bowed limbs Joint subluxation Scoliosis Short stature Conductive HL & SNHL Ureteric obstruction w/hydronephrosis Coloboma Normal intelligence Digits: skin fibromata esp on fingers, camptodactyly, brachydactyly Bowed limbs Scoliosis Short stature Cardiac: septal defects, cardiomyopathy Normal intelligence CNS = central nervous system; Sclerosis of skull base Thickened calvarium Underdeveloped frontal sinuses Mastoids under-pneumatized Mild bowing Dislocation of radial heads Thumb w/short, broad metacarpal Distal phalangeal hypoplasia Accessory proximal ossification center of 2nd metacarpal Accessory carpal ossification centers Fusion of carpal & tarsal bones Contracted No iliac flaring Same as OPD1 Large fontanelles Same as OPD1 Vertebral segmentation anomalies Scoliosis Hypoplastic Thin ribs Bowed Splayed metaphyses Absent fibulae Broad, poorly modeled phalanges, metacarpals & metatarsals ± duplicated terminal phalanges Sclerosis of skull base Thickened calvarium Underdeveloped frontal sinuses Mastoids under-pneumatized Prominent supraorbital ridges Occasionally, craniosynostosis Fusion of C2-3-4 Deficiency of posterior vertebral arches Scoliosis Mild bowing Undertubulation Carpal & tarsal fusions Later erosion of carpal bones Elongation, poor modeling of phalanges, metacarpals, & metatarsals Distal phalangeal hypoplasia (thumbs & great toes) ↑ vertebral body height, esp lumbar Scoliosis Hypoplasia Ribs irregular Wavy clavicle w/expansion of proximal end Bowed, sometimes ribbon-like Cortical irregularity Supra-acetabular constriction Iliac flaring Irregular ossification Cystic lesions near epiphyses Bowed Radial head dislocation Hypoplasia, shortening, irregular ossification &/or fusions of carpals & metacarpals Irregular cortices Narrow ilia Coxa vara • Cleft palate • Characteristic facies: prominent supraorbital ridges, downslanted palpebral fissures, hypertelorism, broad nasal bridge & nasal tip, hypodontia, oligodontia • Digits: short proximally placed thumbs, hypoplastic broad distal phalanges, great toe hypoplasia, long 2nd toe, prominent sandal gap • Limited joint mobility • Limbs w/mild bowing • Conductive HL & SNHL • Normal intelligence • Pierre Robin sequence • Characteristic facies (more severe than OPD1) • Occasional instance of cleft lip • Digits: hypoplastic thumbs & great toes, absent halluces, camptodactyly • Thoracic hypoplasia • Delayed closure of fontanelles • Bowed limbs • Scoliosis • Short stature • Conductive HL & SNHL • Cardiac: septal defects, obstructive lesions to the right ventricular outflow tract • Omphalocele • GU: ureteric obstruction w/hydronephrosis, hypospadias • CNS: hydrocephalus, cerebellar hypoplasia • Developmental delay • Death in neonatal period • Digits: distal phalangeal hypoplasia, progressive contractures of hands • Limited joint mobility (wrists, elbows, knees, ankles) • Scoliosis • Bowed limbs • Conductive HL & SNHL • Underdevelopment of musculature (shoulder girdle, intrinsic muscles of hands) • Subglottic stenosis w/congenital stridor • GU: posterior urethral valves, ureteric & urethral stenosis, prune belly sequence, hydronephrosis • Predisposition to keloid scarring • Dysplastic cardiac valves • Normal intelligence • Digits: long w/mild distal phalangeal hypoplasia • Thoracic hypoplasia • Bowed limbs • Joint subluxation • Scoliosis • Short stature • Conductive HL & SNHL • Ureteric obstruction w/hydronephrosis • Coloboma • Normal intelligence • Digits: skin fibromata esp on fingers, camptodactyly, brachydactyly • Bowed limbs • Scoliosis • Short stature • Cardiac: septal defects, cardiomyopathy • Normal intelligence • Sclerosis of skull base • Thickened calvarium • Underdeveloped frontal sinuses • Mastoids under-pneumatized • Mild bowing • Dislocation of radial heads • Thumb w/short, broad metacarpal • Distal phalangeal hypoplasia • Accessory proximal ossification center of 2nd metacarpal • Accessory carpal ossification centers • Fusion of carpal & tarsal bones • Contracted • No iliac flaring • Same as OPD1 • Large fontanelles • Same as OPD1 • Vertebral segmentation anomalies • Scoliosis • Hypoplastic • Thin ribs • Bowed • Splayed metaphyses • Absent fibulae • Broad, poorly modeled phalanges, metacarpals & metatarsals • ± duplicated terminal phalanges • Sclerosis of skull base • Thickened calvarium • Underdeveloped frontal sinuses • Mastoids under-pneumatized • Prominent supraorbital ridges • Occasionally, craniosynostosis • Fusion of C2-3-4 • Deficiency of posterior vertebral arches • Scoliosis • Mild bowing • Undertubulation • Carpal & tarsal fusions • Later erosion of carpal bones • Elongation, poor modeling of phalanges, metacarpals, & metatarsals • Distal phalangeal hypoplasia (thumbs & great toes) • ↑ vertebral body height, esp lumbar • Scoliosis • Hypoplasia • Ribs irregular • Wavy clavicle w/expansion of proximal end • Bowed, sometimes ribbon-like • Cortical irregularity • Supra-acetabular constriction • Iliac flaring • Irregular ossification • Cystic lesions near epiphyses • Bowed • Radial head dislocation • Hypoplasia, shortening, irregular ossification &/or fusions of carpals & metacarpals • Irregular cortices • Narrow ilia • Coxa vara ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of an Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. A single instance of a multiexon gene deletion that preserved the open reading frame has been described to result in an Targeted analysis for For an introduction to multigene panels click When the diagnosis of an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in FMD = frontometaphyseal dysplasia; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; TOD = terminal osseous dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click FMD is the only OPD spectrum disorder that exhibits locus heterogeneity. 50% of individuals have a pathogenic variant in All but one reported individual with TOD have been heterozygous for the synonymous change Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions and duplications have been associated with allelic conditions such as myxomatous cardiac valvular dystrophy, periventricular nodular heterotopia, and intellectual disability (see • Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. A single instance of a multiexon gene deletion that preserved the open reading frame has been described to result in an • Targeted analysis for • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of an Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. A single instance of a multiexon gene deletion that preserved the open reading frame has been described to result in an Targeted analysis for For an introduction to multigene panels click • Note: Whole-gene deletions cause periventricular nodular heterotopia in females and are likely to be embryonic lethal in males. A single instance of a multiexon gene deletion that preserved the open reading frame has been described to result in an • Targeted analysis for • For an introduction to multigene panels click ## Option 2 When the diagnosis of an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in FMD = frontometaphyseal dysplasia; MNS = Melnick-Needles syndrome; OPD1 = otopalatodigital syndrome type 1; OPD2 = otopalatodigital syndrome type 2; TOD = terminal osseous dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click FMD is the only OPD spectrum disorder that exhibits locus heterogeneity. 50% of individuals have a pathogenic variant in All but one reported individual with TOD have been heterozygous for the synonymous change Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions and duplications have been associated with allelic conditions such as myxomatous cardiac valvular dystrophy, periventricular nodular heterotopia, and intellectual disability (see ## Clinical Characteristics The Little is known about the natural history of In males, the spectrum of severity ranges from mild manifestations in Females exhibit variable expressivity. In Most manifestations of A skeletal dysplasia manifesting clinically by the following: Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. Limited joint movement (elbow extension, wrist abduction) in almost all affected males Limbs may exhibit mild bowing. Mildly reduced final height in some, although males with Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge, and broad nasal tip) Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). Conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher. Cleft palate Oligohypodontia Normal intelligence Normal pubertal development A skeletal dysplasia manifesting clinically as the following: Thoracic hypoplasia Bowed long bones Short stature Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) Delayed closure of the fontanelles Scoliosis (occasional) Characteristic craniofacial features are similar to but more pronounced than those in Sensorineural and conductive deafness (common) Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected males Omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [ Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [ Developmental delay (common) Death commonly occurs in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [ A skeletal dysplasia manifesting clinically as the following: Distal phalangeal hypoplasia Limited joint mobility at the wrists, elbows, knees, and ankles Scoliosis that may be progressive [ Limb bowing Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [ Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints Oligohypodontia (frequent) Conductive and sensorineural hearing loss in almost all affected individuals Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common) Osteoporosis can develop in some adults Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [ Predisposition to keloid scarring Cleft palate (rare) Normal intelligence A subset of individuals with Substantial variability is observed in females with A skeletal dysplasia characterized by the following: Short stature Thoracic hypoplasia Limb bowing Joint subluxation Cortical irregularity of the long bones and ribs Scoliosis Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [ Oligohypodontia (frequent) Sensorineural and conductive deafness (common) Hydronephrosis secondary to ureteric obstruction (common) Bleeding diathesis [ Normal intelligence Normal pubertal development The phenotype of four males with a pathogenic variant associated with The natural history for females with The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis. Digital fibromata appear in infancy, can grow to a large size, and may regrow after excision, but eventually involute before age ten years. Cardiac septal defects and cardiomyopathy Ureteric obstruction (occasional) Alopecia is a variable clinical finding. The most characteristic craniofacial findings are widely spaced eyes, abnormal oral frenula, and punched-out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata, they do not involute with age. Normal intelligence Note: A male presentation of Pathogenic variants associated with Variants leading to In a study of 13 males with One female with a combined FMD-periventricular nodular heterotopia phenotype had an Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ Penetrance in males with an Some obligate heterozygote females with MNS was originally referred to as osteodysplasty. OPD1 was also referred to as Taybi syndrome after its first description in 1963. No population-based studies have been performed to adequately assess prevalence. • A skeletal dysplasia manifesting clinically by the following: • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge, and broad nasal tip) • Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). Conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher. • Cleft palate • Oligohypodontia • Normal intelligence • Normal pubertal development • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • A skeletal dysplasia manifesting clinically as the following: • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • Characteristic craniofacial features are similar to but more pronounced than those in • Sensorineural and conductive deafness (common) • Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected males • Omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [ • Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [ • Developmental delay (common) • Death commonly occurs in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [ • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • A skeletal dysplasia manifesting clinically as the following: • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [ • Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints • Oligohypodontia (frequent) • Conductive and sensorineural hearing loss in almost all affected individuals • Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common) • Osteoporosis can develop in some adults • Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [ • Predisposition to keloid scarring • Cleft palate (rare) • Normal intelligence • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • A skeletal dysplasia characterized by the following: • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [ • Oligohypodontia (frequent) • Sensorineural and conductive deafness (common) • Hydronephrosis secondary to ureteric obstruction (common) • Bleeding diathesis [ • Normal intelligence • Normal pubertal development • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis. • Digital fibromata appear in infancy, can grow to a large size, and may regrow after excision, but eventually involute before age ten years. • Cardiac septal defects and cardiomyopathy • Ureteric obstruction (occasional) • Alopecia is a variable clinical finding. • The most characteristic craniofacial findings are widely spaced eyes, abnormal oral frenula, and punched-out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata, they do not involute with age. • Normal intelligence • • Variants leading to • In a study of 13 males with • One female with a combined FMD-periventricular nodular heterotopia phenotype had an • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ • Variants leading to • In a study of 13 males with • One female with a combined FMD-periventricular nodular heterotopia phenotype had an • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ • Variants leading to • In a study of 13 males with • One female with a combined FMD-periventricular nodular heterotopia phenotype had an • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ ## Clinical Description The Little is known about the natural history of In males, the spectrum of severity ranges from mild manifestations in Females exhibit variable expressivity. In Most manifestations of A skeletal dysplasia manifesting clinically by the following: Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. Limited joint movement (elbow extension, wrist abduction) in almost all affected males Limbs may exhibit mild bowing. Mildly reduced final height in some, although males with Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge, and broad nasal tip) Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). Conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher. Cleft palate Oligohypodontia Normal intelligence Normal pubertal development A skeletal dysplasia manifesting clinically as the following: Thoracic hypoplasia Bowed long bones Short stature Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) Delayed closure of the fontanelles Scoliosis (occasional) Characteristic craniofacial features are similar to but more pronounced than those in Sensorineural and conductive deafness (common) Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected males Omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [ Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [ Developmental delay (common) Death commonly occurs in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [ A skeletal dysplasia manifesting clinically as the following: Distal phalangeal hypoplasia Limited joint mobility at the wrists, elbows, knees, and ankles Scoliosis that may be progressive [ Limb bowing Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [ Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints Oligohypodontia (frequent) Conductive and sensorineural hearing loss in almost all affected individuals Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common) Osteoporosis can develop in some adults Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [ Predisposition to keloid scarring Cleft palate (rare) Normal intelligence A subset of individuals with Substantial variability is observed in females with A skeletal dysplasia characterized by the following: Short stature Thoracic hypoplasia Limb bowing Joint subluxation Cortical irregularity of the long bones and ribs Scoliosis Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [ Oligohypodontia (frequent) Sensorineural and conductive deafness (common) Hydronephrosis secondary to ureteric obstruction (common) Bleeding diathesis [ Normal intelligence Normal pubertal development The phenotype of four males with a pathogenic variant associated with The natural history for females with The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis. Digital fibromata appear in infancy, can grow to a large size, and may regrow after excision, but eventually involute before age ten years. Cardiac septal defects and cardiomyopathy Ureteric obstruction (occasional) Alopecia is a variable clinical finding. The most characteristic craniofacial findings are widely spaced eyes, abnormal oral frenula, and punched-out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata, they do not involute with age. Normal intelligence Note: A male presentation of • A skeletal dysplasia manifesting clinically by the following: • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge, and broad nasal tip) • Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). Conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher. • Cleft palate • Oligohypodontia • Normal intelligence • Normal pubertal development • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • A skeletal dysplasia manifesting clinically as the following: • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • Characteristic craniofacial features are similar to but more pronounced than those in • Sensorineural and conductive deafness (common) • Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected males • Omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [ • Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [ • Developmental delay (common) • Death commonly occurs in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [ • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • A skeletal dysplasia manifesting clinically as the following: • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [ • Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints • Oligohypodontia (frequent) • Conductive and sensorineural hearing loss in almost all affected individuals • Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common) • Osteoporosis can develop in some adults • Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [ • Predisposition to keloid scarring • Cleft palate (rare) • Normal intelligence • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • A skeletal dysplasia characterized by the following: • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [ • Oligohypodontia (frequent) • Sensorineural and conductive deafness (common) • Hydronephrosis secondary to ureteric obstruction (common) • Bleeding diathesis [ • Normal intelligence • Normal pubertal development • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis. • Digital fibromata appear in infancy, can grow to a large size, and may regrow after excision, but eventually involute before age ten years. • Cardiac septal defects and cardiomyopathy • Ureteric obstruction (occasional) • Alopecia is a variable clinical finding. • The most characteristic craniofacial findings are widely spaced eyes, abnormal oral frenula, and punched-out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata, they do not involute with age. • Normal intelligence Most manifestations of A skeletal dysplasia manifesting clinically by the following: Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. Limited joint movement (elbow extension, wrist abduction) in almost all affected males Limbs may exhibit mild bowing. Mildly reduced final height in some, although males with Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge, and broad nasal tip) Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). Conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher. Cleft palate Oligohypodontia Normal intelligence Normal pubertal development • A skeletal dysplasia manifesting clinically by the following: • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with • Characteristic facial features (prominent supraorbital ridges, downslanted palpebral fissures, widely spaced eyes, wide nasal bridge, and broad nasal tip) • Deafness (secondary either to ossicular malformation, neurosensory deficit, or a combination of both). Conductive hearing loss can be caused by fused and misshapen ossicles; attempts to separate the ossicles are usually unsuccessful and can lead to formation of a perilymphatic gusher. • Cleft palate • Oligohypodontia • Normal intelligence • Normal pubertal development • Digital anomalies including short, often proximally placed thumbs with hypoplastic broad distal phalanges. The distal phalanges of the other digits can also be hypoplastic with a squared (or "spatulate") shape to the fingertips. The toes have a characteristic pattern of hypoplasia of the great toe, a long second toe, and a prominent sandal gap. • Limited joint movement (elbow extension, wrist abduction) in almost all affected males • Limbs may exhibit mild bowing. • Mildly reduced final height in some, although males with A skeletal dysplasia manifesting clinically as the following: Thoracic hypoplasia Bowed long bones Short stature Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) Delayed closure of the fontanelles Scoliosis (occasional) Characteristic craniofacial features are similar to but more pronounced than those in Sensorineural and conductive deafness (common) Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected males Omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [ Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [ Developmental delay (common) Death commonly occurs in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [ • A skeletal dysplasia manifesting clinically as the following: • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) • Characteristic craniofacial features are similar to but more pronounced than those in • Sensorineural and conductive deafness (common) • Cardiac septal defects and obstructive lesions to the right ventricular outflow tract in some affected males • Omphalocele, hydronephrosis secondary to ureteric obstruction, and hypospadias [ • Central nervous system anomalies including hydrocephalus, cerebellar hypoplasia, and (rarely) encephalocele and meningomyelocele [ • Developmental delay (common) • Death commonly occurs in the neonatal period as a result of respiratory insufficiency. Survival into the third year of life has been described with intensive medical treatment [ • Thoracic hypoplasia • Bowed long bones • Short stature • Digital anomalies (most commonly hypoplasia of the first digit of the hands and feet or absent halluces, camptodactyly) • Delayed closure of the fontanelles • Scoliosis (occasional) A skeletal dysplasia manifesting clinically as the following: Distal phalangeal hypoplasia Limited joint mobility at the wrists, elbows, knees, and ankles Scoliosis that may be progressive [ Limb bowing Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [ Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints Oligohypodontia (frequent) Conductive and sensorineural hearing loss in almost all affected individuals Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common) Osteoporosis can develop in some adults Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [ Predisposition to keloid scarring Cleft palate (rare) Normal intelligence A subset of individuals with • A skeletal dysplasia manifesting clinically as the following: • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing • Characteristic craniofacial features with very pronounced supraorbital hyperostosis, widely spaced eyes, and downslanted palpebral fissures [ • Progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal and metacarpophalangeal joints • Oligohypodontia (frequent) • Conductive and sensorineural hearing loss in almost all affected individuals • Underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common) • Osteoporosis can develop in some adults • Extraskeletal anomalies including subglottic stenosis (which can present as congenital stridor [ • Predisposition to keloid scarring • Cleft palate (rare) • Normal intelligence • Distal phalangeal hypoplasia • Limited joint mobility at the wrists, elbows, knees, and ankles • Scoliosis that may be progressive [ • Limb bowing Substantial variability is observed in females with A skeletal dysplasia characterized by the following: Short stature Thoracic hypoplasia Limb bowing Joint subluxation Cortical irregularity of the long bones and ribs Scoliosis Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [ Oligohypodontia (frequent) Sensorineural and conductive deafness (common) Hydronephrosis secondary to ureteric obstruction (common) Bleeding diathesis [ Normal intelligence Normal pubertal development The phenotype of four males with a pathogenic variant associated with • A skeletal dysplasia characterized by the following: • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia • Characteristic craniofacial features (prominent lateral margins of the supraorbital ridges, proptosis, full cheeks, micrognathia, facial asymmetry) [ • Oligohypodontia (frequent) • Sensorineural and conductive deafness (common) • Hydronephrosis secondary to ureteric obstruction (common) • Bleeding diathesis [ • Normal intelligence • Normal pubertal development • Short stature • Thoracic hypoplasia • Limb bowing • Joint subluxation • Cortical irregularity of the long bones and ribs • Scoliosis • Digits of both the hands and the feet that are typically long with mild distal phalangeal hypoplasia The natural history for females with The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis. Digital fibromata appear in infancy, can grow to a large size, and may regrow after excision, but eventually involute before age ten years. Cardiac septal defects and cardiomyopathy Ureteric obstruction (occasional) Alopecia is a variable clinical finding. The most characteristic craniofacial findings are widely spaced eyes, abnormal oral frenula, and punched-out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata, they do not involute with age. Normal intelligence Note: A male presentation of • The major skeletal findings are in the hands. There is variable shortening, fusion, and disorganized ossification of the carpals and metacarpals. Camptodactyly can be marked and forms no clear pattern. Additional features include cystic lesions and bowing of the long bones, radial head dislocation, short stature, and scoliosis. • Digital fibromata appear in infancy, can grow to a large size, and may regrow after excision, but eventually involute before age ten years. • Cardiac septal defects and cardiomyopathy • Ureteric obstruction (occasional) • Alopecia is a variable clinical finding. • The most characteristic craniofacial findings are widely spaced eyes, abnormal oral frenula, and punched-out hyperpigmented lesions characteristically over the temporal region. Unlike the fibromata, they do not involute with age. • Normal intelligence ## Genotype-Phenotype Correlations Pathogenic variants associated with Variants leading to In a study of 13 males with One female with a combined FMD-periventricular nodular heterotopia phenotype had an Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ • • Variants leading to • In a study of 13 males with • One female with a combined FMD-periventricular nodular heterotopia phenotype had an • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ • Variants leading to • In a study of 13 males with • One female with a combined FMD-periventricular nodular heterotopia phenotype had an • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ • Variants leading to • In a study of 13 males with • One female with a combined FMD-periventricular nodular heterotopia phenotype had an • Some pathogenic variants are associated with severe male phenotypes including cardiac and urologic malformations [ ## Penetrance Penetrance in males with an Some obligate heterozygote females with ## Nomenclature MNS was originally referred to as osteodysplasty. OPD1 was also referred to as Taybi syndrome after its first description in 1963. ## Prevalence No population-based studies have been performed to adequately assess prevalence. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Skeletal dysplasias of interest in the differential diagnosis of Genes of Interest in the Differential Diagnosis of In males: similar skeletal dysplasia to that in Occasionally, extraskeletal anomalies similar to those in Similar facial features to those in Cleft palate, hearing loss, spatulate fingers & toes Large joint dislocations (in both LS & AOIII) Varying degrees of disordered ossification (in AOIII) Acro-osteolysis, osteopenia, basilar indentation of skull base AD = autosomal dominant; AR = autosomal recessive; FMD = frontometaphyseal dysplasia; ID = intellectual disability; MNS = Melnick-Needles syndrome; MOI = mode of inheritance; OPD = otopalatodigital; XL = X-linked • In males: similar skeletal dysplasia to that in • Occasionally, extraskeletal anomalies similar to those in • Similar facial features to those in • Cleft palate, hearing loss, spatulate fingers & toes • Large joint dislocations (in both LS & AOIII) • Varying degrees of disordered ossification (in AOIII) • Acro-osteolysis, osteopenia, basilar indentation of skull base ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with an Clinical exam of extremities, joints, & spine Complete skeletal survey w/scoliosis series if indicated Assess for clinical evidence of bleeding diathesis (in females w/ Referral to hematologist for those w/evidence of bleeding diathesis (in females w/ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see CPAP Mandibular distraction CPAP = continuous positive airway pressure; To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Hand contractures in those w/ Scoliosis in those w/ DXA = dual-energy x-ray absorptiometry; It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk female relatives of an affected individual in order to identify as early as possible those who would benefit from early evaluations for hearing loss and orthopedic complications, including scoliosis. See Search • Clinical exam of extremities, joints, & spine • Complete skeletal survey w/scoliosis series if indicated • Assess for clinical evidence of bleeding diathesis (in females w/ • Referral to hematologist for those w/evidence of bleeding diathesis (in females w/ • CPAP • Mandibular distraction • Hand contractures in those w/ • Scoliosis in those w/ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an Clinical exam of extremities, joints, & spine Complete skeletal survey w/scoliosis series if indicated Assess for clinical evidence of bleeding diathesis (in females w/ Referral to hematologist for those w/evidence of bleeding diathesis (in females w/ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Clinical exam of extremities, joints, & spine • Complete skeletal survey w/scoliosis series if indicated • Assess for clinical evidence of bleeding diathesis (in females w/ • Referral to hematologist for those w/evidence of bleeding diathesis (in females w/ ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see CPAP Mandibular distraction CPAP = continuous positive airway pressure; • CPAP • Mandibular distraction ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Hand contractures in those w/ Scoliosis in those w/ DXA = dual-energy x-ray absorptiometry; • Hand contractures in those w/ • Scoliosis in those w/ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk female relatives of an affected individual in order to identify as early as possible those who would benefit from early evaluations for hearing loss and orthopedic complications, including scoliosis. See ## Therapies Under Investigation Search ## Genetic Counseling Otopalatodigital syndrome type 1 ( Otopalatodigital syndrome type 2 ( Frontometaphyseal dysplasia ( Melnick-Needles syndrome ( Terminal osseous dysplasia ( The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If a female proband's father is asymptomatic, it is possible that he has the pathogenic variant in some cells in his body (somatic mosaicism). Somatic mosaicism for pathogenic variants leading to If the mother of the proband has an Males who inherit the pathogenic variant will be affected. Penetrance in males with an Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: If the proband represents a simplex case and if the If the mother of the proband has an Males who inherit the pathogenic variant will be affected (see Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see If the father of the proband has an If the proband represents a simplex case and if the Males with Males with Males with See Management, The optimal time for determination of genetic risk and discussion of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Otopalatodigital syndrome type 1 ( • Otopalatodigital syndrome type 2 ( • Frontometaphyseal dysplasia ( • Melnick-Needles syndrome ( • Terminal osseous dysplasia ( • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If a female proband's father is asymptomatic, it is possible that he has the pathogenic variant in some cells in his body (somatic mosaicism). Somatic mosaicism for pathogenic variants leading to • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. Penetrance in males with an • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: • Males who inherit the pathogenic variant will be affected. Penetrance in males with an • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. Penetrance in males with an • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected (see • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see • Males who inherit the pathogenic variant will be affected (see • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see • If the father of the proband has an • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected (see • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see • Males with • Males with • Males with • The optimal time for determination of genetic risk and discussion of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an ## Mode of Inheritance Otopalatodigital syndrome type 1 ( Otopalatodigital syndrome type 2 ( Frontometaphyseal dysplasia ( Melnick-Needles syndrome ( Terminal osseous dysplasia ( • Otopalatodigital syndrome type 1 ( • Otopalatodigital syndrome type 2 ( • Frontometaphyseal dysplasia ( • Melnick-Needles syndrome ( • Terminal osseous dysplasia ( ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If a female proband's father is asymptomatic, it is possible that he has the pathogenic variant in some cells in his body (somatic mosaicism). Somatic mosaicism for pathogenic variants leading to If the mother of the proband has an Males who inherit the pathogenic variant will be affected. Penetrance in males with an Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: If the proband represents a simplex case and if the If the mother of the proband has an Males who inherit the pathogenic variant will be affected (see Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see If the father of the proband has an If the proband represents a simplex case and if the Males with Males with Males with • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If a female proband's father is asymptomatic, it is possible that he has the pathogenic variant in some cells in his body (somatic mosaicism). Somatic mosaicism for pathogenic variants leading to • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. Penetrance in males with an • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: • Males who inherit the pathogenic variant will be affected. Penetrance in males with an • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. Penetrance in males with an • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. Females with: • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected (see • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see • Males who inherit the pathogenic variant will be affected (see • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see • If the father of the proband has an • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected (see • Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see • Males with • Males with • Males with ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an • The optimal time for determination of genetic risk and discussion of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having an ## Prenatal Testing and Preimplantation Genetic Testing Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • United Kingdom • • • • • • • ## Molecular Genetics FLNA-Related Otopalatodigital Spectrum Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for FLNA-Related Otopalatodigital Spectrum Disorders ( Filamin has been proposed to be a sensor of mechanical force, both during development but also during physiologic functions carried out by a mobile organism operating in a gravitational environment. Domains of filamin-A integral to this could be those involved with engagement with the actin cytoskeleton mediated by the N-terminal actin-binding domain, the hinge-1 region, and filamin protein repeats 14-16 and 19-21. These regions of the protein correspond to the sites of causal pathogenic variants of FMD = frontometaphyseal dysplasia; MNS = Melnick-Needles syndrome; TOD = terminal osseous dysplasia Variants listed in the table have been provided by the authors. This variant occurs at the last base of an exon and is predicted to cause no amino acid change but does affect splicing, resulting in deletion of 16 amino acids [ ## Molecular Pathogenesis Filamin has been proposed to be a sensor of mechanical force, both during development but also during physiologic functions carried out by a mobile organism operating in a gravitational environment. Domains of filamin-A integral to this could be those involved with engagement with the actin cytoskeleton mediated by the N-terminal actin-binding domain, the hinge-1 region, and filamin protein repeats 14-16 and 19-21. These regions of the protein correspond to the sites of causal pathogenic variants of FMD = frontometaphyseal dysplasia; MNS = Melnick-Needles syndrome; TOD = terminal osseous dysplasia Variants listed in the table have been provided by the authors. This variant occurs at the last base of an exon and is predicted to cause no amino acid change but does affect splicing, resulting in deletion of 16 amino acids [ ## Chapter Notes Stephen Robertson is Director of the Both Stephen Robertson ( The authors are supported by Curekids New Zealand (SR), the Marsden Fund of New Zealand (SR), and the Health Research Council of New Zealand (SR, EW). 26 June 2025 (sw) Comprehensive update posted live 3 October 2019 (sw) Comprehensive update posted live 2 May 2013 (me) Comprehensive update posted live 25 July 2008 (me) Comprehensive update posted live 30 November 2005 (me) Review posted live 14 March 2005 (sr) Original submission • 26 June 2025 (sw) Comprehensive update posted live • 3 October 2019 (sw) Comprehensive update posted live • 2 May 2013 (me) Comprehensive update posted live • 25 July 2008 (me) Comprehensive update posted live • 30 November 2005 (me) Review posted live • 14 March 2005 (sr) Original submission ## Author Notes Stephen Robertson is Director of the Both Stephen Robertson ( ## Acknowledgments The authors are supported by Curekids New Zealand (SR), the Marsden Fund of New Zealand (SR), and the Health Research Council of New Zealand (SR, EW). ## Revision History 26 June 2025 (sw) Comprehensive update posted live 3 October 2019 (sw) Comprehensive update posted live 2 May 2013 (me) Comprehensive update posted live 25 July 2008 (me) Comprehensive update posted live 30 November 2005 (me) Review posted live 14 March 2005 (sr) Original submission • 26 June 2025 (sw) Comprehensive update posted live • 3 October 2019 (sw) Comprehensive update posted live • 2 May 2013 (me) Comprehensive update posted live • 25 July 2008 (me) Comprehensive update posted live • 30 November 2005 (me) Review posted live • 14 March 2005 (sr) Original submission ## References ## Literature Cited	[]	30/11/2005	26/6/2025	28/4/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
opitz	opitz	[ "X-Linked Opitz Syndrome (XLOS)", "X-Linked Opitz G/BBB Syndrome", "X-Linked Opitz Syndrome (XLOS)", "X-Linked Opitz G/BBB Syndrome", "E3 ubiquitin-protein ligase Midline-1", "MID1", "MID1-Related Opitz G/BBB Syndrome" ]		Germana Meroni	Summary The diagnosis of	## Diagnosis For the purposes of this Hypertelorism and/or telecanthus (present in virtually all affected individuals) Hypospadias Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction Cleft lip and/or palate Intellectual disability and developmental delay Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, persistent left superior vena cava, patent ductus arteriosus) Imperforate or ectopic anus Urinary tract abnormalities including vesicoureteral reflux and hydronephrosis Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Whole-gene deletions have been reported [ • Hypertelorism and/or telecanthus (present in virtually all affected individuals) • Hypospadias • Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction • Cleft lip and/or palate • Intellectual disability and developmental delay • Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, persistent left superior vena cava, patent ductus arteriosus) • Imperforate or ectopic anus • Urinary tract abnormalities including vesicoureteral reflux and hydronephrosis • Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia ## Suggestive Findings Hypertelorism and/or telecanthus (present in virtually all affected individuals) Hypospadias Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction Cleft lip and/or palate Intellectual disability and developmental delay Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, persistent left superior vena cava, patent ductus arteriosus) Imperforate or ectopic anus Urinary tract abnormalities including vesicoureteral reflux and hydronephrosis Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia • Hypertelorism and/or telecanthus (present in virtually all affected individuals) • Hypospadias • Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction • Cleft lip and/or palate • Intellectual disability and developmental delay • Congenital heart defects (e.g., ventricular septal defect, atrial septal defect, persistent left superior vena cava, patent ductus arteriosus) • Imperforate or ectopic anus • Urinary tract abnormalities including vesicoureteral reflux and hydronephrosis • Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Whole-gene deletions have been reported [ ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Whole-gene deletions have been reported [ ## Clinical Characteristics Includes males with Midline brain anatomic defects including agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis and Dandy-Walker malformations were identified in about half of males with an Heterozygous females usually have hypertelorism only, and rarely other manifestations (e.g., characteristic facial features [anteverted nares, short nose, short uvula, high arched palate, micrognathia], tracheoesophageal cleft or esophageal stenosis, anal malformations) [ In general, no genotype-phenotype correlations have been observed. Pathogenic missense, nonsense, splice site, and frameshift variants, insertions, and deletions all result in highly variable phenotypes even within the same family [ Two possible exceptions are: An association between truncating variants and the presence of anatomic brain abnormalities, in particular cerebellar defects [ Possible correlation of a mild phenotype with pathogenic variants in the fibronectin type III domain of the protein [ Usually, the presence of an The title of this Opitz G/BBB syndrome was first reported as two separate entities, BBB syndrome [ Other names, no longer used, include hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated abnormalities, and hypertelorism-hypospadias syndrome. Of note, • An association between truncating variants and the presence of anatomic brain abnormalities, in particular cerebellar defects [ • Possible correlation of a mild phenotype with pathogenic variants in the fibronectin type III domain of the protein [ ## Clinical Description Includes males with Midline brain anatomic defects including agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis and Dandy-Walker malformations were identified in about half of males with an Heterozygous females usually have hypertelorism only, and rarely other manifestations (e.g., characteristic facial features [anteverted nares, short nose, short uvula, high arched palate, micrognathia], tracheoesophageal cleft or esophageal stenosis, anal malformations) [ ## Affected Males Midline brain anatomic defects including agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis and Dandy-Walker malformations were identified in about half of males with an ## Heterozygous Females Heterozygous females usually have hypertelorism only, and rarely other manifestations (e.g., characteristic facial features [anteverted nares, short nose, short uvula, high arched palate, micrognathia], tracheoesophageal cleft or esophageal stenosis, anal malformations) [ ## Genotype-Phenotype Correlations In general, no genotype-phenotype correlations have been observed. Pathogenic missense, nonsense, splice site, and frameshift variants, insertions, and deletions all result in highly variable phenotypes even within the same family [ Two possible exceptions are: An association between truncating variants and the presence of anatomic brain abnormalities, in particular cerebellar defects [ Possible correlation of a mild phenotype with pathogenic variants in the fibronectin type III domain of the protein [ • An association between truncating variants and the presence of anatomic brain abnormalities, in particular cerebellar defects [ • Possible correlation of a mild phenotype with pathogenic variants in the fibronectin type III domain of the protein [ ## Penetrance Usually, the presence of an ## Nomenclature The title of this Opitz G/BBB syndrome was first reported as two separate entities, BBB syndrome [ Other names, no longer used, include hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated abnormalities, and hypertelorism-hypospadias syndrome. Of note, ## Genetically Related (Allelic) Disorders No other phenotype is known to be associated with pathogenic variants in ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Facial dysmorphism Cleft lip/palate Congenital heart defects Laryngotracheoesophageal defects DD Genitourinary defects Skeletal anomalies Autoimmune disorders Hypotonia, polymicrogyria Facial dysmorphism Cryptorchidism DD Feeding problems Joint hyperlaxity Short stature Hypotonia Facial dysmorphism Cleft lip/palate Hypospadias DD Hypoplasia or agenesis of corpus callosum Skeletal, chest, skin, nail, & hair defects Short stature Hypotonia Facial dysmorphism Congenital heart defects Cryptorchidism DD/ID Congenital hypotonia w/joint hyperlaxity evolving into spasticity Chronic constipation Characteristic behavior (affable & eager to please) Facial dysmorphism Cleft lip/palate Congenital heart defects DD/ID Short stature Congenital diaphragmatic hernias Bicornuate uterus Absence of hypospadias Facial dysmorphism Cardiovascular defects Hypospadias DD Hypoplasia or agenesis of corpus callosum Ocular & gastrointestinal abnormalities Short stature Pectus excavatum Hypotonia AD = autosomal dominant; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked It is now recognized that 22q11.2 deletion syndrome encompasses the phenotypes previously described as DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (see An FG syndrome (FGS)-like phenotype has been suggested as a distinct • Facial dysmorphism • Cleft lip/palate • Congenital heart defects • Laryngotracheoesophageal defects • DD • Genitourinary defects • Skeletal anomalies • Autoimmune disorders • Hypotonia, polymicrogyria • Facial dysmorphism • Cryptorchidism • DD • Feeding problems • Joint hyperlaxity • Short stature • Hypotonia • Facial dysmorphism • Cleft lip/palate • Hypospadias • DD • Hypoplasia or agenesis of corpus callosum • Skeletal, chest, skin, nail, & hair defects • Short stature • Hypotonia • Facial dysmorphism • Congenital heart defects • Cryptorchidism • DD/ID • Congenital hypotonia w/joint hyperlaxity evolving into spasticity • Chronic constipation • Characteristic behavior (affable & eager to please) • Facial dysmorphism • Cleft lip/palate • Congenital heart defects • DD/ID • Short stature • Congenital diaphragmatic hernias • Bicornuate uterus • Absence of hypospadias • Facial dysmorphism • Cardiovascular defects • Hypospadias • DD • Hypoplasia or agenesis of corpus callosum • Ocular & gastrointestinal abnormalities • Short stature • Pectus excavatum • Hypotonia ## Management To establish the extent of disease and needs in an individual diagnosed with Referral of persons w/cleft lip/palate to craniofacial surgeon Assessment of feeding & speech Dental assessment Community or Social work involvement for parental support Home nursing referral LTE = laryngotracheoesophageal; Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves management of anomalies by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech-language pathologist, and clinical geneticist) to help assure coordination of care (see Surgical mgmt for cleft lip/palate & other craniofacial anomalies Standard treatments for hearing loss incl PE tubes for recurrent otitis Speech therapy for speech problems secondary to cleft lip/palate Standard dental treatments as needed for hypodontia Surgical treatment of medically significant LTE abnormalities Anti-reflux pharmacologic therapy minimizes risk for aspiration until laryngeal competence is assured. LTE = laryngotracheoesophageal; PE = pressure equalization To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in LTE = laryngotracheoesophageal See Search • Referral of persons w/cleft lip/palate to craniofacial surgeon • Assessment of feeding & speech • Dental assessment • Community or • Social work involvement for parental support • Home nursing referral • Surgical mgmt for cleft lip/palate & other craniofacial anomalies • Standard treatments for hearing loss incl PE tubes for recurrent otitis • Speech therapy for speech problems secondary to cleft lip/palate • Standard dental treatments as needed for hypodontia • Surgical treatment of medically significant LTE abnormalities • Anti-reflux pharmacologic therapy minimizes risk for aspiration until laryngeal competence is assured. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Referral of persons w/cleft lip/palate to craniofacial surgeon Assessment of feeding & speech Dental assessment Community or Social work involvement for parental support Home nursing referral LTE = laryngotracheoesophageal; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Referral of persons w/cleft lip/palate to craniofacial surgeon • Assessment of feeding & speech • Dental assessment • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves management of anomalies by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech-language pathologist, and clinical geneticist) to help assure coordination of care (see Surgical mgmt for cleft lip/palate & other craniofacial anomalies Standard treatments for hearing loss incl PE tubes for recurrent otitis Speech therapy for speech problems secondary to cleft lip/palate Standard dental treatments as needed for hypodontia Surgical treatment of medically significant LTE abnormalities Anti-reflux pharmacologic therapy minimizes risk for aspiration until laryngeal competence is assured. LTE = laryngotracheoesophageal; PE = pressure equalization • Surgical mgmt for cleft lip/palate & other craniofacial anomalies • Standard treatments for hearing loss incl PE tubes for recurrent otitis • Speech therapy for speech problems secondary to cleft lip/palate • Standard dental treatments as needed for hypodontia • Surgical treatment of medically significant LTE abnormalities • Anti-reflux pharmacologic therapy minimizes risk for aspiration until laryngeal competence is assured. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in LTE = laryngotracheoesophageal ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The father of an affected male will not have the disorder, nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, If the proband represents a simplex case and if the All of their daughters, who will be heterozygotes and will usually manifest hypertelorism only; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Heterozygote testing for at-risk female relatives requires prior identification of the Note: Females who are heterozygous for this X-linked disorder will usually manifest hypertelorism only. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, • All of their daughters, who will be heterozygotes and will usually manifest hypertelorism only; • None of their sons. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. ## Mode of Inheritance ## Risk to Family Members The father of an affected male will not have the disorder, nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, If the proband represents a simplex case and if the All of their daughters, who will be heterozygotes and will usually manifest hypertelorism only; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder, nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. (Note: Wide variability in clinical manifestations has been described among affected members of the same family.) • Females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only (see Clinical Description, • All of their daughters, who will be heterozygotes and will usually manifest hypertelorism only; • None of their sons. ## Heterozygote Detection Heterozygote testing for at-risk female relatives requires prior identification of the Note: Females who are heterozygous for this X-linked disorder will usually manifest hypertelorism only. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • • • ## Molecular Genetics MID1-Related Opitz G/BBB Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for MID1-Related Opitz G/BBB Syndrome ( The pathogenic variants are missense and nonsense variants, small deletions, intronic splicing variants, or insertions located along the entire length of the gene – the majority in the most 3' portion of the gene. ## Molecular Pathogenesis The pathogenic variants are missense and nonsense variants, small deletions, intronic splicing variants, or insertions located along the entire length of the gene – the majority in the most 3' portion of the gene. ## Chapter Notes Contact Dr Meroni to inquire about review of This chapter is dedicated to the memory of Dr John M Opitz, whose passion and dedication for children and families affected by 19 October 2023 (sw) Comprehensive update posted live 5 April 2018 (sw) Comprehensive update posted live 28 July 2011 (me) Comprehensive update posted live 18 January 2007 (me) Comprehensive update posted live 17 December 2004 (me) Review posted live 30 June 2004 (gm) Original submission • 19 October 2023 (sw) Comprehensive update posted live • 5 April 2018 (sw) Comprehensive update posted live • 28 July 2011 (me) Comprehensive update posted live • 18 January 2007 (me) Comprehensive update posted live • 17 December 2004 (me) Review posted live • 30 June 2004 (gm) Original submission ## Author Notes Contact Dr Meroni to inquire about review of ## Acknowledgments This chapter is dedicated to the memory of Dr John M Opitz, whose passion and dedication for children and families affected by ## Revision History 19 October 2023 (sw) Comprehensive update posted live 5 April 2018 (sw) Comprehensive update posted live 28 July 2011 (me) Comprehensive update posted live 18 January 2007 (me) Comprehensive update posted live 17 December 2004 (me) Review posted live 30 June 2004 (gm) Original submission • 19 October 2023 (sw) Comprehensive update posted live • 5 April 2018 (sw) Comprehensive update posted live • 28 July 2011 (me) Comprehensive update posted live • 18 January 2007 (me) Comprehensive update posted live • 17 December 2004 (me) Review posted live • 30 June 2004 (gm) Original submission ## References ## Literature Cited	[]	17/12/2004	19/10/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
opmd	opmd	[ "OPMD", "OPMD", "Polyadenylate-binding protein 2", "PABPN1", "Oculopharyngeal Muscular Dystrophy" ]	Oculopharyngeal Muscular Dystrophy	Capucine Trollet, Alexis Boulinguiez, Fanny Roth, Tanya Stojkovic, Gillian Butler-Browne, Teresinha Evangelista, Jean Lacau St Guily, Pascale Richard	Summary Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and dysphagia due to selective involvement of the muscles of the eyelids and pharynx, respectively. For the vast majority of individuals with typical OPMD, the mean age of onset of ptosis is usually 48 years and of dysphagia 50 years; in 5%-10% of individuals with severe OPMD, onset of ptosis and dysphagia occur before age 45 years and is associated with lower limb girdle weakness starting around age 60 years. Swallowing difficulties, which determine prognosis, increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition. Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs. Some individuals with severe involvement will eventually need a wheelchair. Neuropsychological tests have shown altered scores in executive functions in some. The diagnosis of OPMD is established in a proband with a suggestive phenotype in whom either of the following genetic findings are identified: a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of OPMD is inherited in an autosomal dominant manner. The risk to sibs of a proband depends on the genetic status of the parents of the proband: If one parent of a proband is heterozygous for a GCN repeat expansion in If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. If one parent of the proband has biallelic GCN repeat expansions and the other parent has two normal alleles, all sibs will inherit a GCN repeat expansion. If one parent of the proband has biallelic GCN repeat expansions and the other parent is heterozygous for a GCN repeat expansion, sibs of the proband have a 50% risk of inheriting biallelic GCN repeat expansions and 50% risk of inheriting one GCN repeat expansion. Sibs who inherit either one or two GCN repeat expansions will be affected.	## Diagnosis Oculopharyngeal muscular dystrophy (OPMD) Note: Proximal muscle weakness (particularly involving pelvic girdle and scapular girdle) may appear later, usually five to ten years after the onset of ptosis. The diagnosis of OPMD A heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of Biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous (GCN[11]+[11], GCN[12]+[12], or GCN[13]+[13]) (~10% of affected individuals) Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of OPMD, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of OPMD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Oculopharyngeal Muscular Dystrophy See See Sanger sequencing is typically used to determine GCN repeat length and zygosity; however, due to the sequence and size of the repeat, next-generation sequencing (NGS) or fragment analysis can also be used. (Note that while Sanger sequencing is suitable to determine zygosity in individuals with monoallelic heterozygote expanded variants, when there are biallelic expanded variants, fragment size determination and/or NGS should be added to determine zygosity.) Sanger sequencing or NGS can determine the sequence of the repeat; however, it is not necessary to determine the exact sequence of the repeat in order to establish the diagnosis of OPMD. GCN repeat expansion is the only reported cause of OPMD [ • A heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of • Biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous (GCN[11]+[11], GCN[12]+[12], or GCN[13]+[13]) (~10% of affected individuals) • For an introduction to multigene panels click ## Suggestive Findings Oculopharyngeal muscular dystrophy (OPMD) Note: Proximal muscle weakness (particularly involving pelvic girdle and scapular girdle) may appear later, usually five to ten years after the onset of ptosis. ## Establishing the Diagnosis The diagnosis of OPMD A heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of Biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous (GCN[11]+[11], GCN[12]+[12], or GCN[13]+[13]) (~10% of affected individuals) Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of OPMD, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of OPMD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Oculopharyngeal Muscular Dystrophy See See Sanger sequencing is typically used to determine GCN repeat length and zygosity; however, due to the sequence and size of the repeat, next-generation sequencing (NGS) or fragment analysis can also be used. (Note that while Sanger sequencing is suitable to determine zygosity in individuals with monoallelic heterozygote expanded variants, when there are biallelic expanded variants, fragment size determination and/or NGS should be added to determine zygosity.) Sanger sequencing or NGS can determine the sequence of the repeat; however, it is not necessary to determine the exact sequence of the repeat in order to establish the diagnosis of OPMD. GCN repeat expansion is the only reported cause of OPMD [ • A heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of • Biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous (GCN[11]+[11], GCN[12]+[12], or GCN[13]+[13]) (~10% of affected individuals) • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of OPMD, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of OPMD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Oculopharyngeal Muscular Dystrophy See See Sanger sequencing is typically used to determine GCN repeat length and zygosity; however, due to the sequence and size of the repeat, next-generation sequencing (NGS) or fragment analysis can also be used. (Note that while Sanger sequencing is suitable to determine zygosity in individuals with monoallelic heterozygote expanded variants, when there are biallelic expanded variants, fragment size determination and/or NGS should be added to determine zygosity.) Sanger sequencing or NGS can determine the sequence of the repeat; however, it is not necessary to determine the exact sequence of the repeat in order to establish the diagnosis of OPMD. GCN repeat expansion is the only reported cause of OPMD [ ## Muscle Biopsy ## Clinical Characteristics Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and dysphagia due to selective involvement of the muscles of the eyelids and pharynx, respectively. Early manifestations of dysphagia include increased time needed to consume a meal and an acquired avoidance of dry foods. The severity of dysphagia is the major determinant of prognosis, as it leads to potentially life-threatening aspiration pneumonia and poor nutrition. Other manifestations, observed as the disease progresses, are limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, proximal limb girdle weakness predominantly in lower limbs, and proximal upper extremity weakness ( In typical OPMD (i.e., 90%-95% of affected individuals), the mean age of onset of ptosis is usually 48 years and dysphagia 50 years. The mean age of onset of lower proximal weakness is 58 years [ Severe OPMD (5%-10% of affected individuals) is characterized by onset of ptosis and dysphagia before age 45 years and incapacitating proximal leg weakness that starts before age 60 years. Some individuals with severe involvement eventually need a wheelchair. See also Although OPMD does not appear to reduce life span, in individuals with heterozygous GCN repeat expansions, quality of life in later years is greatly diminished [ Select Features of Oculopharyngeal Muscular Dystrophy Altered executive functions (in heterozygotes) Uninhibited behavior & psychotic disorders in homozygotes for the (GCN)13 expansion Of note, while in the past dysphagia resulted in poor nutrition usually causing death by starvation, recent progress (especially in the treatment of pharyngeal dysfunction) has improved the quality of life for persons with OPMD. Chewing and speaking are also frequently affected [ At later stages, the fatty degeneration spreads to the vastus medialis and intermediate muscles, the gastrocnemius, and the peroneus muscles. The sartorius, gracilis, and tibialis muscles are usually conserved for a longer time [ MRI studies also show fatty infiltration of the paraspinal muscles in 76% of affected individuals [ Reduction in FEV1 (forced expiratory volume in one second) ranging from 23% to 59% of the expected values was observed in 13 individuals with OPMD, none of whom required noninvasive ventilation [ Sleep apnea, reported rarely, is probably underestimated [ Cardiomyopathy or rhythm abnormalities have not been associated with OPMD. Although OPMD is considered a primary muscle disorder, there are rare reports of findings suggestive of peripheral nerve involvement including severe depletion of myelinated fibers in endomysial nerve twigs of extraocular, pharyngeal, and lingual muscles [ Variability of age of onset and severity of weakness correlates with GCN repeat size [ In persons with heterozygous repeats, longer repeat length is associated with earlier age of onset. In persons with two expanded alleles (either homozygous or compound heterozygous) age of onset is earlier than in individuals with a single (heterozygous) expanded allele. The most severe disease is associated two expanded alleles. Oculopharyngeal Muscular Dystrophy: Genotype-Phenotype Correlations Adapted from Allele sizes are abbreviated. For example, 10/11 = GCN[10]+[11] Decade-specific cumulative penetrance for individuals with a heterozygous GCN[13] pathogenic variant is [ Age <40 years. 1% Age 40-49 years. 6% Age 50-59 years. 31% Age 60-69 years. 63% Age >69 years. 99% Thus, OPMD resulting from GCN[13] heterozygosity is fully penetrant after age 70 years. Anticipation is not observed. The Historical numbering of the The prevalence of OPMD has been estimated at 1:100,000 in France, 1:1000 in the French-Canadian population of the province of Quebec, and 1:600 among Bukhara Jews living in Israel [ In the United States, the majority of affected individuals are of French-Canadian extraction, though a large number are also of other backgrounds, including Ashkenazi Jewish [ OPMD has been identified in individuals from more than 30 countries. The frequency of GCN[11] alleles is 1% to 2% of North American, European, and Japanese populations. • Altered executive functions (in heterozygotes) • Uninhibited behavior & psychotic disorders in homozygotes for the (GCN)13 expansion • Reduction in FEV1 (forced expiratory volume in one second) ranging from 23% to 59% of the expected values was observed in 13 individuals with OPMD, none of whom required noninvasive ventilation [ • Sleep apnea, reported rarely, is probably underestimated [ • Cardiomyopathy or rhythm abnormalities have not been associated with OPMD. • Although OPMD is considered a primary muscle disorder, there are rare reports of findings suggestive of peripheral nerve involvement including severe depletion of myelinated fibers in endomysial nerve twigs of extraocular, pharyngeal, and lingual muscles [ • In persons with heterozygous repeats, longer repeat length is associated with earlier age of onset. • In persons with two expanded alleles (either homozygous or compound heterozygous) age of onset is earlier than in individuals with a single (heterozygous) expanded allele. • The most severe disease is associated two expanded alleles. • Age <40 years. 1% • Age 40-49 years. 6% • Age 50-59 years. 31% • Age 60-69 years. 63% • Age >69 years. 99% ## Clinical Description Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and dysphagia due to selective involvement of the muscles of the eyelids and pharynx, respectively. Early manifestations of dysphagia include increased time needed to consume a meal and an acquired avoidance of dry foods. The severity of dysphagia is the major determinant of prognosis, as it leads to potentially life-threatening aspiration pneumonia and poor nutrition. Other manifestations, observed as the disease progresses, are limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, proximal limb girdle weakness predominantly in lower limbs, and proximal upper extremity weakness ( In typical OPMD (i.e., 90%-95% of affected individuals), the mean age of onset of ptosis is usually 48 years and dysphagia 50 years. The mean age of onset of lower proximal weakness is 58 years [ Severe OPMD (5%-10% of affected individuals) is characterized by onset of ptosis and dysphagia before age 45 years and incapacitating proximal leg weakness that starts before age 60 years. Some individuals with severe involvement eventually need a wheelchair. See also Although OPMD does not appear to reduce life span, in individuals with heterozygous GCN repeat expansions, quality of life in later years is greatly diminished [ Select Features of Oculopharyngeal Muscular Dystrophy Altered executive functions (in heterozygotes) Uninhibited behavior & psychotic disorders in homozygotes for the (GCN)13 expansion Of note, while in the past dysphagia resulted in poor nutrition usually causing death by starvation, recent progress (especially in the treatment of pharyngeal dysfunction) has improved the quality of life for persons with OPMD. Chewing and speaking are also frequently affected [ At later stages, the fatty degeneration spreads to the vastus medialis and intermediate muscles, the gastrocnemius, and the peroneus muscles. The sartorius, gracilis, and tibialis muscles are usually conserved for a longer time [ MRI studies also show fatty infiltration of the paraspinal muscles in 76% of affected individuals [ Reduction in FEV1 (forced expiratory volume in one second) ranging from 23% to 59% of the expected values was observed in 13 individuals with OPMD, none of whom required noninvasive ventilation [ Sleep apnea, reported rarely, is probably underestimated [ Cardiomyopathy or rhythm abnormalities have not been associated with OPMD. Although OPMD is considered a primary muscle disorder, there are rare reports of findings suggestive of peripheral nerve involvement including severe depletion of myelinated fibers in endomysial nerve twigs of extraocular, pharyngeal, and lingual muscles [ • Altered executive functions (in heterozygotes) • Uninhibited behavior & psychotic disorders in homozygotes for the (GCN)13 expansion • Reduction in FEV1 (forced expiratory volume in one second) ranging from 23% to 59% of the expected values was observed in 13 individuals with OPMD, none of whom required noninvasive ventilation [ • Sleep apnea, reported rarely, is probably underestimated [ • Cardiomyopathy or rhythm abnormalities have not been associated with OPMD. • Although OPMD is considered a primary muscle disorder, there are rare reports of findings suggestive of peripheral nerve involvement including severe depletion of myelinated fibers in endomysial nerve twigs of extraocular, pharyngeal, and lingual muscles [ ## Genotype-Phenotype Correlations Variability of age of onset and severity of weakness correlates with GCN repeat size [ In persons with heterozygous repeats, longer repeat length is associated with earlier age of onset. In persons with two expanded alleles (either homozygous or compound heterozygous) age of onset is earlier than in individuals with a single (heterozygous) expanded allele. The most severe disease is associated two expanded alleles. Oculopharyngeal Muscular Dystrophy: Genotype-Phenotype Correlations Adapted from Allele sizes are abbreviated. For example, 10/11 = GCN[10]+[11] • In persons with heterozygous repeats, longer repeat length is associated with earlier age of onset. • In persons with two expanded alleles (either homozygous or compound heterozygous) age of onset is earlier than in individuals with a single (heterozygous) expanded allele. • The most severe disease is associated two expanded alleles. ## Penetrance Decade-specific cumulative penetrance for individuals with a heterozygous GCN[13] pathogenic variant is [ Age <40 years. 1% Age 40-49 years. 6% Age 50-59 years. 31% Age 60-69 years. 63% Age >69 years. 99% Thus, OPMD resulting from GCN[13] heterozygosity is fully penetrant after age 70 years. • Age <40 years. 1% • Age 40-49 years. 6% • Age 50-59 years. 31% • Age 60-69 years. 63% • Age >69 years. 99% ## Anticipation Anticipation is not observed. The ## Nomenclature Historical numbering of the ## Prevalence The prevalence of OPMD has been estimated at 1:100,000 in France, 1:1000 in the French-Canadian population of the province of Quebec, and 1:600 among Bukhara Jews living in Israel [ In the United States, the majority of affected individuals are of French-Canadian extraction, though a large number are also of other backgrounds, including Ashkenazi Jewish [ OPMD has been identified in individuals from more than 30 countries. The frequency of GCN[11] alleles is 1% to 2% of North American, European, and Japanese populations. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of oculopharyngeal muscular dystrophy (OPMD) should include myasthenia gravis and other late-onset neuromuscular diseases characterized by swallowing difficulties and/or ptosis. Disorders in the differential diagnosis with a known genetic etiology are summarized in Genes of Interest in the Differential Diagnosis of Oculopharyngeal Muscular Dystrophy Distal weakness Earlier onset (3rd decade) than in OPMD Caused by a CGG trinucleotide repeat expansion AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; CMT = Charcot-Marie-Tooth; MOI = mode of inheritance; OPMD = oculopharyngeal muscular dystrophy Blepharophimosis, ptosis, and epicanthus inversus syndrome is usually inherited in an autosomal dominant manner; autosomal recessive inheritance has been reported in one consanguineous family. • Distal weakness • Earlier onset (3rd decade) than in OPMD • Caused by a CGG trinucleotide repeat expansion ## Management To establish the extent of disease and needs of an individual diagnosed with oculopharyngeal muscular dystrophy (OPMD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Oculopharyngeal Muscular Dystrophy Overall disease progression Presence (& severity) of proximal weakness Presence or absence of any other neurologic findings Assess best corrected visual acuity Determine presence (& severity) of ptosis & range of extraocular movement. Surgery is an option when severe ptosis impairs vision. Pulmonary function tests Chest CT History of swallowing difficulties The drink test VESS Nutritional status & diet Assess psychological impact. In some patients: refer to psychologist as needed. Use of community or Need for social work involvement for caregiver support. BDI-PC = Beck's Depression Inventory of Primary Care; CIS = Checklist Individual Strength; MPQ = McGill's Pain Questionnaire; OT = occupational therapy; PT = physical therapy; SCL90 = Symptom Checklist 90; SIP-136 = Sickness Impact Profile; MOI = mode of inheritance; VESS = videoendoscopic swallowing study; VFSS = videofluoroscopic swallowing study Questionnaires used to evaluate the degree of dysphagia and quality of life consequences include the DHI [ The drink test, a global quantitative functional evaluation of swallowing, is abnormal when it takes longer than seven seconds to drink 80 mL of ice-cold water [ VESS gives indirect signs of upper esophageal sphincter (UES) dysfunction. VFSS gives a direct evaluation of the UES using radiopaque barite in the tracheobronchial tree [ Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Resection of the aponeurosis is easily done, but usually needs to be repeated once or twice [ Frontal suspension of the eyelids uses a thread of muscle fascia as a sling; the fascia is inserted through the tarsal plate of the upper eyelid and the ends are attached in the frontalis muscle, which is relatively preserved in OPMD [ Food should be cut into small pieces. Although no controlled trials have been performed [ Cricopharyngeal myotomy, consisting of extramucosal section of the cricopharyngeal muscle that improves swallowing through the upper esophageal sphincter [ Cricopharyngeal dilation is an alternative to cricopharyngeal myotomy [ In social settings involving food consumption, affected individuals should either avoid eating or choose foods that are easy to swallow. Annual flu vaccination is recommended for elderly affected individuals; Consultation should be sought promptly for a productive cough because of the increased risk for lung abscesses; Dietary supplements should be added if weight loss is significant. General anesthesia is not contraindicated, although individuals with OPMD may respond differently to certain anesthetics [ Recommended Surveillance for Individuals with Oculopharyngeal Muscular Dystrophy Patients w/known pulmonary disease: per treating pulmonologist Patients w/o known pulmonary disease: annually Patients known to have nocturnal hypoventilation: per treating pulmonologist Patients w/o known nocturnal hypoventilation: every 2 yrs For functional signs of dysphagia using VESS &/or VFSS; Nutrition status & diet. Use of community or Social work involvement for caregiver support. OT = occupational therapist; PT = physical therapist; VESS = videoendoscopic swallowing study; VFSS = videofluoroscopic swallowing study See Several therapeutic strategies, developed and tested in OPMD models (mammalian cells, nematode, drosophila, mouse) are currently under investigation [ Gene replacement strategies (knockdown of mutated A few clinical trials on therapeutic strategies have already been performed on OPMD: An autologous cell transplantation clinical Phase I/IIa study ( Trehalose has now been tested in a clinical setting in persons with OPMD (Bioblast Biopharma; HOPEMD; Search • Overall disease progression • Presence (& severity) of proximal weakness • Presence or absence of any other neurologic findings • Assess best corrected visual acuity • Determine presence (& severity) of ptosis & range of extraocular movement. • Surgery is an option when severe ptosis impairs vision. • Pulmonary function tests • Chest CT • History of swallowing difficulties • The drink test • VESS • Nutritional status & diet • Assess psychological impact. • In some patients: refer to psychologist as needed. • Use of community or • Need for social work involvement for caregiver support. • Resection of the aponeurosis is easily done, but usually needs to be repeated once or twice [ • Frontal suspension of the eyelids uses a thread of muscle fascia as a sling; the fascia is inserted through the tarsal plate of the upper eyelid and the ends are attached in the frontalis muscle, which is relatively preserved in OPMD [ • Food should be cut into small pieces. • Although no controlled trials have been performed [ • Cricopharyngeal myotomy, consisting of extramucosal section of the cricopharyngeal muscle that improves swallowing through the upper esophageal sphincter [ • Cricopharyngeal dilation is an alternative to cricopharyngeal myotomy [ • In social settings involving food consumption, affected individuals should either avoid eating or choose foods that are easy to swallow. • Annual flu vaccination is recommended for elderly affected individuals; • Consultation should be sought promptly for a productive cough because of the increased risk for lung abscesses; • Dietary supplements should be added if weight loss is significant. • Patients w/known pulmonary disease: per treating pulmonologist • Patients w/o known pulmonary disease: annually • Patients known to have nocturnal hypoventilation: per treating pulmonologist • Patients w/o known nocturnal hypoventilation: every 2 yrs • For functional signs of dysphagia using VESS &/or VFSS; • Nutrition status & diet. • Use of community or • Social work involvement for caregiver support. • An autologous cell transplantation clinical Phase I/IIa study ( • Trehalose has now been tested in a clinical setting in persons with OPMD (Bioblast Biopharma; HOPEMD; ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with oculopharyngeal muscular dystrophy (OPMD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Oculopharyngeal Muscular Dystrophy Overall disease progression Presence (& severity) of proximal weakness Presence or absence of any other neurologic findings Assess best corrected visual acuity Determine presence (& severity) of ptosis & range of extraocular movement. Surgery is an option when severe ptosis impairs vision. Pulmonary function tests Chest CT History of swallowing difficulties The drink test VESS Nutritional status & diet Assess psychological impact. In some patients: refer to psychologist as needed. Use of community or Need for social work involvement for caregiver support. BDI-PC = Beck's Depression Inventory of Primary Care; CIS = Checklist Individual Strength; MPQ = McGill's Pain Questionnaire; OT = occupational therapy; PT = physical therapy; SCL90 = Symptom Checklist 90; SIP-136 = Sickness Impact Profile; MOI = mode of inheritance; VESS = videoendoscopic swallowing study; VFSS = videofluoroscopic swallowing study Questionnaires used to evaluate the degree of dysphagia and quality of life consequences include the DHI [ The drink test, a global quantitative functional evaluation of swallowing, is abnormal when it takes longer than seven seconds to drink 80 mL of ice-cold water [ VESS gives indirect signs of upper esophageal sphincter (UES) dysfunction. VFSS gives a direct evaluation of the UES using radiopaque barite in the tracheobronchial tree [ Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Overall disease progression • Presence (& severity) of proximal weakness • Presence or absence of any other neurologic findings • Assess best corrected visual acuity • Determine presence (& severity) of ptosis & range of extraocular movement. • Surgery is an option when severe ptosis impairs vision. • Pulmonary function tests • Chest CT • History of swallowing difficulties • The drink test • VESS • Nutritional status & diet • Assess psychological impact. • In some patients: refer to psychologist as needed. • Use of community or • Need for social work involvement for caregiver support. ## Treatment of Manifestations Resection of the aponeurosis is easily done, but usually needs to be repeated once or twice [ Frontal suspension of the eyelids uses a thread of muscle fascia as a sling; the fascia is inserted through the tarsal plate of the upper eyelid and the ends are attached in the frontalis muscle, which is relatively preserved in OPMD [ Food should be cut into small pieces. Although no controlled trials have been performed [ Cricopharyngeal myotomy, consisting of extramucosal section of the cricopharyngeal muscle that improves swallowing through the upper esophageal sphincter [ Cricopharyngeal dilation is an alternative to cricopharyngeal myotomy [ In social settings involving food consumption, affected individuals should either avoid eating or choose foods that are easy to swallow. Annual flu vaccination is recommended for elderly affected individuals; Consultation should be sought promptly for a productive cough because of the increased risk for lung abscesses; Dietary supplements should be added if weight loss is significant. General anesthesia is not contraindicated, although individuals with OPMD may respond differently to certain anesthetics [ • Resection of the aponeurosis is easily done, but usually needs to be repeated once or twice [ • Frontal suspension of the eyelids uses a thread of muscle fascia as a sling; the fascia is inserted through the tarsal plate of the upper eyelid and the ends are attached in the frontalis muscle, which is relatively preserved in OPMD [ • Food should be cut into small pieces. • Although no controlled trials have been performed [ • Cricopharyngeal myotomy, consisting of extramucosal section of the cricopharyngeal muscle that improves swallowing through the upper esophageal sphincter [ • Cricopharyngeal dilation is an alternative to cricopharyngeal myotomy [ • In social settings involving food consumption, affected individuals should either avoid eating or choose foods that are easy to swallow. • Annual flu vaccination is recommended for elderly affected individuals; • Consultation should be sought promptly for a productive cough because of the increased risk for lung abscesses; • Dietary supplements should be added if weight loss is significant. ## Surveillance Recommended Surveillance for Individuals with Oculopharyngeal Muscular Dystrophy Patients w/known pulmonary disease: per treating pulmonologist Patients w/o known pulmonary disease: annually Patients known to have nocturnal hypoventilation: per treating pulmonologist Patients w/o known nocturnal hypoventilation: every 2 yrs For functional signs of dysphagia using VESS &/or VFSS; Nutrition status & diet. Use of community or Social work involvement for caregiver support. OT = occupational therapist; PT = physical therapist; VESS = videoendoscopic swallowing study; VFSS = videofluoroscopic swallowing study • Patients w/known pulmonary disease: per treating pulmonologist • Patients w/o known pulmonary disease: annually • Patients known to have nocturnal hypoventilation: per treating pulmonologist • Patients w/o known nocturnal hypoventilation: every 2 yrs • For functional signs of dysphagia using VESS &/or VFSS; • Nutrition status & diet. • Use of community or • Social work involvement for caregiver support. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Several therapeutic strategies, developed and tested in OPMD models (mammalian cells, nematode, drosophila, mouse) are currently under investigation [ Gene replacement strategies (knockdown of mutated A few clinical trials on therapeutic strategies have already been performed on OPMD: An autologous cell transplantation clinical Phase I/IIa study ( Trehalose has now been tested in a clinical setting in persons with OPMD (Bioblast Biopharma; HOPEMD; Search • An autologous cell transplantation clinical Phase I/IIa study ( • Trehalose has now been tested in a clinical setting in persons with OPMD (Bioblast Biopharma; HOPEMD; ## Genetic Counseling Oculopharyngeal muscular dystrophy (OPMD) is inherited in an autosomal dominant manner. The risk to family members depends on whether OPMD in the family is caused by a Most individuals with a heterozygous GCN repeat expansion in Molecular genetic testing is recommended for the parents of a proband, regardless of family history, in order to confirm their genetic status and to allow reliable recurrence risk counseling. Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD. See If the GCN repeat expansion identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Although most individuals with a heterozygous GCN repeat expansion have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has a GCN repeat expansion. If one parent of the proband is heterozygous for a GCN repeat expansion and the other parent has two normal (GCN[10]) alleles, the risk to the sibs of inheriting a GCN repeat expansion is 50%. If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. If one parent of the proband has biallelic GCN repeat expansions and the other parent has two normal alleles, all sibs will inherit a GCN repeat expansion. Sibs who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See If the GCN repeat expansion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the GCN repeat expansion identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for OPMD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. Unless an individual who is heterozygous for a GCN repeat expansion has children with an individual who has heterozygous or biallelic GCN repeat expansions, the individual's offspring have a 50% chance of inheriting the GCN repeat expansion. The likelihood that the reproductive partner of a proband also has heterozygous or biallelic GCN repeat expansions is higher in individuals of French-Canadian extraction and in Bukhara Jews living in Israel (see Both parents of an individual with biallelic GCN repeat expansions are typically heterozygous for a GCN repeat expansion. In rare instances, one parent is heterozygous and the other parent has biallelic GCN repeat expansions. The parents of an individual with biallelic GCN repeat expansions may or may not have manifestations of OPMD depending on the length of their respective GCN repeat expansions. Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD (see Molecular genetic testing is recommended for the parents of a proband to confirm the genetic status of each parent and to allow reliable recurrence risk assessment. If both parents of the proband are heterozygous for a GCN repeat expansion, sibs of the proband have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. If one parent of the proband has biallelic GCN repeat expansions and the other parent is heterozygous for a GCN repeat expansion, sibs of the proband have a 50% risk of inheriting biallelic GCN repeat expansions and 50% risk of inheriting one GCN repeat expansion. Sibs of the proband who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Predictive testing for at-risk relatives is possible once the GCN repeat expansion(s) have been identified in an affected family member. Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of OPMD, it is appropriate to consider testing of symptomatic individuals regardless of age. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing and preimplantation genetic testing. The • Most individuals with a heterozygous GCN repeat expansion in • Molecular genetic testing is recommended for the parents of a proband, regardless of family history, in order to confirm their genetic status and to allow reliable recurrence risk counseling. • Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD. See • If the GCN repeat expansion identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • Although most individuals with a heterozygous GCN repeat expansion have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has a GCN repeat expansion. • The proband has a • The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If one parent of the proband is heterozygous for a GCN repeat expansion and the other parent has two normal (GCN[10]) alleles, the risk to the sibs of inheriting a GCN repeat expansion is 50%. • If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. • If one parent of the proband has biallelic GCN repeat expansions and the other parent has two normal alleles, all sibs will inherit a GCN repeat expansion. • Sibs who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See • If the GCN repeat expansion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the GCN repeat expansion identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for OPMD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Unless an individual who is heterozygous for a GCN repeat expansion has children with an individual who has heterozygous or biallelic GCN repeat expansions, the individual's offspring have a 50% chance of inheriting the GCN repeat expansion. • The likelihood that the reproductive partner of a proband also has heterozygous or biallelic GCN repeat expansions is higher in individuals of French-Canadian extraction and in Bukhara Jews living in Israel (see • Both parents of an individual with biallelic GCN repeat expansions are typically heterozygous for a GCN repeat expansion. In rare instances, one parent is heterozygous and the other parent has biallelic GCN repeat expansions. • The parents of an individual with biallelic GCN repeat expansions may or may not have manifestations of OPMD depending on the length of their respective GCN repeat expansions. Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD (see • Molecular genetic testing is recommended for the parents of a proband to confirm the genetic status of each parent and to allow reliable recurrence risk assessment. • If both parents of the proband are heterozygous for a GCN repeat expansion, sibs of the proband have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. • If one parent of the proband has biallelic GCN repeat expansions and the other parent is heterozygous for a GCN repeat expansion, sibs of the proband have a 50% risk of inheriting biallelic GCN repeat expansions and 50% risk of inheriting one GCN repeat expansion. • Sibs of the proband who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the GCN repeat expansion(s) have been identified in an affected family member. • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors ## Mode of Inheritance Oculopharyngeal muscular dystrophy (OPMD) is inherited in an autosomal dominant manner. The risk to family members depends on whether OPMD in the family is caused by a ## Risk to Family Members – Proband with a Heterozygous GCN Repeat Expansion Most individuals with a heterozygous GCN repeat expansion in Molecular genetic testing is recommended for the parents of a proband, regardless of family history, in order to confirm their genetic status and to allow reliable recurrence risk counseling. Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD. See If the GCN repeat expansion identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Although most individuals with a heterozygous GCN repeat expansion have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has a GCN repeat expansion. If one parent of the proband is heterozygous for a GCN repeat expansion and the other parent has two normal (GCN[10]) alleles, the risk to the sibs of inheriting a GCN repeat expansion is 50%. If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. If one parent of the proband has biallelic GCN repeat expansions and the other parent has two normal alleles, all sibs will inherit a GCN repeat expansion. Sibs who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See If the GCN repeat expansion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the GCN repeat expansion identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for OPMD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. Unless an individual who is heterozygous for a GCN repeat expansion has children with an individual who has heterozygous or biallelic GCN repeat expansions, the individual's offspring have a 50% chance of inheriting the GCN repeat expansion. The likelihood that the reproductive partner of a proband also has heterozygous or biallelic GCN repeat expansions is higher in individuals of French-Canadian extraction and in Bukhara Jews living in Israel (see • Most individuals with a heterozygous GCN repeat expansion in • Molecular genetic testing is recommended for the parents of a proband, regardless of family history, in order to confirm their genetic status and to allow reliable recurrence risk counseling. • Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD. See • If the GCN repeat expansion identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • Although most individuals with a heterozygous GCN repeat expansion have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has a GCN repeat expansion. • The proband has a • The proband inherited a GCN repeat expansions from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If one parent of the proband is heterozygous for a GCN repeat expansion and the other parent has two normal (GCN[10]) alleles, the risk to the sibs of inheriting a GCN repeat expansion is 50%. • If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. • If one parent of the proband has biallelic GCN repeat expansions and the other parent has two normal alleles, all sibs will inherit a GCN repeat expansion. • Sibs who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See • If the GCN repeat expansion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the GCN repeat expansion identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for OPMD because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Unless an individual who is heterozygous for a GCN repeat expansion has children with an individual who has heterozygous or biallelic GCN repeat expansions, the individual's offspring have a 50% chance of inheriting the GCN repeat expansion. • The likelihood that the reproductive partner of a proband also has heterozygous or biallelic GCN repeat expansions is higher in individuals of French-Canadian extraction and in Bukhara Jews living in Israel (see ## Risk to Family Members – Proband with Biallelic GCN Repeat Expansions Both parents of an individual with biallelic GCN repeat expansions are typically heterozygous for a GCN repeat expansion. In rare instances, one parent is heterozygous and the other parent has biallelic GCN repeat expansions. The parents of an individual with biallelic GCN repeat expansions may or may not have manifestations of OPMD depending on the length of their respective GCN repeat expansions. Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD (see Molecular genetic testing is recommended for the parents of a proband to confirm the genetic status of each parent and to allow reliable recurrence risk assessment. If both parents of the proband are heterozygous for a GCN repeat expansion, sibs of the proband have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. If one parent of the proband has biallelic GCN repeat expansions and the other parent is heterozygous for a GCN repeat expansion, sibs of the proband have a 50% risk of inheriting biallelic GCN repeat expansions and 50% risk of inheriting one GCN repeat expansion. Sibs of the proband who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See • Both parents of an individual with biallelic GCN repeat expansions are typically heterozygous for a GCN repeat expansion. In rare instances, one parent is heterozygous and the other parent has biallelic GCN repeat expansions. • The parents of an individual with biallelic GCN repeat expansions may or may not have manifestations of OPMD depending on the length of their respective GCN repeat expansions. Note: A parent who is heterozygous for the GCN[11] repeat expansion may have been previously unrecognized, presenting only mild OPMD (see • Molecular genetic testing is recommended for the parents of a proband to confirm the genetic status of each parent and to allow reliable recurrence risk assessment. • If both parents of the proband are heterozygous for a GCN repeat expansion, sibs of the proband have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion. • If one parent of the proband has biallelic GCN repeat expansions and the other parent is heterozygous for a GCN repeat expansion, sibs of the proband have a 50% risk of inheriting biallelic GCN repeat expansions and 50% risk of inheriting one GCN repeat expansion. • Sibs of the proband who inherit either one or two GCN repeat expansions will be affected. Age of onset and severity of weakness correlate with GCN repeat length and zygosity (i.e., dosage of GCN repeat expansions). See ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Predictive testing for at-risk relatives is possible once the GCN repeat expansion(s) have been identified in an affected family member. Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of OPMD, it is appropriate to consider testing of symptomatic individuals regardless of age. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the GCN repeat expansion(s) have been identified in an affected family member. • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing and preimplantation genetic testing. The ## Resources France Canada United Kingdom • • France • • • • • Canada • • • United Kingdom • • • ## Molecular Genetics Oculopharyngeal Muscular Dystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Oculopharyngeal Muscular Dystrophy ( PABPN1 is ubiquitously expressed at a very low level in skeletal muscle [ Other roles of PABPN1: Splicing regulation [ Nuclear surveillance via hyperadenylation and decay of RNA [ Regulation of noncoding RNA (lncRNA) [ Regulation of small nucleolar RNA (snoRNA) processing [ Regulation of nuclear-encoded mitochondrial RNA [ PABPN1 nuclear aggregates are a pathologic hallmark of the disease; aggregates are found in 5%-15% of myofiber nuclei in affected and unaffected muscle sections of persons with OPMD [ Another emerging hypothesis in OPMD is a PABPN1 loss of function in cells, either directly via mutation of The GCN repeat expansion has been described in various ways. Repeat expansions were first described as pure (GCG) expansions of a (GCG)6 stretch coding for six alanines in the first exon [ The normal GCN[10] allele was referred to as (GCN)6. The pathogenic GCN[11_18] alleles were referred to as (GCN)7-14. When available, the full sequence of normal and pathogenic (expanded) alleles should be reported; for example, an Ala13 allele may have a sequence of GCG[10]GCA[1]GCG[2] (previously reported as (GCG)10(GCA)1(GCG)2). A European Neuromuscular Center (ENMC) workshop on OPMD [ The nomenclature of the Human Genome Variation Society (HGVS) for these alleles is given in Notable Variants listed in the table have been provided by the authors. • Splicing regulation [ • Nuclear surveillance via hyperadenylation and decay of RNA [ • Regulation of noncoding RNA (lncRNA) [ • Regulation of small nucleolar RNA (snoRNA) processing [ • Regulation of nuclear-encoded mitochondrial RNA [ • The normal GCN[10] allele was referred to as (GCN)6. • The pathogenic GCN[11_18] alleles were referred to as (GCN)7-14. ## Molecular Pathogenesis PABPN1 is ubiquitously expressed at a very low level in skeletal muscle [ Other roles of PABPN1: Splicing regulation [ Nuclear surveillance via hyperadenylation and decay of RNA [ Regulation of noncoding RNA (lncRNA) [ Regulation of small nucleolar RNA (snoRNA) processing [ Regulation of nuclear-encoded mitochondrial RNA [ PABPN1 nuclear aggregates are a pathologic hallmark of the disease; aggregates are found in 5%-15% of myofiber nuclei in affected and unaffected muscle sections of persons with OPMD [ Another emerging hypothesis in OPMD is a PABPN1 loss of function in cells, either directly via mutation of The GCN repeat expansion has been described in various ways. Repeat expansions were first described as pure (GCG) expansions of a (GCG)6 stretch coding for six alanines in the first exon [ The normal GCN[10] allele was referred to as (GCN)6. The pathogenic GCN[11_18] alleles were referred to as (GCN)7-14. When available, the full sequence of normal and pathogenic (expanded) alleles should be reported; for example, an Ala13 allele may have a sequence of GCG[10]GCA[1]GCG[2] (previously reported as (GCG)10(GCA)1(GCG)2). A European Neuromuscular Center (ENMC) workshop on OPMD [ The nomenclature of the Human Genome Variation Society (HGVS) for these alleles is given in Notable Variants listed in the table have been provided by the authors. • Splicing regulation [ • Nuclear surveillance via hyperadenylation and decay of RNA [ • Regulation of noncoding RNA (lncRNA) [ • Regulation of small nucleolar RNA (snoRNA) processing [ • Regulation of nuclear-encoded mitochondrial RNA [ • The normal GCN[10] allele was referred to as (GCN)6. • The pathogenic GCN[11_18] alleles were referred to as (GCN)7-14. ## Chapter Notes Alexis Boulinguiez, PhD (2020-present)Bernard Brais, MD, MPhil, PhD; Hôpital Notre-Dame-CHUM, Montréal (2001-2014)Gillian Butler-Browne, PhD (2014-present)Teresinha Evangelista, MD (2020-present)Teresa Gidaro, MD, PhD; Institut de Myologie, Paris (2014-2020)Pierre Klein, PhD; Institut de Myologie, Paris (2014-2020)Jean Lacau St Guily, MD (2014-present)Sophie Périé, MD, PhD; Université Pierre et Marie Curie, Paris (2014-2020)Pascale Richard, PharmD, PhD (2020-present)Fanny Roth, PhD (2020-present)Guy A Rouleau, MD, PhD; Hôpital Notre-Dame-CHUM, Montreal (2001-2014)Capucine Trollet, PhD (2014-present)Tanya Stojkovic, MD (2020-present) 22 October 2020 (bp) Comprehensive update posted live 20 February 2014 (me) Comprehensive update posted live 22 June 2006 (ca) Comprehensive update posted live 3 December 2003 (me) Comprehensive update posted live 8 March 2001 (me) Review posted live December 2000 (bb) Original submission • 22 October 2020 (bp) Comprehensive update posted live • 20 February 2014 (me) Comprehensive update posted live • 22 June 2006 (ca) Comprehensive update posted live • 3 December 2003 (me) Comprehensive update posted live • 8 March 2001 (me) Review posted live • December 2000 (bb) Original submission ## Author Notes ## Author History Alexis Boulinguiez, PhD (2020-present)Bernard Brais, MD, MPhil, PhD; Hôpital Notre-Dame-CHUM, Montréal (2001-2014)Gillian Butler-Browne, PhD (2014-present)Teresinha Evangelista, MD (2020-present)Teresa Gidaro, MD, PhD; Institut de Myologie, Paris (2014-2020)Pierre Klein, PhD; Institut de Myologie, Paris (2014-2020)Jean Lacau St Guily, MD (2014-present)Sophie Périé, MD, PhD; Université Pierre et Marie Curie, Paris (2014-2020)Pascale Richard, PharmD, PhD (2020-present)Fanny Roth, PhD (2020-present)Guy A Rouleau, MD, PhD; Hôpital Notre-Dame-CHUM, Montreal (2001-2014)Capucine Trollet, PhD (2014-present)Tanya Stojkovic, MD (2020-present) ## Revision History 22 October 2020 (bp) Comprehensive update posted live 20 February 2014 (me) Comprehensive update posted live 22 June 2006 (ca) Comprehensive update posted live 3 December 2003 (me) Comprehensive update posted live 8 March 2001 (me) Review posted live December 2000 (bb) Original submission • 22 October 2020 (bp) Comprehensive update posted live • 20 February 2014 (me) Comprehensive update posted live • 22 June 2006 (ca) Comprehensive update posted live • 3 December 2003 (me) Comprehensive update posted live • 8 March 2001 (me) Review posted live • December 2000 (bb) Original submission ## References Association française contre les myopathies. Zoom sur la Dystrophie Musculaire Oculopharyngée. Evry, France: Monographies Myoline. Available Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Association française contre les myopathies. Zoom sur la Dystrophie Musculaire Oculopharyngée. Evry, France: Monographies Myoline. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Published Guidelines / Consensus Statements Association française contre les myopathies. Zoom sur la Dystrophie Musculaire Oculopharyngée. Evry, France: Monographies Myoline. Available Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Association française contre les myopathies. Zoom sur la Dystrophie Musculaire Oculopharyngée. Evry, France: Monographies Myoline. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. 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Hum Mol Genet 2005;14:3673-84", "N Witting, A Mensah, L Kober, H Bundgaard, H Petri, M Duno. Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy.. Acta Neurol Scand. 2014;130:125-30" ]	8/3/2001	22/10/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
os-cs	os-cs	[ "Horan-Beighton Syndrome", "OS-CS", "AMER1-Related Osteopathia Striata with Cranial Sclerosis", "Horan-Beighton Syndrome", "OS-CS", "APC membrane recruitment protein 1", "AMER1", "Osteopathia Striata with Cranial Sclerosis" ]	Osteopathia Striata with Cranial Sclerosis	Russell Gear, Ravi Savarirayan	Summary Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. Males can present with a mild or severe phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the The diagnosis of OS-CS is established in a female proband with characteristic features and a heterozygous pathogenic variant in OS-CS is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and the father. If the mother of the proband has an	## Diagnosis No consensus clinical diagnostic criteria for osteopathia striata with cranial sclerosis (OS-CS) have been published, however the combination of macrocephaly, cranial sclerosis, and longitudinal metaphyseal striations of the long bones are considered highly characteristic of this condition. OS-CS Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw) Macrocephaly and stature short for mid-parental height Orofacial clefting Hearing loss (conductive and sensorineural) and progressive hearing loss Poor or reduced vision Normal intellect or mild developmental delays Sclerosis of the cranium and skull base Sclerosis of lamellar and trabecular bones Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.) Fibular aplasia or hypoplasia Small exostoses Fetal or neonatal death Macrocephaly (50%) Orofacial clefting (cleft palate or cleft lip and palate) Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia) Multiple congenital malformations: Skeletal anomalies (polysyndactyly, talipes) Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) Gastrointestinal anomalies (omphalocele, intestinal malrotation) Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) Brain anomalies (ventriculomegaly, abnormal corpus callosum) Cranial sclerosis Sclerosis of pelvis and long bones Bilateral absent or hypoplastic fibulae Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Osteopathia Striata with Cranial Sclerosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Review of approximately 90 pathogenic variants in the published literature [Author, personal observation], correlation with smaller published case series [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Several contiguous deletions including • Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw) • Macrocephaly and stature short for mid-parental height • Orofacial clefting • Hearing loss (conductive and sensorineural) and progressive hearing loss • Poor or reduced vision • Normal intellect or mild developmental delays • Sclerosis of the cranium and skull base • Sclerosis of lamellar and trabecular bones • Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.) • Fibular aplasia or hypoplasia • Small exostoses • Fetal or neonatal death • Macrocephaly (50%) • Orofacial clefting (cleft palate or cleft lip and palate) • Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia) • Multiple congenital malformations: • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Cranial sclerosis • Sclerosis of pelvis and long bones • Bilateral absent or hypoplastic fibulae • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other skeletal dysplasias, • For an introduction to comprehensive genomic testing click ## Suggestive Findings OS-CS Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw) Macrocephaly and stature short for mid-parental height Orofacial clefting Hearing loss (conductive and sensorineural) and progressive hearing loss Poor or reduced vision Normal intellect or mild developmental delays Sclerosis of the cranium and skull base Sclerosis of lamellar and trabecular bones Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.) Fibular aplasia or hypoplasia Small exostoses Fetal or neonatal death Macrocephaly (50%) Orofacial clefting (cleft palate or cleft lip and palate) Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia) Multiple congenital malformations: Skeletal anomalies (polysyndactyly, talipes) Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) Gastrointestinal anomalies (omphalocele, intestinal malrotation) Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) Brain anomalies (ventriculomegaly, abnormal corpus callosum) Cranial sclerosis Sclerosis of pelvis and long bones Bilateral absent or hypoplastic fibulae • Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw) • Macrocephaly and stature short for mid-parental height • Orofacial clefting • Hearing loss (conductive and sensorineural) and progressive hearing loss • Poor or reduced vision • Normal intellect or mild developmental delays • Sclerosis of the cranium and skull base • Sclerosis of lamellar and trabecular bones • Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.) • Fibular aplasia or hypoplasia • Small exostoses • Fetal or neonatal death • Macrocephaly (50%) • Orofacial clefting (cleft palate or cleft lip and palate) • Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia) • Multiple congenital malformations: • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Cranial sclerosis • Sclerosis of pelvis and long bones • Bilateral absent or hypoplastic fibulae ## Females and Mosaic and/or Mildly Affected Males Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw) Macrocephaly and stature short for mid-parental height Orofacial clefting Hearing loss (conductive and sensorineural) and progressive hearing loss Poor or reduced vision Normal intellect or mild developmental delays Sclerosis of the cranium and skull base Sclerosis of lamellar and trabecular bones Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.) Fibular aplasia or hypoplasia Small exostoses • Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw) • Macrocephaly and stature short for mid-parental height • Orofacial clefting • Hearing loss (conductive and sensorineural) and progressive hearing loss • Poor or reduced vision • Normal intellect or mild developmental delays • Sclerosis of the cranium and skull base • Sclerosis of lamellar and trabecular bones • Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.) • Fibular aplasia or hypoplasia • Small exostoses ## Severely Affected Males Fetal or neonatal death Macrocephaly (50%) Orofacial clefting (cleft palate or cleft lip and palate) Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia) Multiple congenital malformations: Skeletal anomalies (polysyndactyly, talipes) Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) Gastrointestinal anomalies (omphalocele, intestinal malrotation) Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) Brain anomalies (ventriculomegaly, abnormal corpus callosum) Cranial sclerosis Sclerosis of pelvis and long bones Bilateral absent or hypoplastic fibulae • Fetal or neonatal death • Macrocephaly (50%) • Orofacial clefting (cleft palate or cleft lip and palate) • Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia) • Multiple congenital malformations: • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Skeletal anomalies (polysyndactyly, talipes) • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests) • Gastrointestinal anomalies (omphalocele, intestinal malrotation) • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus) • Brain anomalies (ventriculomegaly, abnormal corpus callosum) • Cranial sclerosis • Sclerosis of pelvis and long bones • Bilateral absent or hypoplastic fibulae ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Osteopathia Striata with Cranial Sclerosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Review of approximately 90 pathogenic variants in the published literature [Author, personal observation], correlation with smaller published case series [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Several contiguous deletions including • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other skeletal dysplasias, • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, approximately 90 individuals with a pathogenic variant in Osteopathia Striata with Cranial Sclerosis: Frequency of Select Features in Females and Mildly Affected Males Review of approximately 90 individuals reported with OS-CS and an Association with Wilms tumor (and possibly other cancers) is an emerging feature and a significant departure from what was previously understood about the disorder. Extrapolated from recently published data [ Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, and a depressed nasal bridge). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. There appear to be two distinct phenotypes in males: mild and severe. Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast cell lines [ No genotype-phenotype correlations for Initial reports of truncating variants at the 5' end of Penetrance appears to be 100%, albeit with variable expressivity and severity of the phenotype, even within families. Previous gene names for OS-CS is also known as hyperostosis generalisata with striations. In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ Approximately 90 individuals with molecularly confirmed OS-CS have been reported [Author, personal observation]. ## Clinical Description To date, approximately 90 individuals with a pathogenic variant in Osteopathia Striata with Cranial Sclerosis: Frequency of Select Features in Females and Mildly Affected Males Review of approximately 90 individuals reported with OS-CS and an Association with Wilms tumor (and possibly other cancers) is an emerging feature and a significant departure from what was previously understood about the disorder. Extrapolated from recently published data [ Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, and a depressed nasal bridge). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. There appear to be two distinct phenotypes in males: mild and severe. Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast cell lines [ ## Affected Females Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, and a depressed nasal bridge). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. ## Affected Males There appear to be two distinct phenotypes in males: mild and severe. ## Pathophysiology Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast cell lines [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations for Initial reports of truncating variants at the 5' end of ## Penetrance Penetrance appears to be 100%, albeit with variable expressivity and severity of the phenotype, even within families. ## Nomenclature Previous gene names for OS-CS is also known as hyperostosis generalisata with striations. In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ ## Prevalence Approximately 90 individuals with molecularly confirmed OS-CS have been reported [Author, personal observation]. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Osteopathia Striata with Cranial Sclerosis Metaphyseal flaring Absence of metaphyseal striations Absence of dysmorphic features More diffuse sclerosis of long bones Absence of metaphyseal striations Metaphyseal widening Absence of metaphyseal striations Absence of dysmorphic features Absence of metaphyseal striations Ectodermal manifestations Limb malformations Ocular manifestations Absence of metaphyseal striations Progressive skeletal overgrowth Hyperphosphatasemia Absence of metaphyseal striations Diaphyses of long bones expanded within the cortices Choanal stenosis a common complication Absence of metaphyseal striations 2-3 finger syndactyly, nail dysplasia Absence of metaphyseal striations Pronounced diaphyseal hyperostosis of long bones Proximal muscle weakness & wide-based waddling gait Spondylar changes Absence of OS-CS facial characteristics Absence of sclerosis AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked See also the Nosology of Genetic Skeletal Disorders: 2023 Revision, Group 24 – Osteopetrosis and related osteoclast disorders and Group 25 – Osteosclerotic disorders [ • Metaphyseal flaring • Absence of metaphyseal striations • Absence of dysmorphic features • More diffuse sclerosis of long bones • Absence of metaphyseal striations • Metaphyseal widening • Absence of metaphyseal striations • Absence of dysmorphic features • Absence of metaphyseal striations • Ectodermal manifestations • Limb malformations • Ocular manifestations • Absence of metaphyseal striations • Progressive skeletal overgrowth • Hyperphosphatasemia • Absence of metaphyseal striations • Diaphyses of long bones expanded within the cortices • Choanal stenosis a common complication • Absence of metaphyseal striations • 2-3 finger syndactyly, nail dysplasia • Absence of metaphyseal striations • Pronounced diaphyseal hyperostosis of long bones • Proximal muscle weakness & wide-based waddling gait • Spondylar changes • Absence of OS-CS facial characteristics • Absence of sclerosis ## Management No consensus clinical diagnostic criteria for osteopathia striata with cranial sclerosis (OS-CS) have been published. To establish the extent of disease and needs in an individual diagnosed with OS-CS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Osteopathia Striata with Cranial Sclerosis To assess for renal anomalies in surviving males To evaluate for nephrogenic rests &/or Wilms tumor in females & males Community or Social work involvement for parental support; Home nursing referral. CNS = central nervous system; MOI = mode of inheritance; OS-CS = osteopathia striata with cranial sclerosis Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management by multidisciplinary specialists, including pediatrician, clinical geneticist, orthopedic surgeon, ENT specialist, and, in the presence of congenital malformations, relevant additional subspecialists, is recommended. Treatment of Manifestations in Individuals with Osteopathia Striata with Cranial Sclerosis Management per audiologist Speech-language therapy Surgical management per otolaryngologist should be considered on a case-by-case basis if underlying pathology involves foraminal compression. Community & support groups for hearing loss Sclerotic bone poses surgical challenges [ PT = physical therapy Recommended Surveillance for Individuals with Osteopathia Striata with Cranial Sclerosis The association of OS-CS with Wilms tumor has only recently been established [ It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment of hearing and/or vision loss and congenital heart disease, from cancer surveillance, and from review for congenital anomalies (males). See No specific OS-CS pregnancy management is described, but guidelines for management of pregnant individuals with a skeletal dysplasia should be consulted [ Search • To assess for renal anomalies in surviving males • To evaluate for nephrogenic rests &/or Wilms tumor in females & males • Community or • Social work involvement for parental support; • Home nursing referral. • Management per audiologist • Speech-language therapy • Surgical management per otolaryngologist should be considered on a case-by-case basis if underlying pathology involves foraminal compression. • Community & support groups for hearing loss • Sclerotic bone poses surgical challenges [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with OS-CS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Osteopathia Striata with Cranial Sclerosis To assess for renal anomalies in surviving males To evaluate for nephrogenic rests &/or Wilms tumor in females & males Community or Social work involvement for parental support; Home nursing referral. CNS = central nervous system; MOI = mode of inheritance; OS-CS = osteopathia striata with cranial sclerosis Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To assess for renal anomalies in surviving males • To evaluate for nephrogenic rests &/or Wilms tumor in females & males • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Management by multidisciplinary specialists, including pediatrician, clinical geneticist, orthopedic surgeon, ENT specialist, and, in the presence of congenital malformations, relevant additional subspecialists, is recommended. Treatment of Manifestations in Individuals with Osteopathia Striata with Cranial Sclerosis Management per audiologist Speech-language therapy Surgical management per otolaryngologist should be considered on a case-by-case basis if underlying pathology involves foraminal compression. Community & support groups for hearing loss Sclerotic bone poses surgical challenges [ PT = physical therapy • Management per audiologist • Speech-language therapy • Surgical management per otolaryngologist should be considered on a case-by-case basis if underlying pathology involves foraminal compression. • Community & support groups for hearing loss • Sclerotic bone poses surgical challenges [ ## Surveillance Recommended Surveillance for Individuals with Osteopathia Striata with Cranial Sclerosis The association of OS-CS with Wilms tumor has only recently been established [ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment of hearing and/or vision loss and congenital heart disease, from cancer surveillance, and from review for congenital anomalies (males). See ## Pregnancy Management No specific OS-CS pregnancy management is described, but guidelines for management of pregnant individuals with a skeletal dysplasia should be consulted [ ## Therapies Under Investigation Search ## Genetic Counseling Osteopathia striata with cranial sclerosis (OS-CS) is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote. The affected male may have a Note The mother may have germline mosaicism. Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the A female proband may have inherited the Note: Paternal inheritance has only been reported in mosaic fathers [ Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has an Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. If the father of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Molecular genetic testing may be able to identify the family member in whom a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at increased risk of being affected or heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote. • The affected male may have a • Note • The mother may have germline mosaicism. • The mother may be a heterozygote. • The affected male may have a • Note • The mother may have germline mosaicism. • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • The mother may be a heterozygote. • The affected male may have a • Note • The mother may have germline mosaicism. • If the mother of the proband has an • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • A female proband may have inherited the • Note: Paternal inheritance has only been reported in mosaic fathers [ • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has an • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • If the father of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at increased risk of being affected or heterozygous. ## Mode of Inheritance Osteopathia striata with cranial sclerosis (OS-CS) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote. The affected male may have a Note The mother may have germline mosaicism. Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. If the mother of the proband has an Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the A female proband may have inherited the Note: Paternal inheritance has only been reported in mosaic fathers [ Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has an Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. If the father of the proband has an If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote. • The affected male may have a • Note • The mother may have germline mosaicism. • The mother may be a heterozygote. • The affected male may have a • Note • The mother may have germline mosaicism. • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • The mother may be a heterozygote. • The affected male may have a • Note • The mother may have germline mosaicism. • If the mother of the proband has an • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • A female proband may have inherited the • Note: Paternal inheritance has only been reported in mosaic fathers [ • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has an • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. • If the father of the proband has an • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see • Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at increased risk of being affected or heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at increased risk of being affected or heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics Osteopathia Striata with Cranial Sclerosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Osteopathia Striata with Cranial Sclerosis ( The Reduced expression of Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast-cell lines [ However, two pathogenic variants in the noncoding exon 1 of Mosaicism has also been reported in several males [ Somatic Early studies suggested that germline ## Molecular Pathogenesis The Reduced expression of Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast-cell lines [ However, two pathogenic variants in the noncoding exon 1 of Mosaicism has also been reported in several males [ ## Cancer and Benign Tumors Somatic Early studies suggested that germline ## Chapter Notes Thank you to Professor Stephen Robertson and his working groups for their significant contributions to the OS-CS literature and for communications regarding cancer surveillance recommendations. 30 March 2023 (sw) Revision: " 15 April 2021 (sw) Review posted live 4 February 2021 (rs) Original submission • 30 March 2023 (sw) Revision: " • 15 April 2021 (sw) Review posted live • 4 February 2021 (rs) Original submission ## Author Notes ## Acknowledgments Thank you to Professor Stephen Robertson and his working groups for their significant contributions to the OS-CS literature and for communications regarding cancer surveillance recommendations. ## Revision History 30 March 2023 (sw) Revision: " 15 April 2021 (sw) Review posted live 4 February 2021 (rs) Original submission • 30 March 2023 (sw) Revision: " • 15 April 2021 (sw) Review posted live • 4 February 2021 (rs) Original submission ## References	[ "A Bach, J Mi, M Hunter, BJ Halliday, S Garcia-Minaur, F Sperotto, E Trevisson, D Markie, IM Morison, M Shinawi, DN Willis, SP Robertson. Wilms tumor in patients with osteopathia striata with cranial sclerosis.. Eur J Hum Genet. 2021;29:396-401", "F Brioude, JM Kalish, A Mussa, AC Foster, J Bliek, GB Ferrero, SE Boonen, T Cole, R Baker, M Bertoletti, G Cocchi, C Coze, M De Pellegrin, K Hussain, A Ibrahim, MD Kilby, M Krajewska-Walasek, CP Kratz, EJ Ladusans, P Lapunzina, Y Le Bouc, SM Maas, F Macfonal, K Ounap, L Peruzzi, S Rossignol, S Russo, C Shipster, A Skorka, K Tatton-Brown, J Tenorio, C Tortora, K Gronskov, I Netchine, RC Hennekam, D Prawitt, Z Tumer, T Eggermann, DJG Mackay, A Riccio, ER Maher. Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.. Nat Rev Endocrinol. 2018;14:229-49", "S Chénier, A Noor, L Dupuis, DJ Stavropoulos, R Mendoza-Londono. Osteopathia striata with cranial sclerosis and developmental delay in a male with a mosaic deletion in chromosome region Xq11.2.. 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Am J Med Genet Part A. 2017;173:1931-5", "SB Herman, SK Holman, SP Robertson, L Davidson, B Taragin, J Samanich. Severe osteopathia striata with cranial sclerosis in a female case with whole WTX gene deletion.. Am J Med Genet A. 2013;161A:594-9", "SK Holman, P Daniel, ZA Jenkins, RL Herron, T Morgan, R Savarirayan, CW Chow, A Bohring, A Mosel, D Lacombe, B Steiner, T Schmitt-Mechelke, B Schroter, A Raas-Rothschild, S Garcia-Minaur, M Porteus, M Parker, O Quarrell, D Tapon, V Cormier-Daire, S Manour, R Nash, LA Bindoff, T Fiskerstrand, SP Robertson. The male phenotype in osteopathia striata congenita with cranial sclerosis.. Am J Med Genet Part A. 2011;155A:2397-408", "SK Holman, T Morgan, G Baujat, V Cormier-Daire, T-J Cho, M Lees, J Samanich, D Tapon, HD Hove, A Hing, R Hennekam, SP Robertson. Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the. Clin Genet. 2013;83:251-6", "SJ Huang, LM Amendola, DL Sternen. 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Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1).. J Biol Chem. 2011;286:19204-14", "S Unger, CR Ferreira, GR Mortier, H Ali, DR Bertola, A Calder, DH Cohn, V Cormier-Daire, KM Girisha, C Hall, D Krakow, O Makitie, S Mundlos, G Nishimura, SP Robertson, R Savarirayan, D Sillence, M Simon, VR Sutton, ML Warman, A Superti-Furga. Nosology of genetic skeletal disorders: 2023 revision.. Am J Med Genet A. 2023", "A Vasiljevic, C Azzi, A Lacalm, D Combourieu, S Collardeau-Frechon, F Dijoud, J Massardier, W Van Hul. Fromageoux, Guibaud L, Gaucherand P, Cordier M-P, Massoud M. Prenatal diagnosis of osteopathia striata with cranial sclerosis.. Prenatal Diag. 2015;35:302-4" ]	15/4/2021		30/3/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
otc-def	otc-def	[ "Ornithine Carbamoyltransferase Deficiency", "OTC Deficiency", "OTC Deficiency", "Ornithine Carbamoyltransferase Deficiency", "Ornithine transcarbamylase, mitochondrial", "OTC", "Ornithine Transcarbamylase Deficiency" ]	Ornithine Transcarbamylase Deficiency	Uta Lichter-Konecki, Ljubica Caldovic, Hiroki Morizono, Kara Simpson, Nicholas Ah Mew, Erin MacLeod	Summary Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits. The diagnosis of OTC deficiency is established in a A hemizygous pathogenic variant in A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine and low-to-normal citrulline), as well as absence of biochemical or DNA evidence suggestive of another inborn error of metabolism Decreased OTC enzyme activity in liver The diagnosis of OTC deficiency is usually established in a A heterozygous pathogenic variant in OTC by molecular genetic testing A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine and low-to-normal citrulline), as well as absence of biochemical or DNA evidence suggestive of another inborn error of metabolism Measurement of OTC enzyme activity in liver is not a reliable means of diagnosis in females. OTC deficiency is inherited in an X-linked manner. If the mother of a proband has an	## Diagnosis Diagnostic criteria for ornithine transcarbamylase (OTC) deficiency have been set forth by the Longitudinal Study of Urea Cycle Disorders ( OTC deficiency is universally screened for in eight US states and territories, and likely to be detected and reported in three additional states [ Currently, NBS for OTC deficiency in the US is primarily based on quantification of the analyte citrulline on dried blood spots, either alone or as a ratio with other biochemical markers, which may help to improve the accuracy of the test [ Citrulline values outside the range established by the screening laboratory are considered positive and require follow-up biochemical testing, which may include plasma ammonia, plasma amino acid profile, urine organic acid profile, and urine orotic acid quantification. If follow-up biochemical testing supports the likelihood of OTC deficiency, additional testing is required to establish the diagnosis (see Current NBS methods of screening for OTC deficiency vary greatly in sensitivity and specificity; as a result, medical intervention in response to receipt of an abnormal NBS result is also variable. However, in any scenario, an individual with an out-of-range NBS with evidence of unexplained altered neurologic status or poor feeding requires immediate medical attention and rapid testing of plasma ammonia. Individuals with an elevated ammonia may require dietary protein restriction, alternative pathway medications, and citrulline/arginine and/or renal replacement therapy. A symptomatic individual may have either atypical findings associated with later-onset OTC deficiency or untreated neonatal-onset OTC deficiency resulting from any of the following: Infant symptomatic prior to the results of NBS NBS not performed False negative NBS result Caregivers not adherent to recommended treatment following a positive NBS result Supportive (but nonspecific) clinical findings and preliminary laboratory findings can include the following. Normal at birth Development of reduced oral intake with poor latching and suck Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate) History of recurrent vomiting Migraine headaches Reye-like syndrome Seizures History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods) Unexplained "cerebral palsy" Note: The plasma ammonia concentration at which an individual becomes symptomatic varies but is generally above 100 μmol/L; in Stage 2 coma [ Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [ In a terminally ill individual who has been in a coma for days, acidosis may develop. Note: Because alterations of these metabolites individually are not specific for OTC deficiency, follow-up testing is required to establish or rule out the diagnosis of OTC deficiency (see A hemizygous pathogenic (or likely pathogenic) variant in A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test (see Decreased OTC enzyme activity in liver (See A heterozygous pathogenic (or likely pathogenic) variant in A markedly abnormal increase of orotic acid excretion in a random urine sample or after an allopurinol challenge test (see Note: (1) Liver biopsy is not recommended to establish the diagnosis in females, due to the possibility of false negative results (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ornithine Transcarbamylase (OTC) Deficiency See See A number of additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with biochemically confirmed OTC deficiency (i.e., elevated urinary orotate, a positive allopurinol test, reduced OTC enzyme activity in liver biopsy, or a combination of these findings) [ Data derived from Disease-causing variants in OTC regulatory regions [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described in When sequence analysis was followed by deletion/duplication analysis, a molecular defect was detected in 80%-90% of affected individuals with biochemically confirmed OTC deficiency [ In males and females suspected of having partial OTC deficiency who have normal molecular genetic testing and normal or borderline urinary orotic acid concentration under normal conditions, an allopurinol challenge test should be performed. A markedly abnormal increase of orotic acid excretion ≥20 µmol/mmol creatinine after administering allopurinol is diagnostic [ Previously the gold standard for diagnosing OTC deficiency [ • Infant symptomatic prior to the results of NBS • NBS not performed • False negative NBS result • Caregivers not adherent to recommended treatment following a positive NBS result • Normal at birth • Development of reduced oral intake with poor latching and suck • Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature • Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium • A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate) • History of recurrent vomiting • Migraine headaches • Reye-like syndrome • Seizures • History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods) • Unexplained "cerebral palsy" • Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [ • In a terminally ill individual who has been in a coma for days, acidosis may develop. • A hemizygous pathogenic (or likely pathogenic) variant in • A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test (see • Decreased OTC enzyme activity in liver (See • A heterozygous pathogenic (or likely pathogenic) variant in • A markedly abnormal increase of orotic acid excretion in a random urine sample or after an allopurinol challenge test (see • For an introduction to multigene panels click ## Scenario 1: Abnormal newborn screening (NBS) result Currently, NBS for OTC deficiency in the US is primarily based on quantification of the analyte citrulline on dried blood spots, either alone or as a ratio with other biochemical markers, which may help to improve the accuracy of the test [ Citrulline values outside the range established by the screening laboratory are considered positive and require follow-up biochemical testing, which may include plasma ammonia, plasma amino acid profile, urine organic acid profile, and urine orotic acid quantification. If follow-up biochemical testing supports the likelihood of OTC deficiency, additional testing is required to establish the diagnosis (see Current NBS methods of screening for OTC deficiency vary greatly in sensitivity and specificity; as a result, medical intervention in response to receipt of an abnormal NBS result is also variable. However, in any scenario, an individual with an out-of-range NBS with evidence of unexplained altered neurologic status or poor feeding requires immediate medical attention and rapid testing of plasma ammonia. Individuals with an elevated ammonia may require dietary protein restriction, alternative pathway medications, and citrulline/arginine and/or renal replacement therapy. ## Scenario 2: Symptomatic individual with atypical findings or untreated neonatal-onset OTC deficiency A symptomatic individual may have either atypical findings associated with later-onset OTC deficiency or untreated neonatal-onset OTC deficiency resulting from any of the following: Infant symptomatic prior to the results of NBS NBS not performed False negative NBS result Caregivers not adherent to recommended treatment following a positive NBS result Supportive (but nonspecific) clinical findings and preliminary laboratory findings can include the following. Normal at birth Development of reduced oral intake with poor latching and suck Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate) History of recurrent vomiting Migraine headaches Reye-like syndrome Seizures History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods) Unexplained "cerebral palsy" Note: The plasma ammonia concentration at which an individual becomes symptomatic varies but is generally above 100 μmol/L; in Stage 2 coma [ Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [ In a terminally ill individual who has been in a coma for days, acidosis may develop. Note: Because alterations of these metabolites individually are not specific for OTC deficiency, follow-up testing is required to establish or rule out the diagnosis of OTC deficiency (see • Infant symptomatic prior to the results of NBS • NBS not performed • False negative NBS result • Caregivers not adherent to recommended treatment following a positive NBS result • Normal at birth • Development of reduced oral intake with poor latching and suck • Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature • Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium • A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate) • History of recurrent vomiting • Migraine headaches • Reye-like syndrome • Seizures • History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods) • Unexplained "cerebral palsy" • Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [ • In a terminally ill individual who has been in a coma for days, acidosis may develop. ## Clinical Findings Normal at birth Development of reduced oral intake with poor latching and suck Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate) History of recurrent vomiting Migraine headaches Reye-like syndrome Seizures History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods) Unexplained "cerebral palsy" • Normal at birth • Development of reduced oral intake with poor latching and suck • Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature • Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium • A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate) • History of recurrent vomiting • Migraine headaches • Reye-like syndrome • Seizures • History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods) • Unexplained "cerebral palsy" ## Preliminary Laboratory Findings Note: The plasma ammonia concentration at which an individual becomes symptomatic varies but is generally above 100 μmol/L; in Stage 2 coma [ Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [ In a terminally ill individual who has been in a coma for days, acidosis may develop. Note: Because alterations of these metabolites individually are not specific for OTC deficiency, follow-up testing is required to establish or rule out the diagnosis of OTC deficiency (see • Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [ • In a terminally ill individual who has been in a coma for days, acidosis may develop. ## Establishing the Diagnosis A hemizygous pathogenic (or likely pathogenic) variant in A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test (see Decreased OTC enzyme activity in liver (See A heterozygous pathogenic (or likely pathogenic) variant in A markedly abnormal increase of orotic acid excretion in a random urine sample or after an allopurinol challenge test (see Note: (1) Liver biopsy is not recommended to establish the diagnosis in females, due to the possibility of false negative results (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ornithine Transcarbamylase (OTC) Deficiency See See A number of additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with biochemically confirmed OTC deficiency (i.e., elevated urinary orotate, a positive allopurinol test, reduced OTC enzyme activity in liver biopsy, or a combination of these findings) [ Data derived from Disease-causing variants in OTC regulatory regions [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described in When sequence analysis was followed by deletion/duplication analysis, a molecular defect was detected in 80%-90% of affected individuals with biochemically confirmed OTC deficiency [ In males and females suspected of having partial OTC deficiency who have normal molecular genetic testing and normal or borderline urinary orotic acid concentration under normal conditions, an allopurinol challenge test should be performed. A markedly abnormal increase of orotic acid excretion ≥20 µmol/mmol creatinine after administering allopurinol is diagnostic [ Previously the gold standard for diagnosing OTC deficiency [ • A hemizygous pathogenic (or likely pathogenic) variant in • A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test (see • Decreased OTC enzyme activity in liver (See • A heterozygous pathogenic (or likely pathogenic) variant in • A markedly abnormal increase of orotic acid excretion in a random urine sample or after an allopurinol challenge test (see • For an introduction to multigene panels click ## Molecular Genetic Testing Approaches For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ornithine Transcarbamylase (OTC) Deficiency See See A number of additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals with biochemically confirmed OTC deficiency (i.e., elevated urinary orotate, a positive allopurinol test, reduced OTC enzyme activity in liver biopsy, or a combination of these findings) [ Data derived from Disease-causing variants in OTC regulatory regions [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described in When sequence analysis was followed by deletion/duplication analysis, a molecular defect was detected in 80%-90% of affected individuals with biochemically confirmed OTC deficiency [ • For an introduction to multigene panels click ## Allopurinol Challenge Test In males and females suspected of having partial OTC deficiency who have normal molecular genetic testing and normal or borderline urinary orotic acid concentration under normal conditions, an allopurinol challenge test should be performed. A markedly abnormal increase of orotic acid excretion ≥20 µmol/mmol creatinine after administering allopurinol is diagnostic [ ## OTC Enzyme Activity in Liver Previously the gold standard for diagnosing OTC deficiency [ ## Clinical Characteristics Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Neonatal-onset disease in females is rare. While neonatal-onset OTC deficiency accounted for approximately 60% of all OTC deficiency in the older literature, in its first eight years the longitudinal study of the Urea Cycle Disorders Consortium (UCDC) of the NICHD-supported Rare Disease Clinical Research Network (RDCRN) had enrolled a substantially smaller proportion of individuals with neonatal-onset OTC deficiency than with post-neonatal-onset OTC deficiency. Of 260 individuals who had symptomatic OTC deficiency, 47 (18%) had neonatal-onset disease (42 males and 5 females) and 213 (82%) had post-neonatal onset disease (154 females and 59 males) [ Males with severe OTC deficiency are asymptomatic at birth, but become symptomatic from hyperammonemia in the first week of life (most often on day 2-3) with poor suck, reduced intake, and hypotonia, followed by lethargy progressing to somnolence and coma. They hyperventilate, and may have subclinical/electroencephalographic seizures. By the time neonates with OTC deficiency come to medical attention they typically are catastrophically ill with low body temperature (hypothermia), severe encephalopathy, and respiratory alkalosis. When clinical and laboratory findings support the diagnosis of a urea cycle disorder, rescue therapy is begun immediately (see Management, The prognosis of a newborn in hyperammonemic coma depends on the duration of elevated ammonia level, not the height of the ammonia level or the presence/absence of seizures [ After successful rescue from neonatal hyperammonemic coma, infants with severe neonatal-onset OTC deficiency can easily become hyperammonemic again despite a low-protein diet and treatment with an oral ammonia scavenger. Even on maximum ammonia scavenger therapy a neonate with severe OTC deficiency may only tolerate 1.5 g/kg/day of protein (the minimum amount needed to grow), and growth may be along the third percentile for length. After neonatal rescue therapy, a child with severe neonatal-onset disease can also experience a "honeymoon" period in which the protein tolerance is so high, due to rapid growth, that the child is metabolically stable for some months before experiencing frequent hyperammonemic episodes. Typically, a liver transplant is required to prevent life-threatening hyperammonemic episodes, avert the effect of recurrent hyperammonemia on the brain, and improve quality of life. The overall outcome depends on the severity of brain damage during the initial hyperammonemic crisis and during subsequent hyperammonemic crises, as well as on the success of long-term treatment in maintaining metabolic balance and addressing complications of the disease. Hemizygous males and heterozygous females with partial OTC deficiency can present from infancy to later childhood, adolescence, or adulthood [ When children, adolescents, or adults with post-neonatal-onset disease become encephalopathic they may reach Stage 2 coma [ A stressor can cause an individual with partial OTC deficiency to become symptomatic at any age. In general, the milder the disease, the later the onset and the stronger the stressor required to precipitate symptoms. Adults with very mild disease have become symptomatic after crush injury, following surgery [ The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs nonfavorable X-chromosome inactivation. The amount of OTC enzyme activity in the liver of a heterozygous female depends on the pattern of X-chromosome inactivation in her liver [ Previously, approximately 15% of heterozygous females were thought to become symptomatic during their lifetime [ Recent work suggests that some heterozygous females may be paucisymptomatic: while they may never have hyperammonemia or present with altered mental status, they may in fact have differences in cognitive capability, such as deficits in executive functioning and motor capability [ Attention-deficit/hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [ Approximately half of school-age children with OTC deficiency were reported by their parents as having "internalizing problems" on the Child Behavior Checklist, including being withdrawn, depressed, and/or anxious, or having somatic complaints. Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents. Self-reported difficulties in social relationships, as well as anxiety and depression, have also been described in adults with OTC deficiency, including those who are "asymptomatic" [ Even heterozygous females who have never had biochemical evidence of hyperammonemia and therefore were thought to be asymptomatic, on further scrutiny have been shown to have mild cognitive impairments and deficits in executive function and fine motor tasks even when exhibiting normal IQ on neuropsychological testing. These deficits may be apparent only when these individuals are cognitively challenged [ Although metabolic strokes (involving the caudate and putamen and resulting in extrapyramidal syndromes) have been described in OTC deficiency and CPS1 deficiency [ Better neurologic outcomes are seen in infants with neonatal-onset disease who were treated soon after the onset of coma. During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged. Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [ Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic. Symptomatic individuals with urea cycle disorders are at risk of developing progressive growth impairment over time. Weight is not affected. Growth impairment has recently been shown to be possibly associated with reduced or borderline plasma branched-chain amino acid concentrations. Liver transplant appears to have a beneficial effect on linear growth [ Liver cell carcinoma has been described in a few older individuals (e.g., in a symptomatic heterozygous female age 66 years [ While the following genotype-phenotype correlations do in general exist, it is well established that significant medical problems (e.g., neonatal sepsis or other causes of newborn catabolism) can cause a severe, early presentation in an individual with an In general: Pathogenic missense variants that affect residues essential for catalysis, substrate binding, and folding severely impair or completely abolish OTC enzyme activity and result in neonatal-onset disease in hemizygous males [ Pathogenic nonsense variants, insertions, and deletions that cause frameshift of the open reading frame and single-nucleotide variants in canonic intronic splice sites result in complete absence of functional OTC and neonatal-onset disease in hemizygous males [ Females heterozygous for a pathogenic variant can develop symptoms of OTC deficiency later in life if X-chromosome inactivation in their hepatocytes is skewed in favor of the X chromosome with the pathogenic variant [ Amino acid substitutions that decrease OTC enzyme activity or stability may result in a post-neonatal-onset phenotype in hemizygous males [ Penetrance for OTC deficiency is complete in hemizygous males. The following observations, which may erroneously be interpreted as evidence of incomplete penetrance, are in fact explained by X-chromosome inactivation and environmental factors: Heterozygous females who become symptomatic (the result of skewed X-chromosome inactivation) Hemizygous males with the same mild pathogenic variant, only some of whom develop symptoms (the result of differences in environmental stressors) OTC deficiency is thought to be the most common urea cycle defect (see An early estimated prevalence of OTC deficiency was 1:14,000 live births [ • Attention-deficit/hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [ • Approximately half of school-age children with OTC deficiency were reported by their parents as having "internalizing problems" on the Child Behavior Checklist, including being withdrawn, depressed, and/or anxious, or having somatic complaints. • Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents. • Self-reported difficulties in social relationships, as well as anxiety and depression, have also been described in adults with OTC deficiency, including those who are "asymptomatic" [ • During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged. • Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [ • Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic. • Symptomatic individuals with urea cycle disorders are at risk of developing progressive growth impairment over time. Weight is not affected. Growth impairment has recently been shown to be possibly associated with reduced or borderline plasma branched-chain amino acid concentrations. Liver transplant appears to have a beneficial effect on linear growth [ • Pathogenic missense variants that affect residues essential for catalysis, substrate binding, and folding severely impair or completely abolish OTC enzyme activity and result in neonatal-onset disease in hemizygous males [ • Pathogenic nonsense variants, insertions, and deletions that cause frameshift of the open reading frame and single-nucleotide variants in canonic intronic splice sites result in complete absence of functional OTC and neonatal-onset disease in hemizygous males [ • Females heterozygous for a pathogenic variant can develop symptoms of OTC deficiency later in life if X-chromosome inactivation in their hepatocytes is skewed in favor of the X chromosome with the pathogenic variant [ • Amino acid substitutions that decrease OTC enzyme activity or stability may result in a post-neonatal-onset phenotype in hemizygous males [ • Heterozygous females who become symptomatic (the result of skewed X-chromosome inactivation) • Hemizygous males with the same mild pathogenic variant, only some of whom develop symptoms (the result of differences in environmental stressors) ## Clinical Description Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Neonatal-onset disease in females is rare. While neonatal-onset OTC deficiency accounted for approximately 60% of all OTC deficiency in the older literature, in its first eight years the longitudinal study of the Urea Cycle Disorders Consortium (UCDC) of the NICHD-supported Rare Disease Clinical Research Network (RDCRN) had enrolled a substantially smaller proportion of individuals with neonatal-onset OTC deficiency than with post-neonatal-onset OTC deficiency. Of 260 individuals who had symptomatic OTC deficiency, 47 (18%) had neonatal-onset disease (42 males and 5 females) and 213 (82%) had post-neonatal onset disease (154 females and 59 males) [ Males with severe OTC deficiency are asymptomatic at birth, but become symptomatic from hyperammonemia in the first week of life (most often on day 2-3) with poor suck, reduced intake, and hypotonia, followed by lethargy progressing to somnolence and coma. They hyperventilate, and may have subclinical/electroencephalographic seizures. By the time neonates with OTC deficiency come to medical attention they typically are catastrophically ill with low body temperature (hypothermia), severe encephalopathy, and respiratory alkalosis. When clinical and laboratory findings support the diagnosis of a urea cycle disorder, rescue therapy is begun immediately (see Management, The prognosis of a newborn in hyperammonemic coma depends on the duration of elevated ammonia level, not the height of the ammonia level or the presence/absence of seizures [ After successful rescue from neonatal hyperammonemic coma, infants with severe neonatal-onset OTC deficiency can easily become hyperammonemic again despite a low-protein diet and treatment with an oral ammonia scavenger. Even on maximum ammonia scavenger therapy a neonate with severe OTC deficiency may only tolerate 1.5 g/kg/day of protein (the minimum amount needed to grow), and growth may be along the third percentile for length. After neonatal rescue therapy, a child with severe neonatal-onset disease can also experience a "honeymoon" period in which the protein tolerance is so high, due to rapid growth, that the child is metabolically stable for some months before experiencing frequent hyperammonemic episodes. Typically, a liver transplant is required to prevent life-threatening hyperammonemic episodes, avert the effect of recurrent hyperammonemia on the brain, and improve quality of life. The overall outcome depends on the severity of brain damage during the initial hyperammonemic crisis and during subsequent hyperammonemic crises, as well as on the success of long-term treatment in maintaining metabolic balance and addressing complications of the disease. Hemizygous males and heterozygous females with partial OTC deficiency can present from infancy to later childhood, adolescence, or adulthood [ When children, adolescents, or adults with post-neonatal-onset disease become encephalopathic they may reach Stage 2 coma [ A stressor can cause an individual with partial OTC deficiency to become symptomatic at any age. In general, the milder the disease, the later the onset and the stronger the stressor required to precipitate symptoms. Adults with very mild disease have become symptomatic after crush injury, following surgery [ The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs nonfavorable X-chromosome inactivation. The amount of OTC enzyme activity in the liver of a heterozygous female depends on the pattern of X-chromosome inactivation in her liver [ Previously, approximately 15% of heterozygous females were thought to become symptomatic during their lifetime [ Recent work suggests that some heterozygous females may be paucisymptomatic: while they may never have hyperammonemia or present with altered mental status, they may in fact have differences in cognitive capability, such as deficits in executive functioning and motor capability [ Attention-deficit/hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [ Approximately half of school-age children with OTC deficiency were reported by their parents as having "internalizing problems" on the Child Behavior Checklist, including being withdrawn, depressed, and/or anxious, or having somatic complaints. Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents. Self-reported difficulties in social relationships, as well as anxiety and depression, have also been described in adults with OTC deficiency, including those who are "asymptomatic" [ Even heterozygous females who have never had biochemical evidence of hyperammonemia and therefore were thought to be asymptomatic, on further scrutiny have been shown to have mild cognitive impairments and deficits in executive function and fine motor tasks even when exhibiting normal IQ on neuropsychological testing. These deficits may be apparent only when these individuals are cognitively challenged [ Although metabolic strokes (involving the caudate and putamen and resulting in extrapyramidal syndromes) have been described in OTC deficiency and CPS1 deficiency [ Better neurologic outcomes are seen in infants with neonatal-onset disease who were treated soon after the onset of coma. During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged. Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [ Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic. Symptomatic individuals with urea cycle disorders are at risk of developing progressive growth impairment over time. Weight is not affected. Growth impairment has recently been shown to be possibly associated with reduced or borderline plasma branched-chain amino acid concentrations. Liver transplant appears to have a beneficial effect on linear growth [ Liver cell carcinoma has been described in a few older individuals (e.g., in a symptomatic heterozygous female age 66 years [ • Attention-deficit/hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [ • Approximately half of school-age children with OTC deficiency were reported by their parents as having "internalizing problems" on the Child Behavior Checklist, including being withdrawn, depressed, and/or anxious, or having somatic complaints. • Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents. • Self-reported difficulties in social relationships, as well as anxiety and depression, have also been described in adults with OTC deficiency, including those who are "asymptomatic" [ • During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged. • Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [ • Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic. • Symptomatic individuals with urea cycle disorders are at risk of developing progressive growth impairment over time. Weight is not affected. Growth impairment has recently been shown to be possibly associated with reduced or borderline plasma branched-chain amino acid concentrations. Liver transplant appears to have a beneficial effect on linear growth [ ## Neonatal-Onset OTC Deficiency Males with severe OTC deficiency are asymptomatic at birth, but become symptomatic from hyperammonemia in the first week of life (most often on day 2-3) with poor suck, reduced intake, and hypotonia, followed by lethargy progressing to somnolence and coma. They hyperventilate, and may have subclinical/electroencephalographic seizures. By the time neonates with OTC deficiency come to medical attention they typically are catastrophically ill with low body temperature (hypothermia), severe encephalopathy, and respiratory alkalosis. When clinical and laboratory findings support the diagnosis of a urea cycle disorder, rescue therapy is begun immediately (see Management, The prognosis of a newborn in hyperammonemic coma depends on the duration of elevated ammonia level, not the height of the ammonia level or the presence/absence of seizures [ After successful rescue from neonatal hyperammonemic coma, infants with severe neonatal-onset OTC deficiency can easily become hyperammonemic again despite a low-protein diet and treatment with an oral ammonia scavenger. Even on maximum ammonia scavenger therapy a neonate with severe OTC deficiency may only tolerate 1.5 g/kg/day of protein (the minimum amount needed to grow), and growth may be along the third percentile for length. After neonatal rescue therapy, a child with severe neonatal-onset disease can also experience a "honeymoon" period in which the protein tolerance is so high, due to rapid growth, that the child is metabolically stable for some months before experiencing frequent hyperammonemic episodes. Typically, a liver transplant is required to prevent life-threatening hyperammonemic episodes, avert the effect of recurrent hyperammonemia on the brain, and improve quality of life. The overall outcome depends on the severity of brain damage during the initial hyperammonemic crisis and during subsequent hyperammonemic crises, as well as on the success of long-term treatment in maintaining metabolic balance and addressing complications of the disease. ## Post-Neonatal-Onset (Partial) OTC Deficiency Hemizygous males and heterozygous females with partial OTC deficiency can present from infancy to later childhood, adolescence, or adulthood [ When children, adolescents, or adults with post-neonatal-onset disease become encephalopathic they may reach Stage 2 coma [ A stressor can cause an individual with partial OTC deficiency to become symptomatic at any age. In general, the milder the disease, the later the onset and the stronger the stressor required to precipitate symptoms. Adults with very mild disease have become symptomatic after crush injury, following surgery [ ## Heterozygous Females The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs nonfavorable X-chromosome inactivation. The amount of OTC enzyme activity in the liver of a heterozygous female depends on the pattern of X-chromosome inactivation in her liver [ Previously, approximately 15% of heterozygous females were thought to become symptomatic during their lifetime [ Recent work suggests that some heterozygous females may be paucisymptomatic: while they may never have hyperammonemia or present with altered mental status, they may in fact have differences in cognitive capability, such as deficits in executive functioning and motor capability [ ## Complications of Neonatal-Onset and Post-Neonatal-Onset Disease Attention-deficit/hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [ Approximately half of school-age children with OTC deficiency were reported by their parents as having "internalizing problems" on the Child Behavior Checklist, including being withdrawn, depressed, and/or anxious, or having somatic complaints. Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents. Self-reported difficulties in social relationships, as well as anxiety and depression, have also been described in adults with OTC deficiency, including those who are "asymptomatic" [ Even heterozygous females who have never had biochemical evidence of hyperammonemia and therefore were thought to be asymptomatic, on further scrutiny have been shown to have mild cognitive impairments and deficits in executive function and fine motor tasks even when exhibiting normal IQ on neuropsychological testing. These deficits may be apparent only when these individuals are cognitively challenged [ Although metabolic strokes (involving the caudate and putamen and resulting in extrapyramidal syndromes) have been described in OTC deficiency and CPS1 deficiency [ Better neurologic outcomes are seen in infants with neonatal-onset disease who were treated soon after the onset of coma. During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged. Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [ Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic. Symptomatic individuals with urea cycle disorders are at risk of developing progressive growth impairment over time. Weight is not affected. Growth impairment has recently been shown to be possibly associated with reduced or borderline plasma branched-chain amino acid concentrations. Liver transplant appears to have a beneficial effect on linear growth [ Liver cell carcinoma has been described in a few older individuals (e.g., in a symptomatic heterozygous female age 66 years [ • Attention-deficit/hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [ • Approximately half of school-age children with OTC deficiency were reported by their parents as having "internalizing problems" on the Child Behavior Checklist, including being withdrawn, depressed, and/or anxious, or having somatic complaints. • Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents. • Self-reported difficulties in social relationships, as well as anxiety and depression, have also been described in adults with OTC deficiency, including those who are "asymptomatic" [ • During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged. • Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [ • Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic. • Symptomatic individuals with urea cycle disorders are at risk of developing progressive growth impairment over time. Weight is not affected. Growth impairment has recently been shown to be possibly associated with reduced or borderline plasma branched-chain amino acid concentrations. Liver transplant appears to have a beneficial effect on linear growth [ ## Genotype-Phenotype Correlations While the following genotype-phenotype correlations do in general exist, it is well established that significant medical problems (e.g., neonatal sepsis or other causes of newborn catabolism) can cause a severe, early presentation in an individual with an In general: Pathogenic missense variants that affect residues essential for catalysis, substrate binding, and folding severely impair or completely abolish OTC enzyme activity and result in neonatal-onset disease in hemizygous males [ Pathogenic nonsense variants, insertions, and deletions that cause frameshift of the open reading frame and single-nucleotide variants in canonic intronic splice sites result in complete absence of functional OTC and neonatal-onset disease in hemizygous males [ Females heterozygous for a pathogenic variant can develop symptoms of OTC deficiency later in life if X-chromosome inactivation in their hepatocytes is skewed in favor of the X chromosome with the pathogenic variant [ Amino acid substitutions that decrease OTC enzyme activity or stability may result in a post-neonatal-onset phenotype in hemizygous males [ • Pathogenic missense variants that affect residues essential for catalysis, substrate binding, and folding severely impair or completely abolish OTC enzyme activity and result in neonatal-onset disease in hemizygous males [ • Pathogenic nonsense variants, insertions, and deletions that cause frameshift of the open reading frame and single-nucleotide variants in canonic intronic splice sites result in complete absence of functional OTC and neonatal-onset disease in hemizygous males [ • Females heterozygous for a pathogenic variant can develop symptoms of OTC deficiency later in life if X-chromosome inactivation in their hepatocytes is skewed in favor of the X chromosome with the pathogenic variant [ • Amino acid substitutions that decrease OTC enzyme activity or stability may result in a post-neonatal-onset phenotype in hemizygous males [ ## Penetrance Penetrance for OTC deficiency is complete in hemizygous males. The following observations, which may erroneously be interpreted as evidence of incomplete penetrance, are in fact explained by X-chromosome inactivation and environmental factors: Heterozygous females who become symptomatic (the result of skewed X-chromosome inactivation) Hemizygous males with the same mild pathogenic variant, only some of whom develop symptoms (the result of differences in environmental stressors) • Heterozygous females who become symptomatic (the result of skewed X-chromosome inactivation) • Hemizygous males with the same mild pathogenic variant, only some of whom develop symptoms (the result of differences in environmental stressors) ## Prevalence OTC deficiency is thought to be the most common urea cycle defect (see An early estimated prevalence of OTC deficiency was 1:14,000 live births [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with germline intragenic ## Differential Diagnosis Neonatal-onset urea cycle disorders (UCDs) – N-acetylglutamate synthase (NAGS) deficiency, severe carbamyl phosphate synthetase I (CPSI) deficiency, argininosuccinate synthetase (ASS) deficiency ( Fulminant hepatitis / fulminant liver failure due to neonatal herpes simplex virus infection can cause severe neonatal hyperammonemia. Respiratory alkalosis is a typical finding in UCD and its presence clearly distinguishes a UCD from an organic acidemia presenting with hyperammonemia and ketoacidosis. However, when a child who has been in a coma for days becomes terminally ill, acidosis rather than respiratory alkalosis may be present. Later-onset of NAGS deficiency, CPSI deficiency, ASS deficiency ( Causes of generalized liver dysfunction (e.g., severe infection, multiorgan failure due to hypoxic ischemic or other injury, portal vein thrombosis) and decreased liver synthetic function (e.g., liver failure due to drug [acetaminophen] toxicity, vascular insult) resulting in hyperammonemia should also be considered in the differential diagnosis. • Neonatal-onset urea cycle disorders (UCDs) – N-acetylglutamate synthase (NAGS) deficiency, severe carbamyl phosphate synthetase I (CPSI) deficiency, argininosuccinate synthetase (ASS) deficiency ( • Fulminant hepatitis / fulminant liver failure due to neonatal herpes simplex virus infection can cause severe neonatal hyperammonemia. • Later-onset of NAGS deficiency, CPSI deficiency, ASS deficiency ( • Causes of generalized liver dysfunction (e.g., severe infection, multiorgan failure due to hypoxic ischemic or other injury, portal vein thrombosis) and decreased liver synthetic function (e.g., liver failure due to drug [acetaminophen] toxicity, vascular insult) resulting in hyperammonemia should also be considered in the differential diagnosis. ## Management Clinical management practices have been described in publications of the When OTC deficiency is suspected during the diagnostic evaluation (e.g., due to hyperammonemia, elevated glutamine, low-to-normal citrulline, and/or orotic aciduria), metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center. To establish the extent of disease and needs in an individual diagnosed with OTC deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of Ornithine Transcarbamylase (OTC) Deficiency Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). Plasma ammonia concentration Plasma amino acid analysis Laboratory values that reflect nutritional status (e.g., vitamin D level, ferritin, vitamin B Liver function tests (liver enzymes, bilirubin, albumin) PT/PTT & fibrinogen Renal function tests (BUN, creatinine) MOI = mode of inheritance After a new diagnosis of OTC deficiency in a child, the closest hospital and local pediatrician should also be informed. Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment is best provided by a metabolic physician / biochemical geneticist and a metabolic dietitian. In the Acute Inpatient Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency In the pediatric population CKRT (specifically CVVHD) is recommended for hyperammonemia. High-dose CKRT w/blood flow rate of 30-50 mL/min recommended for initial treatment of those w/ammonia level >1,000 μmol/L Intermittent HD recommended in those who require rapid ammonia clearance due to fast deterioration & signs of cerebral edema Regular CKRT can follow hemodialysis or high-dose CKRT for stabilization when blood ammonia level is <200 μmol/L [ An older patient can receive intermittent HD or high-dose CKRT & can also be switched to a CKRT for stabilization. Treatment utilizes an alternative pathway for excretion of excess nitrogen (see Nitrogen scavenger therapy is available as an IV infusion of a mixture of sodium phenylacetate & sodium benzoate for acute mgmt & as an oral preparation of phenylbutyrate or sodium benzoate for long-term maintenance therapy. Citrulline is supplemented at 170 mg/kg/day or 3.8 g/m Total energy provided should be 100%-120% estimated needs to ensure catabolism reversal. Provide calories from glucose & fat; resume protein intake (in the form of natural protein & an essential amino acid mix) ≤24 hrs after protein intake was discontinued. Use of a high glucose infusion rate supported by continuous insulin infusion to maintain high set point normoglycemia (140-180 mg/dL) as needed. Goal for a newborn in crisis: to deliver ≥100 kcal/kg/day, mostly from glucose & fat. Persons on hemodialysis or hemofiltration need adequate nutrition to overcome catabolism, as nutrients are removed by these procedures. Restart protein intake after 24 hrs, as deficiency of essential amino acids → protein breakdown & uncontrolled nitrogen release. Daily to 2x-wkly quantitative plasma amino acid analysis should guide nutritional therapy. Goal: to keep essential amino acid levels in normal range. Intubated & sedated persons may not show clinical signs of seizures, which are prevalent in acute hyperammonemia. EEG surveillance is thus highly recommended to allow EEG detection & subsequent treatment of seizures. Note: Phenobarbital is removed by dialysis & valproic acid is contraindicated in urea cycle disorders. No other interventions (besides ↓ ammonia level) have proven efficacy for neuroprotection in hyperammonemic coma due to a urea cycle disorder or other conditions. CKRT = continuous kidney replacement therapy; CVVHD = high-dose continuous venovenous hemodialysis; EEG = electroencephalogram/electroencephalographic; HD = hemodialysis; IV = intravenous Intravenous (IV) Ammonia Scavenger Therapy Protocol Used in OTC Deficiency and Carbamyl Phosphate Synthetase I (CPSI) Deficiency Loading dose given over 90 to 120 minutes Maintenance dose given over 24 hours If an affected person has symptomatic hyperammonemia and has not received a full dose of ammonia scavenger in the previous 12 hours, the affected person should first receive an IV bolus directly followed by maintenance infusion. Sodium phenylacetate / sodium benzoate must be diluted with sterile 10% dextrose before administration. The typical dilution is 1:10 for a final concentration of 10 mg/mL. Arginine infusion not to exceed 150 mg/kg/h Long-term treatment (including restriction of protein intake, use of nitrogen scavengers, and liver transplantation) is aimed at promoting growth and development and preventing hyperammonemic episodes. Long-Term Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements. When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia. Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [ Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [ ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; RDA = required daily allowance Brain damage from an initial hyperammonemic coma, frequent hyperammonemic episodes with moderate-to-severe hyperammonemia, and chronic hyperammonemia can lead to learning disabilities and intellectual disability. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Protein Intake for Individuals with Ornithine Transcarbamylase (OTC) Deficiency Individuals with asymptomatic or mild presentations may not require supplementation with essential amino acid medical foods if biochemical markers (plasma ammonia, glutamine, and essential amino acids) remain normal on a diet that meets or exceeds the RDA for protein. Essential amino acid supplementation, when needed, should provide 30%-50% of total protein. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. OTC deficiency is a diagnosis of compassionate allowance per the Social Security Administration. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. In neonatal-onset OTC deficiency diagnosed prenatally, prospective intravenous (IV) treatment with ammonia scavengers at maintenance dose within a few hours of birth (before the ammonia level rises) can prevent a hyperammonemic crisis and coma. Later on, prevention of hyperammonemic episodes is focused on restriction of dietary protein through low-protein diet and administration of oral nitrogen-scavenging drugs balanced with supplementation of essential amino acids (see No matter how mild OTC deficiency appears to be, stressors can at any age precipitate a hyperammonemic crisis that becomes life threatening. The fear of such an event, along with the restrictions on daily living imposed by the dietary therapy, prompt many families to consider liver transplantation even if the disease has been manageable up to that point with diet and medication. In severe, neonatal-onset urea cycle disorders, liver transplantation remains the most effective means of preventing further hyperammonemic crises and neurodevelopmental deterioration [ Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes. Living related donor livers are often considered for partial liver transplantation in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [ A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. Recommended Surveillance for Individuals with Ornithine Transcarbamylase (OTC) Deficiency In severe cases at least every 2 wks at start of therapy (or more often depending on stability of affected person). Slowly extend to every month, every 2 mos, every 3 mos, then every 6 mos, as possible. At least every 2 wks at start of therapy (or more often depending on stability of affected person). Slowly extend to every month, every 2 mos, every 3 mos, then every 4 mos, as possible. DD/ID = developmental delay / intellectual disability Avoid the following: Valproate Haloperidol Fasting Stress, especially physical stress; potentially also psychological stress Systemic corticosteroids because they cause catabolism, which can trigger a hyperammonemic crisis Note: If systemic corticosteroids need to be administered as a life-saving therapy (e.g., during a severe asthma attack or an anaphylactic reaction), a metabolic specialist should be consulted; at the same time, preemptive measures (e.g., increased calorie intake) should be instituted to prevent catabolism. Molecular genetic testing if the Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals). If diagnosis remains unclear after the newborn period OTC enzyme activity measurement in infant liver (males only) may be considered if the In general, for children with neonatal-onset disease, such testing cannot be performed rapidly enough to prevent a metabolic crisis. Therefore, preventive measures at birth should be instituted until such a time as the diagnosis can be ruled out; see description of prospective treatment in Any family member who is a potential liver donor should undergo molecular genetic testing to clarify the family member's genetic status so that those who do not have the See Heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period [ A symptomatic heterozygous female needs to be treated throughout pregnancy according to her pre-pregnancy protocol with adaptation for her needs during pregnancy. Care should be given to the increased protein needs in pregnancy and adjustment to intact versus essential amino acid supplementation may be needed. In the peripartum and immediate postpartum periods proactive measures to prevent catabolism include, for example, administration of a 10% dextrose solution with appropriate electrolytes at 1.5 times maintenance and addition of intralipids as needed to meet caloric requirements during these periods. In an asymptomatic female known to be heterozygous, precautions should be taken in the peripartum and postpartum period to prevent catabolism; in addition, measurement of ammonia levels and administration of dextrose should be considered as heterozygous females have become symptomatic for the first time in the peripartum period. For treatment of OTC deficiency, Clinical Trials Other strategies to reduce blood ammonia levels include attempts to modulate the microbiome ( In preclinical studies, genome editing holds great promise, with data showing in vivo correction of specific OTC alterations in the spf-ash mouse, as well as development of a "universal" vector which introduces an expression cassette with promoter and OTC cDNA into the OTC locus containing the mutation [ Animal models of OTC deficiency had been until recently limited to several mouse strains; however, the ease of genome editing will allow greater control and tailoring of animal models. Of particular note is the recent development of an OTC-deficient pig [ For the most current information see • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). • Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). • Plasma ammonia concentration • Plasma amino acid analysis • Laboratory values that reflect nutritional status (e.g., vitamin D level, ferritin, vitamin B • Liver function tests (liver enzymes, bilirubin, albumin) • PT/PTT & fibrinogen • Renal function tests (BUN, creatinine) • In the pediatric population CKRT (specifically CVVHD) is recommended for hyperammonemia. • High-dose CKRT w/blood flow rate of 30-50 mL/min recommended for initial treatment of those w/ammonia level >1,000 μmol/L • Intermittent HD recommended in those who require rapid ammonia clearance due to fast deterioration & signs of cerebral edema • Regular CKRT can follow hemodialysis or high-dose CKRT for stabilization when blood ammonia level is <200 μmol/L [ • An older patient can receive intermittent HD or high-dose CKRT & can also be switched to a CKRT for stabilization. • Treatment utilizes an alternative pathway for excretion of excess nitrogen (see • Nitrogen scavenger therapy is available as an IV infusion of a mixture of sodium phenylacetate & sodium benzoate for acute mgmt & as an oral preparation of phenylbutyrate or sodium benzoate for long-term maintenance therapy. • Citrulline is supplemented at 170 mg/kg/day or 3.8 g/m • Total energy provided should be 100%-120% estimated needs to ensure catabolism reversal. • Provide calories from glucose & fat; resume protein intake (in the form of natural protein & an essential amino acid mix) ≤24 hrs after protein intake was discontinued. • Use of a high glucose infusion rate supported by continuous insulin infusion to maintain high set point normoglycemia (140-180 mg/dL) as needed. Goal for a newborn in crisis: to deliver ≥100 kcal/kg/day, mostly from glucose & fat. • Persons on hemodialysis or hemofiltration need adequate nutrition to overcome catabolism, as nutrients are removed by these procedures. • Restart protein intake after 24 hrs, as deficiency of essential amino acids → protein breakdown & uncontrolled nitrogen release. • Daily to 2x-wkly quantitative plasma amino acid analysis should guide nutritional therapy. Goal: to keep essential amino acid levels in normal range. • Intubated & sedated persons may not show clinical signs of seizures, which are prevalent in acute hyperammonemia. EEG surveillance is thus highly recommended to allow EEG detection & subsequent treatment of seizures. • Note: Phenobarbital is removed by dialysis & valproic acid is contraindicated in urea cycle disorders. • No other interventions (besides ↓ ammonia level) have proven efficacy for neuroprotection in hyperammonemic coma due to a urea cycle disorder or other conditions. • Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See • Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. • Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements. • When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. • Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. • Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. • High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia. • Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m • Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [ • Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m • Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. • Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [ • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. OTC deficiency is a diagnosis of compassionate allowance per the Social Security Administration. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes. • Living related donor livers are often considered for partial liver transplantation in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [ • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • In severe cases at least every 2 wks at start of therapy (or more often depending on stability of affected person). • Slowly extend to every month, every 2 mos, every 3 mos, then every 6 mos, as possible. • At least every 2 wks at start of therapy (or more often depending on stability of affected person). • Slowly extend to every month, every 2 mos, every 3 mos, then every 4 mos, as possible. • Valproate • Haloperidol • Fasting • Stress, especially physical stress; potentially also psychological stress • Systemic corticosteroids because they cause catabolism, which can trigger a hyperammonemic crisis • Note: If systemic corticosteroids need to be administered as a life-saving therapy (e.g., during a severe asthma attack or an anaphylactic reaction), a metabolic specialist should be consulted; at the same time, preemptive measures (e.g., increased calorie intake) should be instituted to prevent catabolism. • Molecular genetic testing if the • Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals). If diagnosis remains unclear after the newborn period OTC enzyme activity measurement in infant liver (males only) may be considered if the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with OTC deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of Ornithine Transcarbamylase (OTC) Deficiency Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). Plasma ammonia concentration Plasma amino acid analysis Laboratory values that reflect nutritional status (e.g., vitamin D level, ferritin, vitamin B Liver function tests (liver enzymes, bilirubin, albumin) PT/PTT & fibrinogen Renal function tests (BUN, creatinine) MOI = mode of inheritance After a new diagnosis of OTC deficiency in a child, the closest hospital and local pediatrician should also be informed. Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). • Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). • Plasma ammonia concentration • Plasma amino acid analysis • Laboratory values that reflect nutritional status (e.g., vitamin D level, ferritin, vitamin B • Liver function tests (liver enzymes, bilirubin, albumin) • PT/PTT & fibrinogen • Renal function tests (BUN, creatinine) ## Treatment of Manifestations Treatment is best provided by a metabolic physician / biochemical geneticist and a metabolic dietitian. In the Acute Inpatient Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency In the pediatric population CKRT (specifically CVVHD) is recommended for hyperammonemia. High-dose CKRT w/blood flow rate of 30-50 mL/min recommended for initial treatment of those w/ammonia level >1,000 μmol/L Intermittent HD recommended in those who require rapid ammonia clearance due to fast deterioration & signs of cerebral edema Regular CKRT can follow hemodialysis or high-dose CKRT for stabilization when blood ammonia level is <200 μmol/L [ An older patient can receive intermittent HD or high-dose CKRT & can also be switched to a CKRT for stabilization. Treatment utilizes an alternative pathway for excretion of excess nitrogen (see Nitrogen scavenger therapy is available as an IV infusion of a mixture of sodium phenylacetate & sodium benzoate for acute mgmt & as an oral preparation of phenylbutyrate or sodium benzoate for long-term maintenance therapy. Citrulline is supplemented at 170 mg/kg/day or 3.8 g/m Total energy provided should be 100%-120% estimated needs to ensure catabolism reversal. Provide calories from glucose & fat; resume protein intake (in the form of natural protein & an essential amino acid mix) ≤24 hrs after protein intake was discontinued. Use of a high glucose infusion rate supported by continuous insulin infusion to maintain high set point normoglycemia (140-180 mg/dL) as needed. Goal for a newborn in crisis: to deliver ≥100 kcal/kg/day, mostly from glucose & fat. Persons on hemodialysis or hemofiltration need adequate nutrition to overcome catabolism, as nutrients are removed by these procedures. Restart protein intake after 24 hrs, as deficiency of essential amino acids → protein breakdown & uncontrolled nitrogen release. Daily to 2x-wkly quantitative plasma amino acid analysis should guide nutritional therapy. Goal: to keep essential amino acid levels in normal range. Intubated & sedated persons may not show clinical signs of seizures, which are prevalent in acute hyperammonemia. EEG surveillance is thus highly recommended to allow EEG detection & subsequent treatment of seizures. Note: Phenobarbital is removed by dialysis & valproic acid is contraindicated in urea cycle disorders. No other interventions (besides ↓ ammonia level) have proven efficacy for neuroprotection in hyperammonemic coma due to a urea cycle disorder or other conditions. CKRT = continuous kidney replacement therapy; CVVHD = high-dose continuous venovenous hemodialysis; EEG = electroencephalogram/electroencephalographic; HD = hemodialysis; IV = intravenous Intravenous (IV) Ammonia Scavenger Therapy Protocol Used in OTC Deficiency and Carbamyl Phosphate Synthetase I (CPSI) Deficiency Loading dose given over 90 to 120 minutes Maintenance dose given over 24 hours If an affected person has symptomatic hyperammonemia and has not received a full dose of ammonia scavenger in the previous 12 hours, the affected person should first receive an IV bolus directly followed by maintenance infusion. Sodium phenylacetate / sodium benzoate must be diluted with sterile 10% dextrose before administration. The typical dilution is 1:10 for a final concentration of 10 mg/mL. Arginine infusion not to exceed 150 mg/kg/h Long-term treatment (including restriction of protein intake, use of nitrogen scavengers, and liver transplantation) is aimed at promoting growth and development and preventing hyperammonemic episodes. Long-Term Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements. When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia. Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [ Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [ ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; RDA = required daily allowance Brain damage from an initial hyperammonemic coma, frequent hyperammonemic episodes with moderate-to-severe hyperammonemia, and chronic hyperammonemia can lead to learning disabilities and intellectual disability. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Protein Intake for Individuals with Ornithine Transcarbamylase (OTC) Deficiency Individuals with asymptomatic or mild presentations may not require supplementation with essential amino acid medical foods if biochemical markers (plasma ammonia, glutamine, and essential amino acids) remain normal on a diet that meets or exceeds the RDA for protein. Essential amino acid supplementation, when needed, should provide 30%-50% of total protein. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. OTC deficiency is a diagnosis of compassionate allowance per the Social Security Administration. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • In the pediatric population CKRT (specifically CVVHD) is recommended for hyperammonemia. • High-dose CKRT w/blood flow rate of 30-50 mL/min recommended for initial treatment of those w/ammonia level >1,000 μmol/L • Intermittent HD recommended in those who require rapid ammonia clearance due to fast deterioration & signs of cerebral edema • Regular CKRT can follow hemodialysis or high-dose CKRT for stabilization when blood ammonia level is <200 μmol/L [ • An older patient can receive intermittent HD or high-dose CKRT & can also be switched to a CKRT for stabilization. • Treatment utilizes an alternative pathway for excretion of excess nitrogen (see • Nitrogen scavenger therapy is available as an IV infusion of a mixture of sodium phenylacetate & sodium benzoate for acute mgmt & as an oral preparation of phenylbutyrate or sodium benzoate for long-term maintenance therapy. • Citrulline is supplemented at 170 mg/kg/day or 3.8 g/m • Total energy provided should be 100%-120% estimated needs to ensure catabolism reversal. • Provide calories from glucose & fat; resume protein intake (in the form of natural protein & an essential amino acid mix) ≤24 hrs after protein intake was discontinued. • Use of a high glucose infusion rate supported by continuous insulin infusion to maintain high set point normoglycemia (140-180 mg/dL) as needed. Goal for a newborn in crisis: to deliver ≥100 kcal/kg/day, mostly from glucose & fat. • Persons on hemodialysis or hemofiltration need adequate nutrition to overcome catabolism, as nutrients are removed by these procedures. • Restart protein intake after 24 hrs, as deficiency of essential amino acids → protein breakdown & uncontrolled nitrogen release. • Daily to 2x-wkly quantitative plasma amino acid analysis should guide nutritional therapy. Goal: to keep essential amino acid levels in normal range. • Intubated & sedated persons may not show clinical signs of seizures, which are prevalent in acute hyperammonemia. EEG surveillance is thus highly recommended to allow EEG detection & subsequent treatment of seizures. • Note: Phenobarbital is removed by dialysis & valproic acid is contraindicated in urea cycle disorders. • No other interventions (besides ↓ ammonia level) have proven efficacy for neuroprotection in hyperammonemic coma due to a urea cycle disorder or other conditions. • Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See • Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. • Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements. • When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. • Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. • Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. • High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia. • Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m • Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [ • Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m • Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. • Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [ • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. OTC deficiency is a diagnosis of compassionate allowance per the Social Security Administration. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Long-Term Treatment Long-term treatment (including restriction of protein intake, use of nitrogen scavengers, and liver transplantation) is aimed at promoting growth and development and preventing hyperammonemic episodes. Long-Term Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements. When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia. Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [ Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [ ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; RDA = required daily allowance Brain damage from an initial hyperammonemic coma, frequent hyperammonemic episodes with moderate-to-severe hyperammonemia, and chronic hyperammonemia can lead to learning disabilities and intellectual disability. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Protein Intake for Individuals with Ornithine Transcarbamylase (OTC) Deficiency Individuals with asymptomatic or mild presentations may not require supplementation with essential amino acid medical foods if biochemical markers (plasma ammonia, glutamine, and essential amino acids) remain normal on a diet that meets or exceeds the RDA for protein. Essential amino acid supplementation, when needed, should provide 30%-50% of total protein. • Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See • Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. • Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements. • When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. • Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. • Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. • High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia. • Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m • Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [ • Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m • Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. • Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [ ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. OTC deficiency is a diagnosis of compassionate allowance per the Social Security Administration. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. OTC deficiency is a diagnosis of compassionate allowance per the Social Security Administration. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Prevention of Primary Manifestations In neonatal-onset OTC deficiency diagnosed prenatally, prospective intravenous (IV) treatment with ammonia scavengers at maintenance dose within a few hours of birth (before the ammonia level rises) can prevent a hyperammonemic crisis and coma. Later on, prevention of hyperammonemic episodes is focused on restriction of dietary protein through low-protein diet and administration of oral nitrogen-scavenging drugs balanced with supplementation of essential amino acids (see No matter how mild OTC deficiency appears to be, stressors can at any age precipitate a hyperammonemic crisis that becomes life threatening. The fear of such an event, along with the restrictions on daily living imposed by the dietary therapy, prompt many families to consider liver transplantation even if the disease has been manageable up to that point with diet and medication. In severe, neonatal-onset urea cycle disorders, liver transplantation remains the most effective means of preventing further hyperammonemic crises and neurodevelopmental deterioration [ Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes. Living related donor livers are often considered for partial liver transplantation in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [ A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes. • Living related donor livers are often considered for partial liver transplantation in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [ • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. ## Medical and Dietary Prevention of Hyperammonemia In neonatal-onset OTC deficiency diagnosed prenatally, prospective intravenous (IV) treatment with ammonia scavengers at maintenance dose within a few hours of birth (before the ammonia level rises) can prevent a hyperammonemic crisis and coma. Later on, prevention of hyperammonemic episodes is focused on restriction of dietary protein through low-protein diet and administration of oral nitrogen-scavenging drugs balanced with supplementation of essential amino acids (see ## Liver Transplantation No matter how mild OTC deficiency appears to be, stressors can at any age precipitate a hyperammonemic crisis that becomes life threatening. The fear of such an event, along with the restrictions on daily living imposed by the dietary therapy, prompt many families to consider liver transplantation even if the disease has been manageable up to that point with diet and medication. In severe, neonatal-onset urea cycle disorders, liver transplantation remains the most effective means of preventing further hyperammonemic crises and neurodevelopmental deterioration [ Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes. Living related donor livers are often considered for partial liver transplantation in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [ A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes. • Living related donor livers are often considered for partial liver transplantation in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [ • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. • A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient. • After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her. • Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, and additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable. ## Surveillance Recommended Surveillance for Individuals with Ornithine Transcarbamylase (OTC) Deficiency In severe cases at least every 2 wks at start of therapy (or more often depending on stability of affected person). Slowly extend to every month, every 2 mos, every 3 mos, then every 6 mos, as possible. At least every 2 wks at start of therapy (or more often depending on stability of affected person). Slowly extend to every month, every 2 mos, every 3 mos, then every 4 mos, as possible. DD/ID = developmental delay / intellectual disability • In severe cases at least every 2 wks at start of therapy (or more often depending on stability of affected person). • Slowly extend to every month, every 2 mos, every 3 mos, then every 6 mos, as possible. • At least every 2 wks at start of therapy (or more often depending on stability of affected person). • Slowly extend to every month, every 2 mos, every 3 mos, then every 4 mos, as possible. ## Agents/Circumstances to Avoid Avoid the following: Valproate Haloperidol Fasting Stress, especially physical stress; potentially also psychological stress Systemic corticosteroids because they cause catabolism, which can trigger a hyperammonemic crisis Note: If systemic corticosteroids need to be administered as a life-saving therapy (e.g., during a severe asthma attack or an anaphylactic reaction), a metabolic specialist should be consulted; at the same time, preemptive measures (e.g., increased calorie intake) should be instituted to prevent catabolism. • Valproate • Haloperidol • Fasting • Stress, especially physical stress; potentially also psychological stress • Systemic corticosteroids because they cause catabolism, which can trigger a hyperammonemic crisis • Note: If systemic corticosteroids need to be administered as a life-saving therapy (e.g., during a severe asthma attack or an anaphylactic reaction), a metabolic specialist should be consulted; at the same time, preemptive measures (e.g., increased calorie intake) should be instituted to prevent catabolism. ## Evaluation of Relatives at Risk Molecular genetic testing if the Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals). If diagnosis remains unclear after the newborn period OTC enzyme activity measurement in infant liver (males only) may be considered if the In general, for children with neonatal-onset disease, such testing cannot be performed rapidly enough to prevent a metabolic crisis. Therefore, preventive measures at birth should be instituted until such a time as the diagnosis can be ruled out; see description of prospective treatment in Any family member who is a potential liver donor should undergo molecular genetic testing to clarify the family member's genetic status so that those who do not have the See • Molecular genetic testing if the • Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals). If diagnosis remains unclear after the newborn period OTC enzyme activity measurement in infant liver (males only) may be considered if the ## For Early Diagnosis and Treatment Molecular genetic testing if the Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals). If diagnosis remains unclear after the newborn period OTC enzyme activity measurement in infant liver (males only) may be considered if the In general, for children with neonatal-onset disease, such testing cannot be performed rapidly enough to prevent a metabolic crisis. Therefore, preventive measures at birth should be instituted until such a time as the diagnosis can be ruled out; see description of prospective treatment in • Molecular genetic testing if the • Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals). If diagnosis remains unclear after the newborn period OTC enzyme activity measurement in infant liver (males only) may be considered if the ## For Liver Donation Any family member who is a potential liver donor should undergo molecular genetic testing to clarify the family member's genetic status so that those who do not have the See ## Pregnancy Management Heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period [ A symptomatic heterozygous female needs to be treated throughout pregnancy according to her pre-pregnancy protocol with adaptation for her needs during pregnancy. Care should be given to the increased protein needs in pregnancy and adjustment to intact versus essential amino acid supplementation may be needed. In the peripartum and immediate postpartum periods proactive measures to prevent catabolism include, for example, administration of a 10% dextrose solution with appropriate electrolytes at 1.5 times maintenance and addition of intralipids as needed to meet caloric requirements during these periods. In an asymptomatic female known to be heterozygous, precautions should be taken in the peripartum and postpartum period to prevent catabolism; in addition, measurement of ammonia levels and administration of dextrose should be considered as heterozygous females have become symptomatic for the first time in the peripartum period. ## Therapies Under Investigation For treatment of OTC deficiency, Clinical Trials Other strategies to reduce blood ammonia levels include attempts to modulate the microbiome ( In preclinical studies, genome editing holds great promise, with data showing in vivo correction of specific OTC alterations in the spf-ash mouse, as well as development of a "universal" vector which introduces an expression cassette with promoter and OTC cDNA into the OTC locus containing the mutation [ Animal models of OTC deficiency had been until recently limited to several mouse strains; however, the ease of genome editing will allow greater control and tailoring of animal models. Of particular note is the recent development of an OTC-deficient pig [ For the most current information see ## Genetic Counseling Ornithine transcarbamylase (OTC) deficiency is inherited in an X-linked manner. The father of a male with an In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote. The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ The affected male may have a If a molecular diagnosis has been established in the proband, molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. A female who is heterozygous for an Note: Misattributed parentage can also be explored as an alternative explanation for an apparent Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, If the proband represents a simplex case and has an If the mother of the proband has an If the father of a female proband has an If the proband represents a simplex case and has an Males with neonatal-onset OTC deficiency used to die before reproductive age or be too debilitated to reproduce. However, prospective treatment as soon as the child is born and improved rescue therapy followed by liver transplant now allow some such males to reach reproductive age and reproduce. Males with late-onset, moderate-to-mild partial OTC deficiency transmit the All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, None of their sons. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, Note: Molecular genetic testing may be able to identify the family member in whom a Molecular genetic testing to identify female heterozygotes is possible if the OTC deficiency-causing pathogenic variant has been identified in the family. Note: The phenotype of females who are heterozygous for an If the OTC deficiency-causing pathogenic variant in the family cannot be identified, an allopurinol challenge may help clarify the genetic status of female family members (see See Both asymptomatic and symptomatic women who are heterozygous for an The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an OTC deficiency-causing pathogenic variant, or are at risk of having an OTC deficiency-causing pathogenic variant. Once the OTC deficiency-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for OTC deficiency are possible. Because males with a neonatal presentation are more severely affected than heterozygous females, knowing the fetal sex may provide additional information helpful to families and health care providers in the newborn period. In a family with a history of neonatal-onset disease, it is likely (but not certain) that subsequently affected males will have a similar presentation. Because of the unpredictability of X-chromosome inactivation, it is not possible to predict the presentation in heterozygous females (see • The father of a male with an • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote. • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ • The affected male may have a • The mother may be a heterozygote. • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ • The affected male may have a • If a molecular diagnosis has been established in the proband, molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • The mother may be a heterozygote. • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ • The affected male may have a • A female who is heterozygous for an • Note: Misattributed parentage can also be explored as an alternative explanation for an apparent • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, • If the proband represents a simplex case and has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, • If the mother of the proband has an • If the father of a female proband has an • If the proband represents a simplex case and has an • Males with neonatal-onset OTC deficiency used to die before reproductive age or be too debilitated to reproduce. However, prospective treatment as soon as the child is born and improved rescue therapy followed by liver transplant now allow some such males to reach reproductive age and reproduce. • Males with late-onset, moderate-to-mild partial OTC deficiency transmit the • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • None of their sons. • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • Both asymptomatic and symptomatic women who are heterozygous for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an OTC deficiency-causing pathogenic variant, or are at risk of having an OTC deficiency-causing pathogenic variant. • In a family with a history of neonatal-onset disease, it is likely (but not certain) that subsequently affected males will have a similar presentation. • Because of the unpredictability of X-chromosome inactivation, it is not possible to predict the presentation in heterozygous females (see ## Mode of Inheritance Ornithine transcarbamylase (OTC) deficiency is inherited in an X-linked manner. ## Risk to Family Members The father of a male with an In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case): The mother may be a heterozygote. The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ The affected male may have a If a molecular diagnosis has been established in the proband, molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. A female who is heterozygous for an Note: Misattributed parentage can also be explored as an alternative explanation for an apparent Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has an Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, If the proband represents a simplex case and has an If the mother of the proband has an If the father of a female proband has an If the proband represents a simplex case and has an Males with neonatal-onset OTC deficiency used to die before reproductive age or be too debilitated to reproduce. However, prospective treatment as soon as the child is born and improved rescue therapy followed by liver transplant now allow some such males to reach reproductive age and reproduce. Males with late-onset, moderate-to-mild partial OTC deficiency transmit the All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, None of their sons. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, Note: Molecular genetic testing may be able to identify the family member in whom a • The father of a male with an • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case): • The mother may be a heterozygote. • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ • The affected male may have a • The mother may be a heterozygote. • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ • The affected male may have a • If a molecular diagnosis has been established in the proband, molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • The mother may be a heterozygote. • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [ • The affected male may have a • A female who is heterozygous for an • Note: Misattributed parentage can also be explored as an alternative explanation for an apparent • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, • If the proband represents a simplex case and has an • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation (see Clinical Description, • If the mother of the proband has an • If the father of a female proband has an • If the proband represents a simplex case and has an • Males with neonatal-onset OTC deficiency used to die before reproductive age or be too debilitated to reproduce. However, prospective treatment as soon as the child is born and improved rescue therapy followed by liver transplant now allow some such males to reach reproductive age and reproduce. • Males with late-onset, moderate-to-mild partial OTC deficiency transmit the • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, • None of their sons. • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, ## Heterozygote Detection Molecular genetic testing to identify female heterozygotes is possible if the OTC deficiency-causing pathogenic variant has been identified in the family. Note: The phenotype of females who are heterozygous for an If the OTC deficiency-causing pathogenic variant in the family cannot be identified, an allopurinol challenge may help clarify the genetic status of female family members (see ## Related Genetic Counseling Issues See Both asymptomatic and symptomatic women who are heterozygous for an The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an OTC deficiency-causing pathogenic variant, or are at risk of having an OTC deficiency-causing pathogenic variant. • Both asymptomatic and symptomatic women who are heterozygous for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an OTC deficiency-causing pathogenic variant, or are at risk of having an OTC deficiency-causing pathogenic variant. ## Prenatal Testing and Preimplantation Genetic Testing Once the OTC deficiency-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for OTC deficiency are possible. Because males with a neonatal presentation are more severely affected than heterozygous females, knowing the fetal sex may provide additional information helpful to families and health care providers in the newborn period. In a family with a history of neonatal-onset disease, it is likely (but not certain) that subsequently affected males will have a similar presentation. Because of the unpredictability of X-chromosome inactivation, it is not possible to predict the presentation in heterozygous females (see • In a family with a history of neonatal-onset disease, it is likely (but not certain) that subsequently affected males will have a similar presentation. • Because of the unpredictability of X-chromosome inactivation, it is not possible to predict the presentation in heterozygous females (see ## Resources TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom Health Resources & Services Administration Children's National Medical Center • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • • • • • • • • • Health Resources & Services Administration • • • • • • • • • Children's National Medical Center • ## Molecular Genetics Ornithine Transcarbamylase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ornithine Transcarbamylase Deficiency ( OTC catalyzes formation of citrulline from ornithine and carbamylphosphate in the liver and small intestine [ Reduced abundance or complete absence of functional OTC enzyme can result from the following types of pathogenic variants: Frameshift and nonsense variants that cause premature protein termination, missense variants that impair or abolish substrate binding and catalysis, and missense variants that reduce OTC enzyme stability and/or prevent its folding [ Variants that affect mRNA splicing result either in a defective Variants in Structural variants that result in defective • Frameshift and nonsense variants that cause premature protein termination, missense variants that impair or abolish substrate binding and catalysis, and missense variants that reduce OTC enzyme stability and/or prevent its folding [ • Variants that affect mRNA splicing result either in a defective • Variants in • Structural variants that result in defective ## Molecular Pathogenesis OTC catalyzes formation of citrulline from ornithine and carbamylphosphate in the liver and small intestine [ Reduced abundance or complete absence of functional OTC enzyme can result from the following types of pathogenic variants: Frameshift and nonsense variants that cause premature protein termination, missense variants that impair or abolish substrate binding and catalysis, and missense variants that reduce OTC enzyme stability and/or prevent its folding [ Variants that affect mRNA splicing result either in a defective Variants in Structural variants that result in defective • Frameshift and nonsense variants that cause premature protein termination, missense variants that impair or abolish substrate binding and catalysis, and missense variants that reduce OTC enzyme stability and/or prevent its folding [ • Variants that affect mRNA splicing result either in a defective • Variants in • Structural variants that result in defective ## Chapter Notes We would like to acknowledge the support of the National Urea Cycle Disorders Foundation (NUCDF), which partners with physicians with a special focus on urea cycle disorders to further the well-being of patients with urea cycle disorders. We would also like to acknowledge the Urea Cycle Disorders Consortium (UCDC) which has provided a platform for our work and has furthered our knowledge and understanding of OTC deficiency. 26 May 2022 (ha) Revision: variants added to 2 December 2021 (ha) Comprehensive update posted live 14 April 2016 (ma) Comprehensive update posted live 29 August 2013 (me) Review posted live 31 December 2012 (ul-k) Original submission • 26 May 2022 (ha) Revision: variants added to • 2 December 2021 (ha) Comprehensive update posted live • 14 April 2016 (ma) Comprehensive update posted live • 29 August 2013 (me) Review posted live • 31 December 2012 (ul-k) Original submission ## Author Notes ## Acknowledgments We would like to acknowledge the support of the National Urea Cycle Disorders Foundation (NUCDF), which partners with physicians with a special focus on urea cycle disorders to further the well-being of patients with urea cycle disorders. We would also like to acknowledge the Urea Cycle Disorders Consortium (UCDC) which has provided a platform for our work and has furthered our knowledge and understanding of OTC deficiency. ## Revision History 26 May 2022 (ha) Revision: variants added to 2 December 2021 (ha) Comprehensive update posted live 14 April 2016 (ma) Comprehensive update posted live 29 August 2013 (me) Review posted live 31 December 2012 (ul-k) Original submission • 26 May 2022 (ha) Revision: variants added to • 2 December 2021 (ha) Comprehensive update posted live • 14 April 2016 (ma) Comprehensive update posted live • 29 August 2013 (me) Review posted live • 31 December 2012 (ul-k) Original submission ## References ## Literature Cited	[]	29/8/2013	2/12/2021	26/5/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pacs1-ndd	pacs1-ndd	[ "Schuurs-Hoeijmakers Syndrome", "Schuurs-Hoeijmakers Syndrome", "Phosphofurin acidic cluster sorting protein 1", "PACS1", "PACS1 Neurodevelopmental Disorder" ]		Laina Lusk, Simone Smith, Christa Martin, Cora Taylor, Wendy Chung	Summary The diagnosis of	## Diagnosis Developmental delay and/or intellectual disability that are typically moderate, although range includes mild to severe delays Hypotonia Feeding difficulties Epilepsy (partial and tonic seizures reported, often with early or infantile onset; well-controlled by medication) Behavioral features (e.g., autism spectrum disorder, temper tantrums, aggression); overall friendly disposition in individuals of all ages Characteristic facial features (e.g., hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth) Congenital heart anomalies (e.g., atrial septal defect, ventral septal defect, patent ductus arteriosus) The diagnosis of Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Note: (1) Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Since • Developmental delay and/or intellectual disability that are typically moderate, although range includes mild to severe delays • Hypotonia • Feeding difficulties • Epilepsy (partial and tonic seizures reported, often with early or infantile onset; well-controlled by medication) • Behavioral features (e.g., autism spectrum disorder, temper tantrums, aggression); overall friendly disposition in individuals of all ages • Characteristic facial features (e.g., hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth) • Congenital heart anomalies (e.g., atrial septal defect, ventral septal defect, patent ductus arteriosus) ## Suggestive Findings Developmental delay and/or intellectual disability that are typically moderate, although range includes mild to severe delays Hypotonia Feeding difficulties Epilepsy (partial and tonic seizures reported, often with early or infantile onset; well-controlled by medication) Behavioral features (e.g., autism spectrum disorder, temper tantrums, aggression); overall friendly disposition in individuals of all ages Characteristic facial features (e.g., hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth) Congenital heart anomalies (e.g., atrial septal defect, ventral septal defect, patent ductus arteriosus) • Developmental delay and/or intellectual disability that are typically moderate, although range includes mild to severe delays • Hypotonia • Feeding difficulties • Epilepsy (partial and tonic seizures reported, often with early or infantile onset; well-controlled by medication) • Behavioral features (e.g., autism spectrum disorder, temper tantrums, aggression); overall friendly disposition in individuals of all ages • Characteristic facial features (e.g., hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth) • Congenital heart anomalies (e.g., atrial septal defect, ventral septal defect, patent ductus arteriosus) ## Establishing the Diagnosis The diagnosis of Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Note: (1) Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Since ## Clinical Characteristics To date, approximately 35 individuals with Select Features of Moderate impairment in most Language skills more severely affected than motor skills Partial & tonic seizures Infantile seizures reported DD = developmental delay; GI = gastrointestinal; ID = intellectual disability Language skills are universally affected, and more severely affected than motor skills. Most individuals develop verbal language, with several beginning to speak in their second year of life [ Two individuals were greater than the 90th percentile for weight and/or length at birth, but had normal growth parameters at age three years and age 17 years [ No genotype-phenotype correlations have been identified. To date, penetrance appears to be 100%. Prevalence is currently unknown. Approximately 35 individuals with • Moderate impairment in most • Language skills more severely affected than motor skills • Partial & tonic seizures • Infantile seizures reported ## Clinical Description To date, approximately 35 individuals with Select Features of Moderate impairment in most Language skills more severely affected than motor skills Partial & tonic seizures Infantile seizures reported DD = developmental delay; GI = gastrointestinal; ID = intellectual disability Language skills are universally affected, and more severely affected than motor skills. Most individuals develop verbal language, with several beginning to speak in their second year of life [ Two individuals were greater than the 90th percentile for weight and/or length at birth, but had normal growth parameters at age three years and age 17 years [ • Moderate impairment in most • Language skills more severely affected than motor skills • Partial & tonic seizures • Infantile seizures reported ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance To date, penetrance appears to be 100%. ## Prevalence Prevalence is currently unknown. Approximately 35 individuals with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because the phenotypic features associated with ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/severe feeding/growth issues or aspiration risk. Additional eval may be needed for constipation symptoms. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none demonstrated effective specifically for this disorder. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, movement disorders Individuals with See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in those w/severe feeding/growth issues or aspiration risk. • Additional eval may be needed for constipation symptoms. • Community or • Social work involvement for parental support; • Home nursing referral. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, movement disorders ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/severe feeding/growth issues or aspiration risk. Additional eval may be needed for constipation symptoms. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in those w/severe feeding/growth issues or aspiration risk. • Additional eval may be needed for constipation symptoms. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Many ASMs may be effective; none demonstrated effective specifically for this disorder. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Many ASMs may be effective; none demonstrated effective specifically for this disorder. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, movement disorders • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, movement disorders ## Agents/Circumstances to Avoid Individuals with ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling All of the 31 probands with Molecular genetic testing is recommended for the parents of a proband with an apparent If the Theoretically, if the parent is the individual in whom the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All of the 31 probands with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • Theoretically, if the parent is the individual in whom the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members All of the 31 probands with Molecular genetic testing is recommended for the parents of a proband with an apparent If the Theoretically, if the parent is the individual in whom the • All of the 31 probands with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • Theoretically, if the parent is the individual in whom the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources PO Box 2058 Sandwhich MA 02563 United Kingdom • • • • • PO Box 2058 • Sandwhich MA 02563 • • • United Kingdom • • • • ## Molecular Genetics PACS1 Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PACS1 Neurodevelopmental Disorder ( An R Identification of several individuals with the same Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis An R Identification of several individuals with the same Notable Variants listed in the table have been provided by the authors. ## Chapter Notes 16 July 2020 (sw) Review posted live 30 March 2020 (wc) Original submission • 16 July 2020 (sw) Review posted live • 30 March 2020 (wc) Original submission ## Revision History 16 July 2020 (sw) Review posted live 30 March 2020 (wc) Original submission • 16 July 2020 (sw) Review posted live • 30 March 2020 (wc) Original submission ## References ## Literature Cited	[ "L Chad, B HY Chung, CR Marshall, D Merico, R Babul-Hirji, DJ Stavropoulos, D Chitayat. Global developmental delay and characteristic facial features associated with PACS1 gene mutation – report of two cases.. J Med Genet. 2015;52:A1", "AK Dutta. Schuurs-Hoeijmakers syndrome in a patient from India.. Am J Med Genet Part A. 2019;179:522-4", "D Gadzicki, D Döcker, M Schubach, M Menzel, B Schmorl, F Stellmer, S Biskup, D Bartholdi. Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability.. Clin Genet. 2015;88:300-2", "Y Hoshino, T Enokizono, K Imagawa, R Tanaka, H Suzuki, H Fukushima, J Arai, R Sumazaki, T Uehara, T Takenouchi, K. Kosaki. Schuurs-Hoeijmakers syndrome in two patients from Japan.. Am J Med Genet Part A. 2019;179:341-3", "J Kaplanis, N Akawi, G Gallone, JF McRae, E Prigmore, CF Wright, DR Fitzpatrick, HV Firth, JC Barrett, ME Hurles. Deciphering Developmental Disorders study. Exome-wide assessment of the functional impact and pathogenicity of multinucleotide mutations.. Genome Res. 2019;29:1047-56", "A Martinez-Monseny, M Bolasell, C Arjona, L Martorell, D Yubero, J Arsmtrong, J Maynou, G Fernandez, M del Carmen Salgado, F Palau, M. Serrano. Mutation of PACS1: the milder end of the spectrum.. Clin Dysmorphol. 2018;27:148-50", "N Miyake, S Ozasa, H Mabe, S Kimura, M Shiina, E Imagawa, S Miyatake, M Nakashima, T Mizuguchi, A Takata, K Ogata, N. Matsumoto. A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome.. Clinical Genet. 2018;93:929-30", "M Pefkianaki, A Schneider, JE Capasso, B Wasserman, T Bardakjian, AV Levin. Ocular manifestations of PACS1 mutation.. J AAPOS. 2018;22:323-5", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "J HM Schuurs-Hoeijmakers, ML Landsverk, N Foulds, MK Kukolich, RH Gavrilova, S Greville-Heygate, A Hanson-Kahn, JA Bernstein, J Glass, D Chitayat, TA Burrow, A Husami, K Collins, K Wusik, N van der Aa, F Kooy, K Tatton Brown, D Gadzicki, U Kini, S Alvarez, A Fernández-Jaén, F McGehee, K Selby, M Tarailo-Graovac, M Van Allen, C DM van Karnebeek, DJ Stavropoulos, CR Marshall, D Merico, A Gregor, C Zweier, RJ Hopkin, Y Wing-Yiu Chu, B HY Chung, B BA de Vries, K Devriendt, ME Hurles, HG Brunner. DDD study. Clinical delineation of the PACS1-related syndrome—report on 19 patients.. Am J Med Genet. 2016;170:670-5", "J HM Schuurs-Hoeijmakers, EC Oh, L Vissers. ELM, Swinkels M EM, Gilissen C, Willemsen MA, Holvoet M, Steehouwer M, Veltman JA, de Vries B BA, van Bokhoven H, de Brouwer A PM, Katsanis N, Devriendt K, Brunner HG. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.. Am J Hum Genet. 2012;91:1122-7", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "D Stern, MT Cho, R Chikarmane, R Willaert, K Retterer, F Kendall, M Deardorff, S Hopkins, E Bedoukian, A Slavotinek, S Schrier Vergano, B Spangler, M McDonald, A McConkie-Rosell, BK Burton, KH Kim, N Oundjian, D Kronn, N Chandy, B Baskin, MJ Guillen Sacoto, IM Wentzensen, HM McLaughlin, D McKnight, WK Chung. Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.. Clin Genet. 2017;92:221-3" ]	16/7/2020			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pai-1-def	pai-1-def	[ "Complete PAI-1 Deficiency", "Homozygous PAI-1 Deficiency", "Complete PAI-1 Deficiency", "Homozygous PAI-1 Deficiency", "Plasminogen activator inhibitor 1", "SERPINE1", "Complete Plasminogen Activator Inhibitor 1 Deficiency" ]	Complete Plasminogen Activator Inhibitor 1 Deficiency	Meadow Heiman, Sweta Gupta, Magdalena Lewandowska, Amy D Shapiro	Summary Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life-threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding does not occur. While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males due to menorrhagia and postpartum hemorrhage. Fewer than ten families with complete PAI-1 deficiency have been reported to date. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant. In one family from this Old Order Amish population, seven individuals were diagnosed to have cardiac fibrosis of varying degrees. The diagnosis of complete PAI-1 deficiency is established in a proband when PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL and/or biallelic Complete PAI-1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Complete plasminogen activator inhibitor 1 (PAI-1) deficiency Bleeding disorder that typically presents as: Delayed bleeding following injury, trauma, or surgery In females, menorrhagia and abnormal bleeding with pregnancy Absence of other known bleeding disorders including: von Willebrand disease Deficiencies of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII, or factor V & VIII Alpha-2-antiplasmin deficiency Factor XIII deficiency Platelet function disorders (including Scott syndrome and Quebec platelet disorder) Free tissue plasminogen activator (tPA) in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in individuals with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity. Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in individuals with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency. PAI-1 specific assays: PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [ PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [ Note: If the PAI-1 antigen level is normal and PAI-1 activity is decreased, the phenotype is referred to as qualitative PAI-1deficiency or dysfunctional PAI-1 [ The diagnosis of complete PAI-1 deficiency PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL. Note: (1) Because the majority of PAI-1 activity assays are used to detect increased PAI-1 activity rather than decreased PAI-1 activity, they lack the sensitivity to differentiate between low-normal activity and complete deficiency. Thus, a PAI-1 activity level of zero is often reported to be within the normal limits. (2) PAI-1 activity also demonstrates diurnal variation: because higher levels are observed in the morning and lower levels in the afternoon, the activity should be assayed in a sample drawn in the morning. AND/OR Biallelic Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Note: Targeted analysis for the For an introduction to multigene panels click Molecular Genetic Testing Used in Complete Plasminogen Activator Inhibitor 1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click One reported individual with a lifelong history of bleeding associated with surgery and trauma had a heterozygous missense Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no exon or multiexon • Delayed bleeding following injury, trauma, or surgery • In females, menorrhagia and abnormal bleeding with pregnancy • von Willebrand disease • Deficiencies of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII, or factor V & VIII • Alpha-2-antiplasmin deficiency • Factor XIII deficiency • Platelet function disorders (including Scott syndrome and Quebec platelet disorder) • Free tissue plasminogen activator (tPA) in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in individuals with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity. • Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in individuals with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency. • PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [ • PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [ • PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL. • Note: (1) Because the majority of PAI-1 activity assays are used to detect increased PAI-1 activity rather than decreased PAI-1 activity, they lack the sensitivity to differentiate between low-normal activity and complete deficiency. Thus, a PAI-1 activity level of zero is often reported to be within the normal limits. (2) PAI-1 activity also demonstrates diurnal variation: because higher levels are observed in the morning and lower levels in the afternoon, the activity should be assayed in a sample drawn in the morning. • Biallelic • Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ • Note: Targeted analysis for the • For an introduction to multigene panels click ## Suggestive Findings Complete plasminogen activator inhibitor 1 (PAI-1) deficiency Bleeding disorder that typically presents as: Delayed bleeding following injury, trauma, or surgery In females, menorrhagia and abnormal bleeding with pregnancy Absence of other known bleeding disorders including: von Willebrand disease Deficiencies of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII, or factor V & VIII Alpha-2-antiplasmin deficiency Factor XIII deficiency Platelet function disorders (including Scott syndrome and Quebec platelet disorder) Free tissue plasminogen activator (tPA) in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in individuals with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity. Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in individuals with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency. PAI-1 specific assays: PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [ PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [ Note: If the PAI-1 antigen level is normal and PAI-1 activity is decreased, the phenotype is referred to as qualitative PAI-1deficiency or dysfunctional PAI-1 [ • Delayed bleeding following injury, trauma, or surgery • In females, menorrhagia and abnormal bleeding with pregnancy • von Willebrand disease • Deficiencies of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII, or factor V & VIII • Alpha-2-antiplasmin deficiency • Factor XIII deficiency • Platelet function disorders (including Scott syndrome and Quebec platelet disorder) • Free tissue plasminogen activator (tPA) in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in individuals with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity. • Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in individuals with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency. • PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [ • PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [ ## Medical History Bleeding disorder that typically presents as: Delayed bleeding following injury, trauma, or surgery In females, menorrhagia and abnormal bleeding with pregnancy Absence of other known bleeding disorders including: von Willebrand disease Deficiencies of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII, or factor V & VIII Alpha-2-antiplasmin deficiency Factor XIII deficiency Platelet function disorders (including Scott syndrome and Quebec platelet disorder) • Delayed bleeding following injury, trauma, or surgery • In females, menorrhagia and abnormal bleeding with pregnancy • von Willebrand disease • Deficiencies of factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XIII, or factor V & VIII • Alpha-2-antiplasmin deficiency • Factor XIII deficiency • Platelet function disorders (including Scott syndrome and Quebec platelet disorder) ## Laboratory Findings Free tissue plasminogen activator (tPA) in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in individuals with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity. Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in individuals with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency. PAI-1 specific assays: PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [ PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [ Note: If the PAI-1 antigen level is normal and PAI-1 activity is decreased, the phenotype is referred to as qualitative PAI-1deficiency or dysfunctional PAI-1 [ • Free tissue plasminogen activator (tPA) in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in individuals with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity. • Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in individuals with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency. • PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [ • PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [ ## Establishing the Diagnosis The diagnosis of complete PAI-1 deficiency PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL. Note: (1) Because the majority of PAI-1 activity assays are used to detect increased PAI-1 activity rather than decreased PAI-1 activity, they lack the sensitivity to differentiate between low-normal activity and complete deficiency. Thus, a PAI-1 activity level of zero is often reported to be within the normal limits. (2) PAI-1 activity also demonstrates diurnal variation: because higher levels are observed in the morning and lower levels in the afternoon, the activity should be assayed in a sample drawn in the morning. AND/OR Biallelic Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Note: Targeted analysis for the For an introduction to multigene panels click Molecular Genetic Testing Used in Complete Plasminogen Activator Inhibitor 1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click One reported individual with a lifelong history of bleeding associated with surgery and trauma had a heterozygous missense Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no exon or multiexon • PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL. • Note: (1) Because the majority of PAI-1 activity assays are used to detect increased PAI-1 activity rather than decreased PAI-1 activity, they lack the sensitivity to differentiate between low-normal activity and complete deficiency. Thus, a PAI-1 activity level of zero is often reported to be within the normal limits. (2) PAI-1 activity also demonstrates diurnal variation: because higher levels are observed in the morning and lower levels in the afternoon, the activity should be assayed in a sample drawn in the morning. • Biallelic • Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ • Note: Targeted analysis for the • For an introduction to multigene panels click ## Clinical Characteristics Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life-threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding episodes such as those observed in classic While males and females with complete PAI-1 deficiency are affected equally, females may present with clinical manifestations more frequently or earlier in life than males, due to menorrhagia and postpartum hemorrhage. In addition, females experience bleeding with pregnancy and can have difficulty carrying a pregnancy to term. Post-traumatic bleeding can include joint bleeds and hematomas [ The male reported by A 17-year-old male with molecularly confirmed complete PAI-1 deficiency experienced a recurrent iliopsoas bleed over several years. He had a previous history of liver hematoma after a fall at age seven years [ Postsurgical bleeding has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency: A child age five years experienced postoperative bleeding following surgical repair of a ventricular septal defect [ A member of the Old Order Amish community had delayed bleeding after surgical repair of an inguinal hernia [ Delayed bleeding was reported after total hip arthroplasty [ Prolonged bleeding after dental extraction has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency [ A palatal hemorrhage complicated a dental abscess, requiring hospitalization and transfusion [ Prolonged wound healing occurred in one individual [ Menorrhagia is a consistent characteristic of complete PAI-1 deficiency [ In one woman rupture of an ovarian follicle resulted in hemoperitoneum requiring hospitalization, treatment with antifibrinolytics, and red blood cell transfusion. Pregnancy can be complicated by sporadic antenatal bleeding, preterm labor, postpartum bleeding, and miscarriage. Because data on the phenotype associated with biallelic Complete PAI-1 deficiency, the topic of this Qualitative PAI-1 deficiency, not addressed in this The prevalence of complete PAI-1 deficiency is unknown, in large part because of the inability of the majority of tests of PAI-1 activity to differentiate between low-normal activity and complete deficiency (see Fewer than ten families with complete PAI-1 deficiency have been reported to date. Complete PAI-1 deficiency has no known racial or ethnic predominance. It has been reported in North America, Europe, and Asia. Of note, the incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see • A child age five years experienced postoperative bleeding following surgical repair of a ventricular septal defect [ • A member of the Old Order Amish community had delayed bleeding after surgical repair of an inguinal hernia [ • Delayed bleeding was reported after total hip arthroplasty [ ## Clinical Description Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life-threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding episodes such as those observed in classic While males and females with complete PAI-1 deficiency are affected equally, females may present with clinical manifestations more frequently or earlier in life than males, due to menorrhagia and postpartum hemorrhage. In addition, females experience bleeding with pregnancy and can have difficulty carrying a pregnancy to term. Post-traumatic bleeding can include joint bleeds and hematomas [ The male reported by A 17-year-old male with molecularly confirmed complete PAI-1 deficiency experienced a recurrent iliopsoas bleed over several years. He had a previous history of liver hematoma after a fall at age seven years [ Postsurgical bleeding has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency: A child age five years experienced postoperative bleeding following surgical repair of a ventricular septal defect [ A member of the Old Order Amish community had delayed bleeding after surgical repair of an inguinal hernia [ Delayed bleeding was reported after total hip arthroplasty [ Prolonged bleeding after dental extraction has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency [ A palatal hemorrhage complicated a dental abscess, requiring hospitalization and transfusion [ Prolonged wound healing occurred in one individual [ Menorrhagia is a consistent characteristic of complete PAI-1 deficiency [ In one woman rupture of an ovarian follicle resulted in hemoperitoneum requiring hospitalization, treatment with antifibrinolytics, and red blood cell transfusion. Pregnancy can be complicated by sporadic antenatal bleeding, preterm labor, postpartum bleeding, and miscarriage. • A child age five years experienced postoperative bleeding following surgical repair of a ventricular septal defect [ • A member of the Old Order Amish community had delayed bleeding after surgical repair of an inguinal hernia [ • Delayed bleeding was reported after total hip arthroplasty [ ## Genotype-Phenotype Correlations Because data on the phenotype associated with biallelic ## Nomenclature Complete PAI-1 deficiency, the topic of this Qualitative PAI-1 deficiency, not addressed in this ## Prevalence The prevalence of complete PAI-1 deficiency is unknown, in large part because of the inability of the majority of tests of PAI-1 activity to differentiate between low-normal activity and complete deficiency (see Fewer than ten families with complete PAI-1 deficiency have been reported to date. Complete PAI-1 deficiency has no known racial or ethnic predominance. It has been reported in North America, Europe, and Asia. Of note, the incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Complete Plasminogen Activator Inhibitor 1 Deficiency AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PLI = plasmin inhibitor The moderate bleeding seen in alpha-2-antiplasmin deficiency is not characteristically associated with injury, surgery, or dental procedures. ## Management To establish the extent of disease and needs in an individual diagnosed with complete plasminogen activator inhibitor 1 (PAI-1) deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Questions to elicit an individual's history of: Epistaxis Poor wound healing Bleeding in association with injury or trauma Bleeding with dental extractions Additional oral bleeding Postsurgical bleeding In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation History of therapies tried in the past and the response to each specific therapy Note: Response to antifibrinolytic therapy may support the diagnosis of complete PAI-1 deficiency (see Evaluation by a hematologist with expertise in disorders of coagulation Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of complete PAI-1 deficiency in order to facilitate medical and personal decision making Severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation), have been successfully managed with intravenous antifibrinolytics. Response to both epsilon-aminocaproic acid (EACA) and tranexamic acid have been documented. If PAI-1 activity needs to be increased prior to achieving the therapeutic steady-state level of antifibrinolytics, infusion of fresh-frozen plasma (FFP) (10-15 mL/kg) can be used. Duration of use of FFP is individualized based on clinical course and response to therapy. Of note, monitoring PAI-1 levels is not recommended during treatment with FFP; assessment of clinical response should guide therapy decisions. Note: The use of FFP does not appear to be effective in pregnancy for the prevention of bleeding in women with complete PAI-1 deficiency [ Heavy menstrual bleeding can often be effectively managed with continuous or intermittent prophylactic use of the antifibrinolytics tranexamic acid and EACA and/or hormonal suppression therapy (oral contraceptives). Occasionally, individuals with complete PAI-1 deficiency experience excessive menstrual bleeding or bleeding following a procedure or trauma that requires infusion of packed red blood cells to manage the acute blood loss. Education regarding bleeding manifestations and when to seek treatment includes the following: For females, anticipatory counseling regarding onset of menses and potential complications Prompt reporting of injuries and planned procedures to allow early initiation of treatment to prevent significant bleeding Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures. Antifibrinolytics can be administered intravenously, orally, or topically, the latter especially during dental procedures. For menstruating females: Regular monitoring of hemoglobin and/or hematocrit and iron studies including ferritin for possible iron deficiency and/or anemia Assessment of the effectiveness of therapeutic interventions such as antifibrinolytics or hormonal suppressive agents (oral contraceptives) The following should be avoided: Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies High-risk activities such as contact sports It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: Molecular genetic testing if the Measurement of PAI-1 antigen levels and PAI-1 activity if the See Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are administration of either tranexamic acid (25 mg/kg per dose, maximum 1,300 mg, orally 3-4 times per day) or epsilon-aminocaproic acid (EACA) (100 mg/kg per dose, maximum 3 g, orally 4 times per day) for intermittent bleeding in the first and second trimester, continuous treatment from 26 weeks' gestation through delivery to prevent preterm labor, and for at least two weeks postpartum to prevent postpartum bleeding [ A woman with complete PAI-1 deficiency was treated with FFP during three pregnancies at eight to 11 weeks' gestation two to three times per week; FFP treatment was increased to daily at 20 to 28 weeks' gestation. The first pregnancy ended in miscarriage at 19 weeks. The second and third pregnancies were delivered at 32 and 27 weeks' gestation, respectively, as a result of uncontrollable contractions and placental abruption [ Of note, the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited. There is a need to establish dosing guidelines for the use of antifibrinolytics during pregnancy and the postpartum period. See Search • Questions to elicit an individual's history of: • Epistaxis • Poor wound healing • Bleeding in association with injury or trauma • Bleeding with dental extractions • Additional oral bleeding • Postsurgical bleeding • In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation • Epistaxis • Poor wound healing • Bleeding in association with injury or trauma • Bleeding with dental extractions • Additional oral bleeding • Postsurgical bleeding • In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation • History of therapies tried in the past and the response to each specific therapy • Note: Response to antifibrinolytic therapy may support the diagnosis of complete PAI-1 deficiency (see • Evaluation by a hematologist with expertise in disorders of coagulation • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of complete PAI-1 deficiency in order to facilitate medical and personal decision making • Epistaxis • Poor wound healing • Bleeding in association with injury or trauma • Bleeding with dental extractions • Additional oral bleeding • Postsurgical bleeding • In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation • For females, anticipatory counseling regarding onset of menses and potential complications • Prompt reporting of injuries and planned procedures to allow early initiation of treatment to prevent significant bleeding • Regular monitoring of hemoglobin and/or hematocrit and iron studies including ferritin for possible iron deficiency and/or anemia • Assessment of the effectiveness of therapeutic interventions such as antifibrinolytics or hormonal suppressive agents (oral contraceptives) • Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies • High-risk activities such as contact sports • Molecular genetic testing if the • Measurement of PAI-1 antigen levels and PAI-1 activity if the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with complete plasminogen activator inhibitor 1 (PAI-1) deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Questions to elicit an individual's history of: Epistaxis Poor wound healing Bleeding in association with injury or trauma Bleeding with dental extractions Additional oral bleeding Postsurgical bleeding In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation History of therapies tried in the past and the response to each specific therapy Note: Response to antifibrinolytic therapy may support the diagnosis of complete PAI-1 deficiency (see Evaluation by a hematologist with expertise in disorders of coagulation Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of complete PAI-1 deficiency in order to facilitate medical and personal decision making • Questions to elicit an individual's history of: • Epistaxis • Poor wound healing • Bleeding in association with injury or trauma • Bleeding with dental extractions • Additional oral bleeding • Postsurgical bleeding • In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation • Epistaxis • Poor wound healing • Bleeding in association with injury or trauma • Bleeding with dental extractions • Additional oral bleeding • Postsurgical bleeding • In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation • History of therapies tried in the past and the response to each specific therapy • Note: Response to antifibrinolytic therapy may support the diagnosis of complete PAI-1 deficiency (see • Evaluation by a hematologist with expertise in disorders of coagulation • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of complete PAI-1 deficiency in order to facilitate medical and personal decision making • Epistaxis • Poor wound healing • Bleeding in association with injury or trauma • Bleeding with dental extractions • Additional oral bleeding • Postsurgical bleeding • In females: heavy menstrual bleeding, postpartum bleeding, bleeding during pregnancy, preterm delivery, and bleeding in association with ovulation ## Treatment of Manifestations Severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation), have been successfully managed with intravenous antifibrinolytics. Response to both epsilon-aminocaproic acid (EACA) and tranexamic acid have been documented. If PAI-1 activity needs to be increased prior to achieving the therapeutic steady-state level of antifibrinolytics, infusion of fresh-frozen plasma (FFP) (10-15 mL/kg) can be used. Duration of use of FFP is individualized based on clinical course and response to therapy. Of note, monitoring PAI-1 levels is not recommended during treatment with FFP; assessment of clinical response should guide therapy decisions. Note: The use of FFP does not appear to be effective in pregnancy for the prevention of bleeding in women with complete PAI-1 deficiency [ Heavy menstrual bleeding can often be effectively managed with continuous or intermittent prophylactic use of the antifibrinolytics tranexamic acid and EACA and/or hormonal suppression therapy (oral contraceptives). Occasionally, individuals with complete PAI-1 deficiency experience excessive menstrual bleeding or bleeding following a procedure or trauma that requires infusion of packed red blood cells to manage the acute blood loss. Education regarding bleeding manifestations and when to seek treatment includes the following: For females, anticipatory counseling regarding onset of menses and potential complications Prompt reporting of injuries and planned procedures to allow early initiation of treatment to prevent significant bleeding • For females, anticipatory counseling regarding onset of menses and potential complications • Prompt reporting of injuries and planned procedures to allow early initiation of treatment to prevent significant bleeding ## Prevention of Primary Manifestations Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures. Antifibrinolytics can be administered intravenously, orally, or topically, the latter especially during dental procedures. ## Surveillance For menstruating females: Regular monitoring of hemoglobin and/or hematocrit and iron studies including ferritin for possible iron deficiency and/or anemia Assessment of the effectiveness of therapeutic interventions such as antifibrinolytics or hormonal suppressive agents (oral contraceptives) • Regular monitoring of hemoglobin and/or hematocrit and iron studies including ferritin for possible iron deficiency and/or anemia • Assessment of the effectiveness of therapeutic interventions such as antifibrinolytics or hormonal suppressive agents (oral contraceptives) ## Agents/Circumstances to Avoid The following should be avoided: Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies High-risk activities such as contact sports • Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies • High-risk activities such as contact sports ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: Molecular genetic testing if the Measurement of PAI-1 antigen levels and PAI-1 activity if the See • Molecular genetic testing if the • Measurement of PAI-1 antigen levels and PAI-1 activity if the ## Pregnancy Management Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are administration of either tranexamic acid (25 mg/kg per dose, maximum 1,300 mg, orally 3-4 times per day) or epsilon-aminocaproic acid (EACA) (100 mg/kg per dose, maximum 3 g, orally 4 times per day) for intermittent bleeding in the first and second trimester, continuous treatment from 26 weeks' gestation through delivery to prevent preterm labor, and for at least two weeks postpartum to prevent postpartum bleeding [ A woman with complete PAI-1 deficiency was treated with FFP during three pregnancies at eight to 11 weeks' gestation two to three times per week; FFP treatment was increased to daily at 20 to 28 weeks' gestation. The first pregnancy ended in miscarriage at 19 weeks. The second and third pregnancies were delivered at 32 and 27 weeks' gestation, respectively, as a result of uncontrollable contractions and placental abruption [ Of note, the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited. There is a need to establish dosing guidelines for the use of antifibrinolytics during pregnancy and the postpartum period. See ## Therapies Under Investigation Search ## Genetic Counseling Complete plasminogen activator inhibitor 1 (PAI-1) deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. Unless an affected individual's reproductive partner also has complete PAI-1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant, increasing the risk that an affected individual may have a reproductive partner who is heterozygous for a Molecular genetic carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. This includes issues related to pregnancy in affected women and the risk to the fetus due to risk of prematurity (see Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. • Unless an affected individual's reproductive partner also has complete PAI-1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant, increasing the risk that an affected individual may have a reproductive partner who is heterozygous for a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. This includes issues related to pregnancy in affected women and the risk to the fetus due to risk of prematurity (see • Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see ## Mode of Inheritance Complete plasminogen activator inhibitor 1 (PAI-1) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. Unless an affected individual's reproductive partner also has complete PAI-1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant, increasing the risk that an affected individual may have a reproductive partner who is heterozygous for a • The parents of an affected individual are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. • Unless an affected individual's reproductive partner also has complete PAI-1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant, increasing the risk that an affected individual may have a reproductive partner who is heterozygous for a ## Carrier Detection Molecular genetic carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. This includes issues related to pregnancy in affected women and the risk to the fetus due to risk of prematurity (see Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. This includes issues related to pregnancy in affected women and the risk to the fetus due to risk of prematurity (see • Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics Complete Plasminogen Activator Inhibitor 1 Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Complete Plasminogen Activator Inhibitor 1 Deficiency ( Plasminogen activator inhibitor 1 (PAI-1), a protein that is a member of the serine protease inhibitor (SERPIN) superfamily, is involved in a variety of pathophysiologic systems including embryogenesis, angiogenesis, ovulation, inflammation, and tumor metastasis. These observations suggest that the plasminogen activation system is an important mediator of tissue remodeling and cell migration [ In hemostasis, PAI-1 regulates fibrinolysis (i.e., the degradation of thrombi) [ Heterozygous pathogenic variants in Although beyond the scope of diagnostic laboratories, studies to determine the functional consequences of a Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Numbering relative to full-length protein Not associated with the complete plasminogen activator inhibitor 1 (PAI-1) deficiency phenotype but can affect measured PAI-1 activity levels. A 1-bp guanine deletion/insertion variant in the ## Molecular Pathogenesis Plasminogen activator inhibitor 1 (PAI-1), a protein that is a member of the serine protease inhibitor (SERPIN) superfamily, is involved in a variety of pathophysiologic systems including embryogenesis, angiogenesis, ovulation, inflammation, and tumor metastasis. These observations suggest that the plasminogen activation system is an important mediator of tissue remodeling and cell migration [ In hemostasis, PAI-1 regulates fibrinolysis (i.e., the degradation of thrombi) [ Heterozygous pathogenic variants in Although beyond the scope of diagnostic laboratories, studies to determine the functional consequences of a Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Numbering relative to full-length protein Not associated with the complete plasminogen activator inhibitor 1 (PAI-1) deficiency phenotype but can affect measured PAI-1 activity levels. A 1-bp guanine deletion/insertion variant in the ## Chapter Notes Meadow Heiman ( The authors would like to thank the Old Order Amish community in Indiana, who have participated in multiple research projects regarding complete PAI-1 deficiency; the Indiana Hemophilia & Thrombosis Center Board of Directors for their continued support in the care of ultra-rare disorders; and the multiple collaborators who have been involved in our research over many years. Sweta Gupta, MD (2017-present)Meadow Heiman, MS (2017-present)Sadiya S Khan, MD; Northwestern University Feinberg School of Medicine (2017-2023)Magdalena Lewandowska, MD (2023-present)Amy D Shapiro, MD (2017-present)Douglas E Vaughan, MD; Northwestern University Feinberg School of Medicine (2017-2023) 23 February 2023 (sw) Comprehensive update posted live 3 August 2017 (bp) Review posted live 30 June 2016 (mh) Original submission • 23 February 2023 (sw) Comprehensive update posted live • 3 August 2017 (bp) Review posted live • 30 June 2016 (mh) Original submission ## Author Notes Meadow Heiman ( ## Acknowledgments The authors would like to thank the Old Order Amish community in Indiana, who have participated in multiple research projects regarding complete PAI-1 deficiency; the Indiana Hemophilia & Thrombosis Center Board of Directors for their continued support in the care of ultra-rare disorders; and the multiple collaborators who have been involved in our research over many years. ## Author History Sweta Gupta, MD (2017-present)Meadow Heiman, MS (2017-present)Sadiya S Khan, MD; Northwestern University Feinberg School of Medicine (2017-2023)Magdalena Lewandowska, MD (2023-present)Amy D Shapiro, MD (2017-present)Douglas E Vaughan, MD; Northwestern University Feinberg School of Medicine (2017-2023) ## Revision History 23 February 2023 (sw) Comprehensive update posted live 3 August 2017 (bp) Review posted live 30 June 2016 (mh) Original submission • 23 February 2023 (sw) Comprehensive update posted live • 3 August 2017 (bp) Review posted live • 30 June 2016 (mh) Original submission ## References ## Literature Cited Plasminogen activators – urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) – circulate in plasma as a reversible complex with plasminogen activator inhibitor 1 (PAI-1). When the fibrin clot is formed, plasminogen and tPA or uPA bind to the clot and form plasmin, resulting in lysis of the cross-linked fibrin-to-fibrin degradation products. PAI-1 also binds to fibrin and, when bound, can irreversibly inhibit plasminogen activators. From	[ "J Diéval, G Nguyen, S Gross, J Delobel, EK Kruithof. A lifelong bleeding disorder associated with deficiency of plasminogen activator inhibitor type 1.. Blood. 1991;77:528-32", "WP Fay, AC Parker, LR Condrey, AD Shapiro. Human plasminogen activator inhibitor -1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene.. Blood. 1997;90:204-8", "WP Fay, AD Shapiro, JL Shih, RR Schleef, D Ginsburg. Brief report: complete deficiency of plasminogen activator inhibitor type 1 due to a frameshift mutation.. NEJM 1992;327:1729-33", "P Flevaris, SS Khan, M Eren, AJ Schuldt, SJ Shah, DC Lee, S Gupta, A Shapiro, P Burridge, AK Ghosh, DE Vaughan. Plasminogen activator inhibitor type I controls cardiomyocyte transforming growth factor-β and cardiac fibrosis.. Circulation. 2017;136:664-79", "P Flevaris, D Vaughan. The role of plasminogen activator inhibitor type-1 in fibrosis.. Semin Thromb Hemost. 2017;43:169-77", "AK Ghosh, WS Bradham, LA Gleaves, B De Taeye, SB Murphy, JW Covington, DE Vaughan. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice.. Circulation. 2010;122:1200-9", "AK Ghosh, SB Murphy, R Kishore, DE Vaughan. Global gene expression profiling PAI-1 knockout murine heart and kidney: Molecular basis of cardiac-selective fibrosis.. PLoS One. 2013;8", "M Heiman, S Gupta, AD Shapiro. The obstetric, gynaecological and fertility implications of homozygous PAI-1 deficiency: single-centre experience.. Haemophilia. 2014;20:407-12", "J Hirose, H Takedani, M Kubota, J Kinkawa, M Noguchi. Total hip arthroplasty and total knee arthroplasty in a patient with congenital deficiency of plasminogen activator inhibitor-1.. Haemophilia. 2016;22:e237-9", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "Z Huang, W Tang, Q Chen, M Li, S Lao, H Pan, L Huang, M Huang, X Hu, J. Zhao. Plasminogen activator inhibitor-1 polymorphism confers a genetic contribution to the risk of spontaneous abortion: an updated meta-analysis.. Reprod Sci. 2017;24:1551-60", "T Iwaki, K Nagahashi, T Kobayashi, K Umemura, T Terao, N Kanayama. The first report of uncontrollable subchorionic retroplacental haemorrhage inducing preterm labour in complete PAI-1 deficiency in a human.. Thromb Res. 2012;129:e161-3", "T Iwaki, A Tanaka, Y Miyawaki, A Suzuki, T Kobayashi, J Takamatsu, T Matsushita, K Umemura, T Urano, T Kojima, T Terao, N Kanayama. Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans.. J Thromb Haemost. 2011;9:1200-6", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "SS Khan, SJ Shah, JL Strande, AS Baldridge, P Flevaris, MJ Puckelwartz, EM McNally, LJ Rasmussen-Torvik, DC Lee, JC Carr, BC Benefield, MZ Afzal, M Heiman, S Gupta, AD Shapiro, DE Vaughan. Identification of cardiac fibrosis in young adults with a homozygous frameshift variant in SERPINE1.. JAMA Cardiol. 2021;6:841-6", "HP Kohler, PJ Grant. Plasminogen-activator inhibitor type 1 and coronary artery disease.. NEJM 2000;342:1792-801", "R Mehta, AD Shapiro. Plasminogen activator inhibitor type 1 deficiency.. Haemophilia. 2008;14:1255-60", "H Minowa, Y Takahashi, T Tanaka, K Naganuma, S Ida, I Maki, A Yoshioka. Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency.. Haemostasis. 1999;29:286-91", "JA Peterson, S Gupta, ND Martinez, B Hardesty, SA Maroney, AE Mast. Factor V east Texas variant causes bleeding in a three-generation family.. J Thromb Haemost. 2022;20:565-73", "A Prabhudesai, R Sharma, S Shetty, A Phadnis, B. Kulkarni. Congenital PAI-1 deficiency results in psoas hematoma in an Indian patient.. Thrombosis Research. 2020;190:35-8", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "RR Schleef, DL Higgins, E Pillemer, LJ Levitt. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor.. J Clin Invest. 1989;83:1747-52", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "ZY Zhang, ZY Wang, NZ Dong, X Bai, W Zhang, CG Ruan. A case of deficiency of plasma plasminogen activator inhibitor-1 related to Ala15Thr mutation in its signal peptide.. Blood Coagul Fibrinolysis. 2005;16:79-84" ]	3/8/2017	23/2/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pancreatitis-ov	pancreatitis-ov	[ "Calcific Pancreatitis", "Chronic Pancreatitis", "SPINK1-Related Hereditary Pancreatitis", "PRSS1-Related Hereditary Pancreatitis", "CTRC-Related Hereditary Pancreatitis", "CFTR-Related Hereditary Pancreatitis", "Bile salt-activated lipase", "Carboxypeptidase A1", "Chymotrypsin-C", "Claudin-2", "Cystic fibrosis transmembrane conductance regulator", "E3 ubiquitin-protein ligase UBR1", "Extracellular calcium-sensing receptor", "Glutathione hydrolase 1 proenzyme", "Ribosome maturation protein SBDS", "Serine protease 1", "Serine protease inhibitor Kazal-type 1", "Transient receptor potential cation channel subfamily V member 6", "CASR", "CEL", "CFTR", "CLDN2", "CPA1", "CTRC", "GGT1", "PRSS1", "SBDS", "SPINK1", "TRPV6", "UBR1", "Pancreatitis Overview", "Overview" ]	Pancreatitis Overview	Celeste Shelton, Jessica LaRusch, David C Whitcomb	Summary The purpose of this overview is: Review the Provide an Review Inform	## Pancreatitis: Definitions Sudden onset of typical epigastric abdominal pain Elevation of serum amylase or lipase more than three times the upper limits of normal [ Characteristic findings of acute pancreatitis such as pancreatic edema, fat stranding, and peripancreatic fluid collections on abdominal imaging [ Manifestations of AP can range from vague abdominal pain lasting one to three days to severe abdominal pain, systemic inflammation, and multiorgan failure lasting days to weeks and requiring hospitalization with care in an intensive care unit (i.e., In most populations, about one third of individuals with AP develop RAP, and about one third of individuals with RAP develop CP. Because of the high risk of progression to an irreversible condition, efforts to stop the progression should begin with the first episode of AP. The pancreas has two cell types in the exocrine pancreas: acinar cells that secrete zymogens (inactive digestive enzymes), and duct cells that flush the zymogens into the small intestine where they become active. The endocrine pancreas has four cell types, collectively referred to as islet cells. Beta cells are the most important as they secrete insulin. Alpha cells secrete glucagon, an antagonist of insulin. The last two islet cell types secrete pancreatic polypeptide and somatostatin. In addition, the pancreas has a rich nerve innervation including sensory nerves. The inflammatory process can destroy any of the parenchymal cells, activate nerves causing pain, and cause DNA damage to acinar and duct cells, thereby increasing the risk for pancreatic ductal adenocarcinoma. Damage to islet cells may increase the risk for neuroendocrine tumors. • Sudden onset of typical epigastric abdominal pain • Elevation of serum amylase or lipase more than three times the upper limits of normal [ • Characteristic findings of acute pancreatitis such as pancreatic edema, fat stranding, and peripancreatic fluid collections on abdominal imaging [ ## Clinical Features of CP The pancreas has two cell types in the exocrine pancreas: acinar cells that secrete zymogens (inactive digestive enzymes), and duct cells that flush the zymogens into the small intestine where they become active. The endocrine pancreas has four cell types, collectively referred to as islet cells. Beta cells are the most important as they secrete insulin. Alpha cells secrete glucagon, an antagonist of insulin. The last two islet cell types secrete pancreatic polypeptide and somatostatin. In addition, the pancreas has a rich nerve innervation including sensory nerves. The inflammatory process can destroy any of the parenchymal cells, activate nerves causing pain, and cause DNA damage to acinar and duct cells, thereby increasing the risk for pancreatic ductal adenocarcinoma. Damage to islet cells may increase the risk for neuroendocrine tumors. ## Risk Factors and Etiologies of Recurrent Acute Pancreatitis / Chronic Pancreatitis The common risk factors and etiologies of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are represented by the acronym Extra pancreatic etiology of duct Recurrent Acute Pancreatitis / Chronic Pancreatitis Genetic Risk Factors Common variants assoc w/mild-to-moderate risk ↑ risk w/alcohol abuse, esp in hemizygous males & homozygous females Heterozygotes are at ↑ risk. Several pathogenic variants assoc w/pancreatitis do not cause lung disease of cystic fibrosis. See footnote 5 for modifiers. ↑ risk for CP following AP Early-onset aggressive pancreatitis assoc w/biallelic p.Asn34Ser Heterozygous & biallelic pathogenic variants reported w/↓ penetrance Several common variants assoc w/mild-to-moderate risk Founder variants reported in US, Europe, India, China, Japan, & Korea More common in Europe Misfolding variants may cause AD CP. Loss-of-function variants assoc w/moderately ↑ risk Common risk variant c.180C>T may ↑ risk for CP in persons w/variants in Loss-of-function variants may ↑ risk in persons w/variants in Common gain-of-function variant assoc w/moderate ↑ risk, particularly w/alcohol use. Diabetes mellitus Pancreatic lipomatosis Pancreatic exocrine, endocrine dysfunction CP w/o severe malnutrition Exon &/or multiexon deletions/ duplications reported Nonallelic homologous recombination between AD = autosomal dominant; AP = acute pancreatitis; AR = autosomal recessive; CP = chronic pancreatitis; MOI = mode of inheritance; RAP = recurrent acute pancreatitis Percentage of individuals with CP who have a common risk variant in Variant(s) in this gene increase the risk for recurrent acute and/or chronic pancreatitis and can be contributors to complex (e.g., multifactorial, polygenic) inheritance pattern. SNPs in This percentage does not include the common gain-of-function variant associated with moderate increased risk for pancreatitis in those with alcohol use. Syndromes Associated with Recurrent Acute Pancreatitis / Chronic Pancreatitis Cholestasis Congenital heart defects Typical facial features Butterfly vertebrae Hepatosplenomegaly Eruptive xanthomas Hypertriglyceridemia Lipemia retinalis Progressive encephalopathy Ataxia Optic atrophy Infantile intrahepatic cholestasis Childhood failure to thrive Dyslipidemia Adult-onset hyperammonemia w/neuropsychiatric symptoms Bronchiectasis Infertility in males Chronic sinusitis Severe hypertriglyceridemia Recurrent acute pancreatitis Xanthomata Hepatosplenomegaly Congenital exocrine pancreatic inflammation & insufficiency Multiple malformations incl nasal wing aplasia Intellectual disability (frequently) Metabolic decompensation on protein-containing diet Intellectual disability Tubulointerstitial nephritis Acute or chronic pancreatitis Exocrine & endocrine pancreatic dysfunction Pancreatic fibrosis Bone marrow failure Sideroblastic anemia Often fatal in infancy Progressive encephalopathy Metabolic crises Cardiomyopathy Exocrine pancreatic insufficiency Pancreatic lipomatosis Bone marrow failure Skeletal abnormalities Risk for myeloid leukemias Liver disease Movement disorder or rigid dystonia Psychiatric manifestations Gastrointestinal polyps Cancers of (e.g.,) bowel, pancreas, thyroid AD = autosomal dominant; AR = autosomal recessive; MT = mitochondrial; MOI = mode of inheritance Individuals with symptoms of pancreatitis and a heterozygous In addition to the major known monogenic causes of pancreatitis ( ABO blood group [ • Extra pancreatic etiology of duct • Common variants assoc w/mild-to-moderate risk • ↑ risk w/alcohol abuse, esp in hemizygous males & homozygous females • Heterozygotes are at ↑ risk. • Several pathogenic variants assoc w/pancreatitis do not cause lung disease of cystic fibrosis. • See footnote 5 for modifiers. • ↑ risk for CP following AP • Early-onset aggressive pancreatitis assoc w/biallelic p.Asn34Ser • Heterozygous & biallelic pathogenic variants reported w/↓ penetrance • Several common variants assoc w/mild-to-moderate risk • Founder variants reported in US, Europe, India, China, Japan, & Korea • More common in Europe • Misfolding variants may cause AD CP. • Loss-of-function variants assoc w/moderately ↑ risk • Common risk variant c.180C>T may ↑ risk for CP in persons w/variants in • Loss-of-function variants may ↑ risk in persons w/variants in • Common gain-of-function variant assoc w/moderate ↑ risk, particularly w/alcohol use. • Diabetes mellitus • Pancreatic lipomatosis • Pancreatic exocrine, endocrine dysfunction • CP w/o severe malnutrition • Exon &/or multiexon deletions/ duplications reported • Nonallelic homologous recombination between • Cholestasis • Congenital heart defects • Typical facial features • Butterfly vertebrae • Hepatosplenomegaly • Eruptive xanthomas • Hypertriglyceridemia • Lipemia retinalis • Progressive encephalopathy • Ataxia • Optic atrophy • Infantile intrahepatic cholestasis • Childhood failure to thrive • Dyslipidemia • Adult-onset hyperammonemia w/neuropsychiatric symptoms • Bronchiectasis • Infertility in males • Chronic sinusitis • Severe hypertriglyceridemia • Recurrent acute pancreatitis • Xanthomata • Hepatosplenomegaly • Congenital exocrine pancreatic inflammation & insufficiency • Multiple malformations incl nasal wing aplasia • Intellectual disability (frequently) • Metabolic decompensation on protein-containing diet • Intellectual disability • Tubulointerstitial nephritis • Acute or chronic pancreatitis • Exocrine & endocrine pancreatic dysfunction • Pancreatic fibrosis • Bone marrow failure • Sideroblastic anemia • Often fatal in infancy • Progressive encephalopathy • Metabolic crises • Cardiomyopathy • Exocrine pancreatic insufficiency • Pancreatic lipomatosis • Bone marrow failure • Skeletal abnormalities • Risk for myeloid leukemias • Liver disease • Movement disorder or rigid dystonia • Psychiatric manifestations • Gastrointestinal polyps • Cancers of (e.g.,) bowel, pancreas, thyroid • ABO blood group [ ## Emerging Genetic Risk Factors for Pancreatitis In addition to the major known monogenic causes of pancreatitis ( ABO blood group [ • ABO blood group [ ## Evaluation Strategies to Identify Genetic Risk Factors in a Proband with Pancreatitis The evaluation of an individual at risk for chronic pancreatitis (CP) should begin at the time of the first episode of acute pancreatitis (AP), after common causes of AP have been ruled out such as a gallstone, trauma, hypertriglyceridemia, or hypercalcemia. If another etiology for AP is not identified, molecular genetic testing is indicated [ Establishing a specific genetic cause of pancreatitis: Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical and family history, physical examination, and genomic/genetic testing. The most important part of the clinical evaluation is a careful family history and review of systems. The objective is to identify familial disorders such as hereditary pancreatitis, Early-onset pancreatitis (age <35 years) is often indicative of pancreatitis with an underlying genetic etiology (e.g., single-gene or polygenic disorder), whereas late-onset pancreatitis may indicate a complex pathology with both genetic and environmental causes. Ongoing and high levels of alcohol and tobacco use may indicate an alcohol-related etiology, but excessive alcohol use does not exclude consideration of genetic risk for pancreatitis. Molecular genetic testing for hereditary pancreatitis is indicated in a proband with pancreatitis and at least one of the following: An unexplained documented episode of acute pancreatitis in childhood Recurrent acute attacks of pancreatitis of unknown cause Chronic pancreatitis of unknown cause, particularly with onset before age 35 years without a history of heavy alcohol use (>5 drinks per day). A history of at least one relative with recurrent acute pancreatitis, chronic pancreatitis of unknown cause, or childhood pancreatitis of unknown cause The physical examination should focus on identifying syndromes associated with pancreatitis (see Molecular genetic testing approaches can include a combination of Note: (1) For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Note: Very few individuals with pancreatitis are found to have hereditary pancreatitis caused by a highly penetrant autosomal dominant pathogenic variant (e.g., • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical and family history, physical examination, and genomic/genetic testing. • An unexplained documented episode of acute pancreatitis in childhood • Recurrent acute attacks of pancreatitis of unknown cause • Chronic pancreatitis of unknown cause, particularly with onset before age 35 years without a history of heavy alcohol use (>5 drinks per day). • A history of at least one relative with recurrent acute pancreatitis, chronic pancreatitis of unknown cause, or childhood pancreatitis of unknown cause • Note: (1) • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Medical and Family History The most important part of the clinical evaluation is a careful family history and review of systems. The objective is to identify familial disorders such as hereditary pancreatitis, Early-onset pancreatitis (age <35 years) is often indicative of pancreatitis with an underlying genetic etiology (e.g., single-gene or polygenic disorder), whereas late-onset pancreatitis may indicate a complex pathology with both genetic and environmental causes. Ongoing and high levels of alcohol and tobacco use may indicate an alcohol-related etiology, but excessive alcohol use does not exclude consideration of genetic risk for pancreatitis. Molecular genetic testing for hereditary pancreatitis is indicated in a proband with pancreatitis and at least one of the following: An unexplained documented episode of acute pancreatitis in childhood Recurrent acute attacks of pancreatitis of unknown cause Chronic pancreatitis of unknown cause, particularly with onset before age 35 years without a history of heavy alcohol use (>5 drinks per day). A history of at least one relative with recurrent acute pancreatitis, chronic pancreatitis of unknown cause, or childhood pancreatitis of unknown cause • An unexplained documented episode of acute pancreatitis in childhood • Recurrent acute attacks of pancreatitis of unknown cause • Chronic pancreatitis of unknown cause, particularly with onset before age 35 years without a history of heavy alcohol use (>5 drinks per day). • A history of at least one relative with recurrent acute pancreatitis, chronic pancreatitis of unknown cause, or childhood pancreatitis of unknown cause ## Physical Examination The physical examination should focus on identifying syndromes associated with pancreatitis (see ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of Note: (1) For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Note: Very few individuals with pancreatitis are found to have hereditary pancreatitis caused by a highly penetrant autosomal dominant pathogenic variant (e.g., • Note: (1) • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Medical Management of Pancreatitis Imaging of the pancreas is one of the most useful tests for staging pancreatic disease (asymptomatic, acute pancreatitis / recurrent acute pancreatitis, [AP/RAP], early chronic pancreatitis [CP], established CP, end-stage CP) and detecting some complications [ The initial test should be a CT scan to evaluate the size, shape and features of the pancreas including calcification, atrophy, pseudocysts, cysts, inflammatory masses, tumors, and extrapancreatic diagnoses. MRI and MR cholangiopancreatography (MRCP) provide additional information about the parenchyma. Secretin-stimulated MRCP is more accurate than standard MRCP in the depiction of subtle ductal changes and for diagnosing pancreatic divisum. MRI is not as useful as CT for diagnosing pancreatic calcifications. Endoscopic ultrasound (EUS) can also be used to diagnose parenchymal and ductal changes mainly during the early stage of the disease. The advantages of EUS include being able to add fine needle aspiration of suspicious lesions and diagnosis of microlithiasis in the biliary tree. However, early EUS changes are nonspecific and cannot be used to diagnose early CP. Identifying changes in pancreatic function is often more challenging than imaging studies. The following evaluations are recommended: Referral to a gastroenterologist specializing in the pancreas for evaluation of pancreatic exocrine function using invasive or noninvasive testing Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance) and lipid disorders (e.g., hypertriglyceridemia) Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. Referral to a pancreatic cancer surveillance program in persons with longstanding chronic pancreatitis. Risk for pancreatic cancer is highest in individuals with a history of smoking, a familial cancer syndrome, a history of Referral to a clinical geneticist and/or genetic counselor if the individual has a family history of pancreatitis or pancreatic cancer, or genetic testing identifies a high-risk pathogenic variant Medical treatment and management for hereditary pancreatitis are similar to those for nonhereditary pancreatitis. AP is a sudden event that requires prompt evaluation by physicians trained in emergency medicine, gastroenterology, or abdominal surgery. Treatment of CP focuses on improving quality of life by managing pancreatic pain, maldigestion, and diabetes mellitus. Obstruction of the pancreatic duct. Endoscopic treatment by a gastroenterologist (therapeutic endoscopist) is the first line of treatment for duct obstruction. Surgical treatment is indicated if endoscopic treatment fails or if there are significant pancreatic calcifications or an inflammatory mass. Analgesics are offered for other types of pain, using a step-up approach [ Antioxidants have been reported to improve pain control in a few individuals with hereditary pancreatitis and nonalcoholic CP [ Total pancreatectomy with islet autotransplantation (TPIAT) may be considered at specialized centers in individuals with severe pain and/or inflammation that cannot be controlled by other approaches [ PERT improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea, and/or diarrhea [ The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU; 1 IU = 3 USP units [ Routine screening of individuals with chronic pancreatitis for glucose intolerance Recommendations for management and referral have been published [ Chronic pancreatitis with pancreatic exocrine insufficiency or pancreatic surgery may confound management of diabetes since the rate of nutrient digestion and absorption may be different from delivery of insulin (asynchrony). Attention to symptoms surrounding meals and multidisciplinary evaluation (gastroenterologists and endocrinologists) are needed to address these challenges. See also The ability to prevent the primary manifestations of pancreatitis is limited. The following recommendations are for individuals with (or at risk for) hereditary pancreatitis. Following these recommendations from early childhood may help prevent attacks of acute pancreatitis: • The initial test should be a CT scan to evaluate the size, shape and features of the pancreas including calcification, atrophy, pseudocysts, cysts, inflammatory masses, tumors, and extrapancreatic diagnoses. • MRI and MR cholangiopancreatography (MRCP) provide additional information about the parenchyma. Secretin-stimulated MRCP is more accurate than standard MRCP in the depiction of subtle ductal changes and for diagnosing pancreatic divisum. MRI is not as useful as CT for diagnosing pancreatic calcifications. • Endoscopic ultrasound (EUS) can also be used to diagnose parenchymal and ductal changes mainly during the early stage of the disease. The advantages of EUS include being able to add fine needle aspiration of suspicious lesions and diagnosis of microlithiasis in the biliary tree. However, early EUS changes are nonspecific and cannot be used to diagnose early CP. • Referral to a gastroenterologist specializing in the pancreas for evaluation of pancreatic exocrine function using invasive or noninvasive testing • Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). • Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. • Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the • Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. • Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). • Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. • Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the • Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. • Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance) and lipid disorders (e.g., hypertriglyceridemia) • Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ • A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. • Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. • Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ • A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. • Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. • Referral to a pancreatic cancer surveillance program in persons with longstanding chronic pancreatitis. Risk for pancreatic cancer is highest in individuals with a history of smoking, a familial cancer syndrome, a history of • Referral to a clinical geneticist and/or genetic counselor if the individual has a family history of pancreatitis or pancreatic cancer, or genetic testing identifies a high-risk pathogenic variant • Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). • Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. • Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the • Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. • Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ • A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. • Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. • Obstruction of the pancreatic duct. Endoscopic treatment by a gastroenterologist (therapeutic endoscopist) is the first line of treatment for duct obstruction. Surgical treatment is indicated if endoscopic treatment fails or if there are significant pancreatic calcifications or an inflammatory mass. • Analgesics are offered for other types of pain, using a step-up approach [ • Antioxidants have been reported to improve pain control in a few individuals with hereditary pancreatitis and nonalcoholic CP [ • Total pancreatectomy with islet autotransplantation (TPIAT) may be considered at specialized centers in individuals with severe pain and/or inflammation that cannot be controlled by other approaches [ • PERT improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea, and/or diarrhea [ • The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU; 1 IU = 3 USP units [ • Routine screening of individuals with chronic pancreatitis for glucose intolerance Recommendations for management and referral have been published [ • Chronic pancreatitis with pancreatic exocrine insufficiency or pancreatic surgery may confound management of diabetes since the rate of nutrient digestion and absorption may be different from delivery of insulin (asynchrony). Attention to symptoms surrounding meals and multidisciplinary evaluation (gastroenterologists and endocrinologists) are needed to address these challenges. See also ## Evaluations Following Initial Diagnosis Imaging of the pancreas is one of the most useful tests for staging pancreatic disease (asymptomatic, acute pancreatitis / recurrent acute pancreatitis, [AP/RAP], early chronic pancreatitis [CP], established CP, end-stage CP) and detecting some complications [ The initial test should be a CT scan to evaluate the size, shape and features of the pancreas including calcification, atrophy, pseudocysts, cysts, inflammatory masses, tumors, and extrapancreatic diagnoses. MRI and MR cholangiopancreatography (MRCP) provide additional information about the parenchyma. Secretin-stimulated MRCP is more accurate than standard MRCP in the depiction of subtle ductal changes and for diagnosing pancreatic divisum. MRI is not as useful as CT for diagnosing pancreatic calcifications. Endoscopic ultrasound (EUS) can also be used to diagnose parenchymal and ductal changes mainly during the early stage of the disease. The advantages of EUS include being able to add fine needle aspiration of suspicious lesions and diagnosis of microlithiasis in the biliary tree. However, early EUS changes are nonspecific and cannot be used to diagnose early CP. Identifying changes in pancreatic function is often more challenging than imaging studies. The following evaluations are recommended: Referral to a gastroenterologist specializing in the pancreas for evaluation of pancreatic exocrine function using invasive or noninvasive testing Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance) and lipid disorders (e.g., hypertriglyceridemia) Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. Referral to a pancreatic cancer surveillance program in persons with longstanding chronic pancreatitis. Risk for pancreatic cancer is highest in individuals with a history of smoking, a familial cancer syndrome, a history of Referral to a clinical geneticist and/or genetic counselor if the individual has a family history of pancreatitis or pancreatic cancer, or genetic testing identifies a high-risk pathogenic variant • The initial test should be a CT scan to evaluate the size, shape and features of the pancreas including calcification, atrophy, pseudocysts, cysts, inflammatory masses, tumors, and extrapancreatic diagnoses. • MRI and MR cholangiopancreatography (MRCP) provide additional information about the parenchyma. Secretin-stimulated MRCP is more accurate than standard MRCP in the depiction of subtle ductal changes and for diagnosing pancreatic divisum. MRI is not as useful as CT for diagnosing pancreatic calcifications. • Endoscopic ultrasound (EUS) can also be used to diagnose parenchymal and ductal changes mainly during the early stage of the disease. The advantages of EUS include being able to add fine needle aspiration of suspicious lesions and diagnosis of microlithiasis in the biliary tree. However, early EUS changes are nonspecific and cannot be used to diagnose early CP. • Referral to a gastroenterologist specializing in the pancreas for evaluation of pancreatic exocrine function using invasive or noninvasive testing • Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). • Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. • Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the • Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. • Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). • Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. • Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the • Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. • Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance) and lipid disorders (e.g., hypertriglyceridemia) • Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ • A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. • Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. • Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ • A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. • Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. • Referral to a pancreatic cancer surveillance program in persons with longstanding chronic pancreatitis. Risk for pancreatic cancer is highest in individuals with a history of smoking, a familial cancer syndrome, a history of • Referral to a clinical geneticist and/or genetic counselor if the individual has a family history of pancreatitis or pancreatic cancer, or genetic testing identifies a high-risk pathogenic variant • Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein). • Fecal elastase-1 analysis. Can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency. • Secretin-stimulated pancreatic bicarbonate secretion testing. Requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but primarily assesses pancreatic duct function. The test is intended to document a loss of pancreatic parenchyma but should be interpreted in the context of the • Serum trypsin or trypsinogen. A blood test that measures the leakage of pancreatic digestive enzymes (zymogens) into the blood stream. Under normal conditions a reduction in serum trypsin or trypsinogen levels reflects loss of parenchyma, with large reductions associated with exocrine pancreatic insufficiency. In some instances, abdominal pain is caused by mild acute pancreatitis flare and all pancreatic enzymes will be elevated in the blood, including trypsin and trypsinogen, possibly resulting in a pseudo-normalization of levels despite pancreatic insufficiency. • Annual fasting blood sugar, hemoglobin A1C, and fasting lipid panel are recommended. In addition, risk for type 2 diabetes should be noted including ancestry, family history, and body mass index [ • A standard glucose tolerance test or mixed meal test is recommended to evaluate beta-cell function and hormonal responses in individuals with pancreatitis. This can help sort out the cause of glucose intolerance including peripheral insulin resistance, beta-cell dysfunction, and/or islet cell loss. • Hypertriglyceridemia is a risk factor for RAP and CP. Endocrinologists typically measure fasting lipid levels as a risk for cardiovascular disease, whereas pancreatologists are more interested in peak levels as a risk for AP. There is no consensus on an approach. Endocrinologists, however, are the specialists who manage lipid disorders. ## Treatment of Manifestations Medical treatment and management for hereditary pancreatitis are similar to those for nonhereditary pancreatitis. AP is a sudden event that requires prompt evaluation by physicians trained in emergency medicine, gastroenterology, or abdominal surgery. Treatment of CP focuses on improving quality of life by managing pancreatic pain, maldigestion, and diabetes mellitus. Obstruction of the pancreatic duct. Endoscopic treatment by a gastroenterologist (therapeutic endoscopist) is the first line of treatment for duct obstruction. Surgical treatment is indicated if endoscopic treatment fails or if there are significant pancreatic calcifications or an inflammatory mass. Analgesics are offered for other types of pain, using a step-up approach [ Antioxidants have been reported to improve pain control in a few individuals with hereditary pancreatitis and nonalcoholic CP [ Total pancreatectomy with islet autotransplantation (TPIAT) may be considered at specialized centers in individuals with severe pain and/or inflammation that cannot be controlled by other approaches [ PERT improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea, and/or diarrhea [ The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU; 1 IU = 3 USP units [ Routine screening of individuals with chronic pancreatitis for glucose intolerance Recommendations for management and referral have been published [ Chronic pancreatitis with pancreatic exocrine insufficiency or pancreatic surgery may confound management of diabetes since the rate of nutrient digestion and absorption may be different from delivery of insulin (asynchrony). Attention to symptoms surrounding meals and multidisciplinary evaluation (gastroenterologists and endocrinologists) are needed to address these challenges. See also • Obstruction of the pancreatic duct. Endoscopic treatment by a gastroenterologist (therapeutic endoscopist) is the first line of treatment for duct obstruction. Surgical treatment is indicated if endoscopic treatment fails or if there are significant pancreatic calcifications or an inflammatory mass. • Analgesics are offered for other types of pain, using a step-up approach [ • Antioxidants have been reported to improve pain control in a few individuals with hereditary pancreatitis and nonalcoholic CP [ • Total pancreatectomy with islet autotransplantation (TPIAT) may be considered at specialized centers in individuals with severe pain and/or inflammation that cannot be controlled by other approaches [ • PERT improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea, and/or diarrhea [ • The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU; 1 IU = 3 USP units [ • Routine screening of individuals with chronic pancreatitis for glucose intolerance Recommendations for management and referral have been published [ • Chronic pancreatitis with pancreatic exocrine insufficiency or pancreatic surgery may confound management of diabetes since the rate of nutrient digestion and absorption may be different from delivery of insulin (asynchrony). Attention to symptoms surrounding meals and multidisciplinary evaluation (gastroenterologists and endocrinologists) are needed to address these challenges. See also ## Prevention of Primary Manifestations The ability to prevent the primary manifestations of pancreatitis is limited. The following recommendations are for individuals with (or at risk for) hereditary pancreatitis. Following these recommendations from early childhood may help prevent attacks of acute pancreatitis: ## Agents/Circumstances to Avoid ## Genetic Risk Assessment Pancreatitis can occur as an isolated finding or as part of a rare genetic syndrome. This section reviews genetic counseling issues associated with isolated pancreatitis. Pathogenic variants associated with an increased risk for pancreatitis as an isolated finding may be inherited in an autosomal dominant, autosomal recessive, or polygenic manner. The risk to family members depends on the underlying etiology. Autosomal dominant hereditary pancreatitis (HP) is associated with either of the following: Heterozygous gain-of-function Rare heterozygous variants in Autosomal recessive familial pancreatitis is associated with either of the following: Biallelic pathogenic variants in Biallelic pathogenic variants in Polygenic inheritance is associated with either of the following: The presence of heterozygous pathogenic variants in two different pancreatitis-associated genes. Examples include: Additive or epistatic contributions of variants in multiple genes at different loci. Examples include Many individuals diagnosed as having Rarely, an individual diagnosed with Recommendations for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a Note: If a proband is reported to have a Although most individuals diagnosed with If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected or has a If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the The parents of an individual diagnosed as having autosomal recessive familial pancreatitis are obligate heterozygotes (i.e., presumed to be carriers a single copy of a pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. ( The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of not being a carrier. The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). Identification of heterozygous pathogenic variants in two different hereditary pancreatitis-associated genes or additive contributions of variants in multiple genes at different loci indicates complex disease and genetic risk assessment should be handled on a case-by-case basis. Specific combinations of genetic factors may be epistatic while others are additive. No systematic approach is available to predict the effects of most of these complex genotypes. Genetic testing can only determine if a person has or has not inherited a variant that confers high risk for disease. Genetic testing cannot determine if the individual will develop disease, the age of disease onset, or disease severity. The assessment of risk to family members of developing pancreatitis depends on several variables: genetic risk factors, smoking, alcohol use, sex, and developmental differences such as pancreas divisum (incomplete pancreatic duct development resulting in two duct systems rather than one, with most of the pancreas draining through a high-resistance papilla), as well as unknown environmental and genetic risk factors. Thus, risk assessment needs to be tailored to each individual and family. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for hereditary pancreatitis are possible. Note: The reduced penetrance and inability to predict the natural disease course or severity of disease based on a genetic test result generally make interpretation of prenatal testing indeterminate. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Heterozygous gain-of-function • Rare heterozygous variants in • Biallelic pathogenic variants in • Biallelic pathogenic variants in • The presence of heterozygous pathogenic variants in two different pancreatitis-associated genes. Examples include: • Additive or epistatic contributions of variants in multiple genes at different loci. Examples include • Many individuals diagnosed as having • Rarely, an individual diagnosed with • Recommendations for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • Note: If a proband is reported to have a • Although most individuals diagnosed with • If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected or has a • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the • The parents of an individual diagnosed as having autosomal recessive familial pancreatitis are obligate heterozygotes (i.e., presumed to be carriers a single copy of a pathogenic variant based on family history). • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. ( • The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). • If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of not being a carrier. • The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). • Genetic testing can only determine if a person has or has not inherited a variant that confers high risk for disease. Genetic testing cannot determine if the individual will develop disease, the age of disease onset, or disease severity. • The assessment of risk to family members of developing pancreatitis depends on several variables: genetic risk factors, smoking, alcohol use, sex, and developmental differences such as pancreas divisum (incomplete pancreatic duct development resulting in two duct systems rather than one, with most of the pancreas draining through a high-resistance papilla), as well as unknown environmental and genetic risk factors. Thus, risk assessment needs to be tailored to each individual and family. ## Modes of Inheritance Pancreatitis can occur as an isolated finding or as part of a rare genetic syndrome. This section reviews genetic counseling issues associated with isolated pancreatitis. Pathogenic variants associated with an increased risk for pancreatitis as an isolated finding may be inherited in an autosomal dominant, autosomal recessive, or polygenic manner. The risk to family members depends on the underlying etiology. Autosomal dominant hereditary pancreatitis (HP) is associated with either of the following: Heterozygous gain-of-function Rare heterozygous variants in Autosomal recessive familial pancreatitis is associated with either of the following: Biallelic pathogenic variants in Biallelic pathogenic variants in Polygenic inheritance is associated with either of the following: The presence of heterozygous pathogenic variants in two different pancreatitis-associated genes. Examples include: Additive or epistatic contributions of variants in multiple genes at different loci. Examples include • Heterozygous gain-of-function • Rare heterozygous variants in • Biallelic pathogenic variants in • Biallelic pathogenic variants in • The presence of heterozygous pathogenic variants in two different pancreatitis-associated genes. Examples include: • Additive or epistatic contributions of variants in multiple genes at different loci. Examples include ## Autosomal Dominant Inheritance (PRSS1-HP) – Risk to Family Members Many individuals diagnosed as having Rarely, an individual diagnosed with Recommendations for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a Note: If a proband is reported to have a Although most individuals diagnosed with If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected or has a If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the • Many individuals diagnosed as having • Rarely, an individual diagnosed with • Recommendations for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • Note: If a proband is reported to have a • Although most individuals diagnosed with • If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected or has a • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an individual diagnosed as having autosomal recessive familial pancreatitis are obligate heterozygotes (i.e., presumed to be carriers a single copy of a pathogenic variant based on family history). Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. ( The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of not being a carrier. The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). • The parents of an individual diagnosed as having autosomal recessive familial pancreatitis are obligate heterozygotes (i.e., presumed to be carriers a single copy of a pathogenic variant based on family history). • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment. ( • The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). • If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of not being a carrier. • The risk for pancreatitis in individuals heterozygous for a pathogenic variant in a gene associated with autosomal recessive inheritance is presumed to be similar to that of the general population. Note: The risk for pancreatitis may be slightly increased if the heterozygous individual has additional genetic risk factors (i.e., a second heterozygous pathogenic variant in a different hereditary pancreatitis-associated gene or additive contributions of variants in multiple genes at different loci). ## Polygenic Inheritance – Risk to Family Members Identification of heterozygous pathogenic variants in two different hereditary pancreatitis-associated genes or additive contributions of variants in multiple genes at different loci indicates complex disease and genetic risk assessment should be handled on a case-by-case basis. Specific combinations of genetic factors may be epistatic while others are additive. No systematic approach is available to predict the effects of most of these complex genotypes. ## Related Genetic Counseling Issues Genetic testing can only determine if a person has or has not inherited a variant that confers high risk for disease. Genetic testing cannot determine if the individual will develop disease, the age of disease onset, or disease severity. The assessment of risk to family members of developing pancreatitis depends on several variables: genetic risk factors, smoking, alcohol use, sex, and developmental differences such as pancreas divisum (incomplete pancreatic duct development resulting in two duct systems rather than one, with most of the pancreas draining through a high-resistance papilla), as well as unknown environmental and genetic risk factors. Thus, risk assessment needs to be tailored to each individual and family. • Genetic testing can only determine if a person has or has not inherited a variant that confers high risk for disease. Genetic testing cannot determine if the individual will develop disease, the age of disease onset, or disease severity. • The assessment of risk to family members of developing pancreatitis depends on several variables: genetic risk factors, smoking, alcohol use, sex, and developmental differences such as pancreas divisum (incomplete pancreatic duct development resulting in two duct systems rather than one, with most of the pancreas draining through a high-resistance papilla), as well as unknown environmental and genetic risk factors. Thus, risk assessment needs to be tailored to each individual and family. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for hereditary pancreatitis are possible. Note: The reduced penetrance and inability to predict the natural disease course or severity of disease based on a genetic test result generally make interpretation of prenatal testing indeterminate. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Chapter Notes Dr Whitcomb is a physician-scientist who has dedicated his career to understanding the complexity of pancreatic physiology, pathophysiology, and pancreatic diseases in humans. He is the principal investigator of the Hereditary Pancreatitis Study and the North American Pancreatitis Study II (NAPS2), which includes over 25 major pancreas centers in the United States. He also serves as Chief, Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh and UPMC. He is the editor and webmaster of pancreas.org and co-editor, with Sheila Solomon, MS, CGC, of a patient-directed newsletter, Pancreas Education and Research Letter (PEaRL). Dr Whitcomb's work is focused on personalized medicine, with emphasis on early detection and prevention of a variety of pancreatic disorders using next-generation DNA sequencing, biomarkers, and comparative effectiveness research. A specialized Pancreas Center of Excellence incorporating genetic testing and counseling early in the evaluation of pancreatic disease has been established [ Jessica LaRusch, PhD (2014-present)Celeste Shelton, PhD, CGC (2020-present)Sheila Solomon, MS, CGC; GeneDx, Inc (2014-2020)David C Whitcomb, MD, PhD (2014-present) 2 July 2020 (sw) Comprehensive update posted live 13 March 2014 (me) Review posted live 20 December 2010 (dcw) Original submission • 2 July 2020 (sw) Comprehensive update posted live • 13 March 2014 (me) Review posted live • 20 December 2010 (dcw) Original submission ## Author Notes Dr Whitcomb is a physician-scientist who has dedicated his career to understanding the complexity of pancreatic physiology, pathophysiology, and pancreatic diseases in humans. He is the principal investigator of the Hereditary Pancreatitis Study and the North American Pancreatitis Study II (NAPS2), which includes over 25 major pancreas centers in the United States. He also serves as Chief, Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh and UPMC. He is the editor and webmaster of pancreas.org and co-editor, with Sheila Solomon, MS, CGC, of a patient-directed newsletter, Pancreas Education and Research Letter (PEaRL). Dr Whitcomb's work is focused on personalized medicine, with emphasis on early detection and prevention of a variety of pancreatic disorders using next-generation DNA sequencing, biomarkers, and comparative effectiveness research. A specialized Pancreas Center of Excellence incorporating genetic testing and counseling early in the evaluation of pancreatic disease has been established [ ## Author History Jessica LaRusch, PhD (2014-present)Celeste Shelton, PhD, CGC (2020-present)Sheila Solomon, MS, CGC; GeneDx, Inc (2014-2020)David C Whitcomb, MD, PhD (2014-present) ## Revision History 2 July 2020 (sw) Comprehensive update posted live 13 March 2014 (me) Review posted live 20 December 2010 (dcw) Original submission • 2 July 2020 (sw) Comprehensive update posted live • 13 March 2014 (me) Review posted live • 20 December 2010 (dcw) Original submission ## References Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, Schwarzenberg SJ, Lowe ME, Rickels MR, Whitcomb DC, Matthews JB. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. 2014. Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: chronic pancreatitis. Am J Gastroenterol. 2020;115:322-39. [ Rickels MR, Bellin M, Toledo FG, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC; PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. 2013. Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. 2016. Whitcomb DC, Shimosegawa T, Chari ST, Forsmark CE, Frulloni L, Garg P, Hegyi P, Hirooka Y, Irisawa A, Ishikawa T, Isaji S, Lerch MM, Levy P, Masamune A, Wilcox CM, Windsor J, Yadav D, Sheel A, Neoptolemos JP, et al. International consensus statements on early chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club. Pancreatology. 2018;18:516-27. [ • Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, Schwarzenberg SJ, Lowe ME, Rickels MR, Whitcomb DC, Matthews JB. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. 2014. • Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: chronic pancreatitis. Am J Gastroenterol. 2020;115:322-39. [ • Rickels MR, Bellin M, Toledo FG, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC; PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. 2013. • Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. 2016. • Whitcomb DC, Shimosegawa T, Chari ST, Forsmark CE, Frulloni L, Garg P, Hegyi P, Hirooka Y, Irisawa A, Ishikawa T, Isaji S, Lerch MM, Levy P, Masamune A, Wilcox CM, Windsor J, Yadav D, Sheel A, Neoptolemos JP, et al. International consensus statements on early chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club. Pancreatology. 2018;18:516-27. [ ## Published Guidelines / Consensus Statements Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, Schwarzenberg SJ, Lowe ME, Rickels MR, Whitcomb DC, Matthews JB. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. 2014. Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: chronic pancreatitis. Am J Gastroenterol. 2020;115:322-39. [ Rickels MR, Bellin M, Toledo FG, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC; PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. 2013. Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. 2016. Whitcomb DC, Shimosegawa T, Chari ST, Forsmark CE, Frulloni L, Garg P, Hegyi P, Hirooka Y, Irisawa A, Ishikawa T, Isaji S, Lerch MM, Levy P, Masamune A, Wilcox CM, Windsor J, Yadav D, Sheel A, Neoptolemos JP, et al. International consensus statements on early chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club. Pancreatology. 2018;18:516-27. [ • Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, Schwarzenberg SJ, Lowe ME, Rickels MR, Whitcomb DC, Matthews JB. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. 2014. • Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: chronic pancreatitis. Am J Gastroenterol. 2020;115:322-39. [ • Rickels MR, Bellin M, Toledo FG, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC; PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. 2013. • Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. 2016. • Whitcomb DC, Shimosegawa T, Chari ST, Forsmark CE, Frulloni L, Garg P, Hegyi P, Hirooka Y, Irisawa A, Ishikawa T, Isaji S, Lerch MM, Levy P, Masamune A, Wilcox CM, Windsor J, Yadav D, Sheel A, Neoptolemos JP, et al. International consensus statements on early chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club. Pancreatology. 2018;18:516-27. [ ## Literature Cited	[]	13/3/2014	2/7/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
papr	papr	[ "Papillorenal Syndrome", "Renal Coloboma Syndrome", "Papillorenal Syndrome", "Renal Coloboma Syndrome", "Paired box protein Pax-2", "PAX2", "PAX2-Related Disorder" ]		Matthew A Bower, Lisa A Schimmenti, Michael R Eccles	Summary The diagnosis of	## Diagnosis Renal coloboma syndrome (or papillorenal syndrome) was the name given to an autosomal dominant condition associated with renal hypodysplasia and abnormalities of the optic nerve and a heterozygous pathogenic variant in There are no formal diagnostic criteria for Note: Abnormalities of kidney structure and/or function are the most frequent finding in individuals with The primary eye finding is The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc exit instead from the periphery [ A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. Note: (1) Differences exist in the terminology used to designate dysplasia of the optic nerve with abnormal passage of retinal vessels from the periphery of the optic nerve head. Some ophthalmologists refer to this finding as congenital excavation of the optic nerve and others as "optic nerve coloboma." However, the use of the term coloboma can be confusing in this setting because coloboma usually refers to non-closure of the optic fissure during the seventh week of gestation, resulting in typical uveal colobomas (iris and retinal colobomas). The developmental mechanism underlying the optic nerve abnormalities observed in Note: (1) Some individuals with A wide range of non-renal and non-ophthalmologic findings including high-frequency sensorineural hearing loss – or more rarely, CNS malformations, developmental delay, hyperuricemia (gout), soft skin, joint laxity, and elevated pancreatic amylase – have been reported in individuals with The diagnosis of Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Note: A single case of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Based on 136/144 probands with pathogenic variants detected by sequence analysis in the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted methods will detect from single-exon to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Two intragenic Six whole-gene deletions have been reported [ A single individual with a • The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc exit instead from the periphery [ • A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. • The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. • Note: A single case of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Note: Abnormalities of kidney structure and/or function are the most frequent finding in individuals with The primary eye finding is The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc exit instead from the periphery [ A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. Note: (1) Differences exist in the terminology used to designate dysplasia of the optic nerve with abnormal passage of retinal vessels from the periphery of the optic nerve head. Some ophthalmologists refer to this finding as congenital excavation of the optic nerve and others as "optic nerve coloboma." However, the use of the term coloboma can be confusing in this setting because coloboma usually refers to non-closure of the optic fissure during the seventh week of gestation, resulting in typical uveal colobomas (iris and retinal colobomas). The developmental mechanism underlying the optic nerve abnormalities observed in Note: (1) Some individuals with A wide range of non-renal and non-ophthalmologic findings including high-frequency sensorineural hearing loss – or more rarely, CNS malformations, developmental delay, hyperuricemia (gout), soft skin, joint laxity, and elevated pancreatic amylase – have been reported in individuals with • The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc exit instead from the periphery [ • A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. • The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. ## Kidney Abnormalities of kidney structure and/or function are the most frequent finding in individuals with ## Eye The primary eye finding is The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc exit instead from the periphery [ A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. Note: (1) Differences exist in the terminology used to designate dysplasia of the optic nerve with abnormal passage of retinal vessels from the periphery of the optic nerve head. Some ophthalmologists refer to this finding as congenital excavation of the optic nerve and others as "optic nerve coloboma." However, the use of the term coloboma can be confusing in this setting because coloboma usually refers to non-closure of the optic fissure during the seventh week of gestation, resulting in typical uveal colobomas (iris and retinal colobomas). The developmental mechanism underlying the optic nerve abnormalities observed in Note: (1) Some individuals with • The most severe form is characterized by an apparently enlarged disc in which the vessels that normally exit from the center of the disc exit instead from the periphery [ • A milder form is an optic nerve pit characterized by a relatively localized (or sub-total) excavation of the optic disc. • The mildest form is the exiting of the retinal vessels from the periphery of the disc without malformation of the disc itself. ## Other A wide range of non-renal and non-ophthalmologic findings including high-frequency sensorineural hearing loss – or more rarely, CNS malformations, developmental delay, hyperuricemia (gout), soft skin, joint laxity, and elevated pancreatic amylase – have been reported in individuals with ## Establishing the Diagnosis The diagnosis of Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Note: A single case of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Based on 136/144 probands with pathogenic variants detected by sequence analysis in the Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted methods will detect from single-exon to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Two intragenic Six whole-gene deletions have been reported [ A single individual with a • Note: A single case of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics In some instances a detailed eye examination is necessary to reveal the ocular findings of A wide range of kidney and eye findings can be found in individuals with The natural history of vesicoureteral reflux varies: in some individuals ureteral reimplantation has been required [ The natural history of visual acuity in individuals with Review of all reported cases to date does not reveal a consistent genotype/phenotype correlation. This is most dramatically illustrated by the tremendous Only one individual with a pathogenic variant in Terms previously used for renal coloboma (papillorenal syndrome) syndrome: Coloboma-ureteral-renal syndrome Optic nerve coloboma with renal disease Coloboma of the optic nerve with renal disease Optic coloboma-vesicoureteral reflux-renal anomalies Controversy regarding the naming of this syndrome has caused confusion in the field. The condition was named renal coloboma syndrome based on the presence of kidney abnormalities and the optic nerve abnormalities described by the ophthalmologists who identified the original families found to have The prevalence of • Coloboma-ureteral-renal syndrome • Optic nerve coloboma with renal disease • Coloboma of the optic nerve with renal disease • Optic coloboma-vesicoureteral reflux-renal anomalies ## Clinical Description In some instances a detailed eye examination is necessary to reveal the ocular findings of A wide range of kidney and eye findings can be found in individuals with The natural history of vesicoureteral reflux varies: in some individuals ureteral reimplantation has been required [ The natural history of visual acuity in individuals with ## Genotype-Phenotype Correlations Review of all reported cases to date does not reveal a consistent genotype/phenotype correlation. This is most dramatically illustrated by the tremendous ## Penetrance Only one individual with a pathogenic variant in ## Nomenclature Terms previously used for renal coloboma (papillorenal syndrome) syndrome: Coloboma-ureteral-renal syndrome Optic nerve coloboma with renal disease Coloboma of the optic nerve with renal disease Optic coloboma-vesicoureteral reflux-renal anomalies Controversy regarding the naming of this syndrome has caused confusion in the field. The condition was named renal coloboma syndrome based on the presence of kidney abnormalities and the optic nerve abnormalities described by the ophthalmologists who identified the original families found to have • Coloboma-ureteral-renal syndrome • Optic nerve coloboma with renal disease • Coloboma of the optic nerve with renal disease • Optic coloboma-vesicoureteral reflux-renal anomalies ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked An estimated 65%-70% of individuals with CHARGE syndrome have pathogenic variants in or deletions of Although Joubert syndrome is inherited predominantly in an autosomal recessive manner. Joubert syndrome is characterized by a distinctive cerebellar and brain stem malformation (the "molar tooth sign" seen on cranial MRI), hypotonia, developmental delays, and either episodic hyperpnea (or apnea) or atypical eye movements, or both. Most children with Joubert syndrome develop truncal ataxia. ## Management To establish the extent of disease and needs in an individual diagnosed with Evaluation of renal structure by renal ultrasound examination Measurement of renal function by serum electrolyte concentrations, BUN, and creatinine Urinalysis to evaluate for the presence of blood and protein Evaluation for vesicoureteral reflux, by voiding cystourethrogram (VCUG) Dilated eye examination Audiologic assessment (See Consultation with a clinical geneticist and/or genetic counselor A team approach that includes specialists in ophthalmology, nephrology, audiology, and clinical genetics is recommended. Management is focused on preventing complications of end-stage renal disease (ESRD) and/or vision loss resulting from retinal detachment. Ongoing treatment of hypertension and/or vesicoureteral reflux (if present) may preserve renal function. ESRD is treated with renal replacement therapy (i.e., dialysis and/or renal transplantation). Low vision experts can assist with adaptive functioning of those with significant vision loss. Prevention of retinal detachment in those with congenital optic nerve abnormalities includes close follow up with an ophthalmologist and use of protective eyewear. No disease-specific guidelines have been developed. The following ongoing evaluations are recommended in all individuals with Follow up by a nephrologist to monitor renal function and blood pressure Follow up by an ophthalmologist to monitor vision. Any change in vision could indicate a retinal detachment and should be treated as a medical emergency. Audiometric evaluation with periodic follow up Avoid the following: Use of medications known to affect renal function (requires consultation with a specialist in nephrology) Contact sports It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing of the See It is important that a female with Search • Evaluation of renal structure by renal ultrasound examination • Measurement of renal function by serum electrolyte concentrations, BUN, and creatinine • Urinalysis to evaluate for the presence of blood and protein • Evaluation for vesicoureteral reflux, by voiding cystourethrogram (VCUG) • Dilated eye examination • Audiologic assessment (See • Consultation with a clinical geneticist and/or genetic counselor • Ongoing treatment of hypertension and/or vesicoureteral reflux (if present) may preserve renal function. • ESRD is treated with renal replacement therapy (i.e., dialysis and/or renal transplantation). • Low vision experts can assist with adaptive functioning of those with significant vision loss. • Follow up by a nephrologist to monitor renal function and blood pressure • Follow up by an ophthalmologist to monitor vision. Any change in vision could indicate a retinal detachment and should be treated as a medical emergency. • Audiometric evaluation with periodic follow up • Use of medications known to affect renal function (requires consultation with a specialist in nephrology) • Contact sports ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Evaluation of renal structure by renal ultrasound examination Measurement of renal function by serum electrolyte concentrations, BUN, and creatinine Urinalysis to evaluate for the presence of blood and protein Evaluation for vesicoureteral reflux, by voiding cystourethrogram (VCUG) Dilated eye examination Audiologic assessment (See Consultation with a clinical geneticist and/or genetic counselor • Evaluation of renal structure by renal ultrasound examination • Measurement of renal function by serum electrolyte concentrations, BUN, and creatinine • Urinalysis to evaluate for the presence of blood and protein • Evaluation for vesicoureteral reflux, by voiding cystourethrogram (VCUG) • Dilated eye examination • Audiologic assessment (See • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations A team approach that includes specialists in ophthalmology, nephrology, audiology, and clinical genetics is recommended. Management is focused on preventing complications of end-stage renal disease (ESRD) and/or vision loss resulting from retinal detachment. Ongoing treatment of hypertension and/or vesicoureteral reflux (if present) may preserve renal function. ESRD is treated with renal replacement therapy (i.e., dialysis and/or renal transplantation). Low vision experts can assist with adaptive functioning of those with significant vision loss. • Ongoing treatment of hypertension and/or vesicoureteral reflux (if present) may preserve renal function. • ESRD is treated with renal replacement therapy (i.e., dialysis and/or renal transplantation). • Low vision experts can assist with adaptive functioning of those with significant vision loss. ## Prevention of Secondary Complications Prevention of retinal detachment in those with congenital optic nerve abnormalities includes close follow up with an ophthalmologist and use of protective eyewear. ## Surveillance No disease-specific guidelines have been developed. The following ongoing evaluations are recommended in all individuals with Follow up by a nephrologist to monitor renal function and blood pressure Follow up by an ophthalmologist to monitor vision. Any change in vision could indicate a retinal detachment and should be treated as a medical emergency. Audiometric evaluation with periodic follow up • Follow up by a nephrologist to monitor renal function and blood pressure • Follow up by an ophthalmologist to monitor vision. Any change in vision could indicate a retinal detachment and should be treated as a medical emergency. • Audiometric evaluation with periodic follow up ## Agents/Circumstances to Avoid Avoid the following: Use of medications known to affect renal function (requires consultation with a specialist in nephrology) Contact sports • Use of medications known to affect renal function (requires consultation with a specialist in nephrology) • Contact sports ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing of the See ## Pregnancy Management It is important that a female with ## Therapies Under Investigation Search ## Genetic Counseling Approximately 35% of individuals with Approximately 65% of probands with Recommendations for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or neither parent has clinical findings consistent with a diagnosis of Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Ophthalmologic abnormalities consistent with If a parent of the proband is affected, the risk to the sibs is 50%. If the parents of a proband with A parent of the proband has the If the See The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Approximately 35% of individuals with • Approximately 65% of probands with • Recommendations for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or neither parent has clinical findings consistent with a diagnosis of • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • Ophthalmologic abnormalities consistent with • If a parent of the proband is affected, the risk to the sibs is 50%. • If the parents of a proband with • A parent of the proband has the • If the • A parent of the proband has the • If the • A parent of the proband has the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Approximately 35% of individuals with Approximately 65% of probands with Recommendations for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or neither parent has clinical findings consistent with a diagnosis of Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Ophthalmologic abnormalities consistent with If a parent of the proband is affected, the risk to the sibs is 50%. If the parents of a proband with A parent of the proband has the If the • Approximately 35% of individuals with • Approximately 65% of probands with • Recommendations for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or neither parent has clinical findings consistent with a diagnosis of • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • Ophthalmologic abnormalities consistent with • If a parent of the proband is affected, the risk to the sibs is 50%. • If the parents of a proband with • A parent of the proband has the • If the • A parent of the proband has the • If the • A parent of the proband has the • If the ## Related Genetic Counseling Issues See The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada • • • • Canada • • • • • ## Molecular Genetics PAX2-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PAX2-Related Disorder ( The pattern of abnormalities in Frameshift variants are the most common type; nonsense and missense variants, splice site changes, and in-frame duplications have also been reported. Pathogenic variants tend to cluster in the paired domain (exons 2-4), the homeodomain (exon 7), and the 5' portion of the transactivation domain (exon 8). A limited number of missense variants have been reported in exons 9-12, but the pathogenicity of these variants is not clearly established. A small number of genomic deletions and rearrangements have been reported. Partial-gene deletions are not a common pathogenic mechanism [ The most common recurring pathogenic variant, c.76dupG (previously called c.619insG), is a duplication of a G residue in a stretch of seven Gs and has been reported in more than 25 independent families. Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions To date, all clearly pathogenic in-frame variants (missense, in-frame deletions, and in-frame duplications) are located in the paired domain (exons 2-4). It is not known if these pathogenic variants exert their effect by reducing the binding to normal DNA targets or by allowing binding to abnormal DNA targets. Six missense variants have been reported outside of the paired domain. Each of these variants has been reported in a single individual and the evidence for pathogenicity is not as strong as with other ## Molecular Pathogenesis The pattern of abnormalities in Frameshift variants are the most common type; nonsense and missense variants, splice site changes, and in-frame duplications have also been reported. Pathogenic variants tend to cluster in the paired domain (exons 2-4), the homeodomain (exon 7), and the 5' portion of the transactivation domain (exon 8). A limited number of missense variants have been reported in exons 9-12, but the pathogenicity of these variants is not clearly established. A small number of genomic deletions and rearrangements have been reported. Partial-gene deletions are not a common pathogenic mechanism [ The most common recurring pathogenic variant, c.76dupG (previously called c.619insG), is a duplication of a G residue in a stretch of seven Gs and has been reported in more than 25 independent families. Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions To date, all clearly pathogenic in-frame variants (missense, in-frame deletions, and in-frame duplications) are located in the paired domain (exons 2-4). It is not known if these pathogenic variants exert their effect by reducing the binding to normal DNA targets or by allowing binding to abnormal DNA targets. Six missense variants have been reported outside of the paired domain. Each of these variants has been reported in a single individual and the evidence for pathogenicity is not as strong as with other ## Chapter Notes 14 August 2025 (aa) Revision: 8 February 2018 (ha) Comprehensive update posted live 20 November 2014 (me) Comprehensive update posted live 12 July 2012 (me) Comprehensive update posted live 8 June 2007 (me) Review posted live 8 December 2006 (las) Original submission • 14 August 2025 (aa) Revision: • 8 February 2018 (ha) Comprehensive update posted live • 20 November 2014 (me) Comprehensive update posted live • 12 July 2012 (me) Comprehensive update posted live • 8 June 2007 (me) Review posted live • 8 December 2006 (las) Original submission ## Revision History 14 August 2025 (aa) Revision: 8 February 2018 (ha) Comprehensive update posted live 20 November 2014 (me) Comprehensive update posted live 12 July 2012 (me) Comprehensive update posted live 8 June 2007 (me) Review posted live 8 December 2006 (las) Original submission • 14 August 2025 (aa) Revision: • 8 February 2018 (ha) Comprehensive update posted live • 20 November 2014 (me) Comprehensive update posted live • 12 July 2012 (me) Comprehensive update posted live • 8 June 2007 (me) Review posted live • 8 December 2006 (las) Original submission ## References ## Literature Cited	[]	8/6/2007	8/2/2018	14/8/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
paragangliomas	paragangliomas	[ "Protein max", "Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial", "Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial", "Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial", "Succinate dehydrogenase assembly factor 2, mitochondrial", "Succinate dehydrogenase cytochrome b560 subunit, mitochondrial", "Transmembrane protein 127", "MAX", "SDHA", "SDHAF2", "SDHB", "SDHC", "SDHD", "TMEM127", "Hereditary Paraganglioma-Pheochromocytoma Syndromes" ]	Hereditary Paraganglioma-Pheochromocytoma Syndromes	Tobias Else, Samantha Greenberg, Lauren Fishbein	Summary Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck paragangliomas [HNPGLs]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, extra-adrenal sympathetic paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCCs result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas. Additional tumors reported in individuals with hereditary PGL/PCC syndromes include gastrointestinal stromal tumors (GISTs), pulmonary chondromas, and clear cell renal cell carcinoma. A diagnosis of a hereditary PGL/PCC syndrome is strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma. The diagnosis is established in a proband with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in Hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent; rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a	## Diagnosis The Endocrine Society guidelines for pheochromocytoma and paraganglioma [ A hereditary PGL/PCC syndrome Tumors that are: Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma Multifocal, with multiple synchronous or metachronous tumors Recurrent Early onset (i.e., age <45 years) Extra-adrenal Metastatic A family history of paraganglioma or pheochromocytoma, or relatives with unexplained or incompletely explained sudden death Note: Many individuals with a hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal medulla, or pelvis and no family history of paraganglioma or pheochromocytoma. The following clinical and laboratory features suggest a paraganglioma or pheochromocytoma. Note that many paragangliomas and pheochromocytomas are discovered incidentally on imaging done for other reasons. Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. Palpable abdominal mass Enlarging mass of the skull base or neck Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) Tinnitus Metanephrine or its precursor epinephrine (adrenaline) Normetanephrine or its precursor norepinephrine (noradrenaline) Dopamine and its major metabolite 3-methyoxytyramine Note: (1) Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations [ The diagnosis of a The diagnosis of Note: (1) Some families have multiple individuals with a paraganglioma or pheochromocytoma and no identifiable pathogenic variant in a known susceptibility gene. These families likely have a hereditary PGL/PCC syndrome either from a pathogenic variant in a regulatory element not found through standard molecular analysis or from a pathogenic variant in an unidentified susceptibility gene. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches include the use of a For an introduction to multigene panels click Molecular Genetic Testing Used in Hereditary Paraganglioma-Pheochromocytoma Syndromes PGL = paraganglioma; PCC = pheochromocytoma Genes are listed in alphabetic order. See Data derived from the subscription-based professional view of Human Gene Mutation Database [ See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to pseudogenes, many labs do not perform An An This table includes the core genes associated with hereditary paraganglioma-pheochromocytoma syndromes. If germline molecular genetic testing for hereditary PGL/PCC syndromes is not readily available, the results of immunohistochemical tumor analysis may suggest the presence of an underlying germline pathogenic variant. When any component of the mitochondrial respiratory chain complex 2 is completely inactivated, often the entire complex becomes unstable, resulting in degradation of the SDHB subunit. Therefore, negative immunohistochemistry staining for SDHB appears to occur when a germline pathogenic variant in For these reasons, some recommend SDHB immunohistochemistry in individuals with familial and apparently sporadic PGL/PCC to guide molecular genetic testing; however, evidence is currently insufficient to advocate for the routine use of immunohistochemistry to guide molecular testing, as several nonconcordant cases have been reported [ • Tumors that are: • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma • Multifocal, with multiple synchronous or metachronous tumors • Recurrent • Early onset (i.e., age <45 years) • Extra-adrenal • Metastatic • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma • Multifocal, with multiple synchronous or metachronous tumors • Recurrent • Early onset (i.e., age <45 years) • Extra-adrenal • Metastatic • A family history of paraganglioma or pheochromocytoma, or relatives with unexplained or incompletely explained sudden death • Note: Many individuals with a hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal medulla, or pelvis and no family history of paraganglioma or pheochromocytoma. • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma • Multifocal, with multiple synchronous or metachronous tumors • Recurrent • Early onset (i.e., age <45 years) • Extra-adrenal • Metastatic • • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) • Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. • Palpable abdominal mass • Enlarging mass of the skull base or neck • Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) • Tinnitus • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) • Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. • Palpable abdominal mass • Enlarging mass of the skull base or neck • Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) • Tinnitus • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methyoxytyramine • Note: (1) Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations [ • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methyoxytyramine • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) • Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. • Palpable abdominal mass • Enlarging mass of the skull base or neck • Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) • Tinnitus • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methyoxytyramine • For an introduction to multigene panels click ## Suggestive Findings A hereditary PGL/PCC syndrome Tumors that are: Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma Multifocal, with multiple synchronous or metachronous tumors Recurrent Early onset (i.e., age <45 years) Extra-adrenal Metastatic A family history of paraganglioma or pheochromocytoma, or relatives with unexplained or incompletely explained sudden death Note: Many individuals with a hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal medulla, or pelvis and no family history of paraganglioma or pheochromocytoma. The following clinical and laboratory features suggest a paraganglioma or pheochromocytoma. Note that many paragangliomas and pheochromocytomas are discovered incidentally on imaging done for other reasons. Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. Palpable abdominal mass Enlarging mass of the skull base or neck Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) Tinnitus Metanephrine or its precursor epinephrine (adrenaline) Normetanephrine or its precursor norepinephrine (noradrenaline) Dopamine and its major metabolite 3-methyoxytyramine Note: (1) Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations [ • Tumors that are: • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma • Multifocal, with multiple synchronous or metachronous tumors • Recurrent • Early onset (i.e., age <45 years) • Extra-adrenal • Metastatic • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma • Multifocal, with multiple synchronous or metachronous tumors • Recurrent • Early onset (i.e., age <45 years) • Extra-adrenal • Metastatic • A family history of paraganglioma or pheochromocytoma, or relatives with unexplained or incompletely explained sudden death • Note: Many individuals with a hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal medulla, or pelvis and no family history of paraganglioma or pheochromocytoma. • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma • Multifocal, with multiple synchronous or metachronous tumors • Recurrent • Early onset (i.e., age <45 years) • Extra-adrenal • Metastatic • • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) • Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. • Palpable abdominal mass • Enlarging mass of the skull base or neck • Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) • Tinnitus • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) • Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. • Palpable abdominal mass • Enlarging mass of the skull base or neck • Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) • Tinnitus • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methyoxytyramine • Note: (1) Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations [ • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methyoxytyramine • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., pallor, nausea/vomiting, and sudden change in glycemic control) • Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition. • Palpable abdominal mass • Enlarging mass of the skull base or neck • Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome) • Tinnitus • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methyoxytyramine ## Establishing the Diagnosis The diagnosis of a The diagnosis of Note: (1) Some families have multiple individuals with a paraganglioma or pheochromocytoma and no identifiable pathogenic variant in a known susceptibility gene. These families likely have a hereditary PGL/PCC syndrome either from a pathogenic variant in a regulatory element not found through standard molecular analysis or from a pathogenic variant in an unidentified susceptibility gene. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches include the use of a For an introduction to multigene panels click Molecular Genetic Testing Used in Hereditary Paraganglioma-Pheochromocytoma Syndromes PGL = paraganglioma; PCC = pheochromocytoma Genes are listed in alphabetic order. See Data derived from the subscription-based professional view of Human Gene Mutation Database [ See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to pseudogenes, many labs do not perform An An This table includes the core genes associated with hereditary paraganglioma-pheochromocytoma syndromes. If germline molecular genetic testing for hereditary PGL/PCC syndromes is not readily available, the results of immunohistochemical tumor analysis may suggest the presence of an underlying germline pathogenic variant. When any component of the mitochondrial respiratory chain complex 2 is completely inactivated, often the entire complex becomes unstable, resulting in degradation of the SDHB subunit. Therefore, negative immunohistochemistry staining for SDHB appears to occur when a germline pathogenic variant in For these reasons, some recommend SDHB immunohistochemistry in individuals with familial and apparently sporadic PGL/PCC to guide molecular genetic testing; however, evidence is currently insufficient to advocate for the routine use of immunohistochemistry to guide molecular testing, as several nonconcordant cases have been reported [ • For an introduction to multigene panels click ## Tumor Immunohistochemistry If germline molecular genetic testing for hereditary PGL/PCC syndromes is not readily available, the results of immunohistochemical tumor analysis may suggest the presence of an underlying germline pathogenic variant. When any component of the mitochondrial respiratory chain complex 2 is completely inactivated, often the entire complex becomes unstable, resulting in degradation of the SDHB subunit. Therefore, negative immunohistochemistry staining for SDHB appears to occur when a germline pathogenic variant in For these reasons, some recommend SDHB immunohistochemistry in individuals with familial and apparently sporadic PGL/PCC to guide molecular genetic testing; however, evidence is currently insufficient to advocate for the routine use of immunohistochemistry to guide molecular testing, as several nonconcordant cases have been reported [ ## Clinical Characteristics In individuals with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, tumors arise within the paraganglia – collections of neural crest cells distributed along the paravertebral axis from the base of the skull to the pelvis – as well as in some visceral locations. The 2022 World Health Organization (WHO) Classification of Endocrine Tumours classifies paragangliomas by location and (directly or indirectly) secretory status (adrenal paraganglioma [called pheochromocytoma], sympathetic abdominal paraganglioma, sympathetic head and neck paraganglioma, and parasympathetic paraganglioma) [ Signs and symptoms of catecholamine excess, including episodic or sustained elevations in blood pressure and pulse, headaches, palpitations (perceived episodic, forceful, often rapid heartbeat), arrhythmias, excessive sweating, pallor, apprehension, and anxiety. Nausea, emesis, fatigue, sudden alteration in glycemic control, and weight loss can also be seen. Paroxysmal symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in individuals with urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria. Signs and symptoms related to mass effects from the neoplasm (particularly HNPGLs), which can compromise cranial nerves (e.g., VII, IX, X, XI) and sympathetic nerves in the head and neck area, leading to hoarseness, dysphagia, soft palate paresis, Horner syndrome, and/or tinnitus. Incidentally discovered mass on MRI/CT performed for other reasons Screening of at-risk relatives Metanephrine or its precursor epinephrine (adrenaline) Normetanephrine or its precursor norepinephrine (noradrenaline) Dopamine and its major metabolite 3-methoxytyramine Note: Plasma chromogranin A is not a catecholamine but is a protein often secreted by PGL/PCCs and can suggest a diagnosis of a PGL/PCC. However, elevation of plasma chromogranin A is not specific, as many other medical conditions (e.g., liver and kidney disease; gastrointestinal conditions such as atrophic gastritis, irritable bowel syndrome, and colon cancer; other malignancies and neuroendocrine tumors) and medications (e.g., proton pump inhibitors) can cause elevated plasma chromogranin A levels. Therefore, it is not recommended to measure plasma chromogranin A in those with suspected PGL/PCC. Paragangliomas can be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the para-aortic sympathetic chain, as well as some other visceral locations. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall. PGL/PCCs usually exhibit high signal intensity on T Multiple tumors can be present. Digital subtraction angiography (DSA) is sensitive for the detection of small paragangliomas and can be diagnostically definitive. DSA is essential if preoperative embolization or carotid artery occlusion is to be performed. Some experts suggest using The most common sites of PGL/PCC metastases are bone, lung, liver, and lymph nodes. For PGL/PCCs that have not metastasized, operative treatment can be curative. However, once metastases have occurred there is no cure, with a five-year survival rate of 50%-69% [ Other tumors including papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors have been described in individuals with Although persons with Distinguishing Clinical Features of Hereditary PGL/PCC Syndromes by Genetic Etiology AD = autosomal dominant; MOI = mode of inheritance; PCC = pheochromocytoma; PGL = paraganglioma General rules of thumb; exceptions exist. Mode of inheritance is likely paternal; only a few pedigrees have been described. Phenotype is not well described as only a few families have been reported. Maternal transmission has been rarely reported. No consistent genotype-phenotype correlations have been identified. Estimated Penetrance for PCC = pheochromocytoma; PGL = paraganglioma This estimate is higher than expected based on clinical experience. The hereditary PGL/PCC syndromes were initially referred to as the hereditary paraganglioma syndromes before the discovery of their association with pheochromocytomas. Hereditary paragangliomas of the head and neck have also been referred to as familial glomus tumors and familial nonchromaffin paragangliomas. Prior to the identification of the genes underlying hereditary PGL/PCC syndrome loci, the syndromes were referred to by their locus (i.e., PGL1, PGL2, PGL3, PGL4, and PGL5). A dyadic gene and phenotype-based naming approach is now preferred (e.g., In 2017 WHO replaced the term "malignant pheochromocytoma" with "metastatic pheochromocytoma" to avoid confusion in the definition. PGL/PCCs are now considered localized or metastatic, not benign or malignant. Carney-Stratakis syndrome (OMIM Pheochromocytomas are tumors of the adrenal medulla, which is a specialized paraganglion. Paragangliomas arise from paraganglial tissue anywhere in the body, usually as head and neck paragangliomas (HNPGLs; e.g., carotid body tumor, glomus jugulare tumor, glomus tympanicum tumor, glomus vagale tumor), as thoracic paragangliomas either arising from paraganglia associated with the large arteries or the paraspinal sympathetic chain, or as abdominal paragangliomas (e.g., organ of Zuckerkandl, para-adrenal, bladder wall). The term "chromaffin" tumor is largely historical and refers to positive staining by chromium salts, which react with catecholamines. Therefore, usually only catecholamine-secreting tumors, such as pheochromocytomas and sympathetic paragangliomas, are truly chromaffin, while most parasympathetic tumors are silent. The incidence of hereditary PGL/PCC syndromes is not precisely known. The incidence of pheochromocytoma is approximately 0.6 in 100,000 per year [ • Signs and symptoms of catecholamine excess, including episodic or sustained elevations in blood pressure and pulse, headaches, palpitations (perceived episodic, forceful, often rapid heartbeat), arrhythmias, excessive sweating, pallor, apprehension, and anxiety. Nausea, emesis, fatigue, sudden alteration in glycemic control, and weight loss can also be seen. Paroxysmal symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in individuals with urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria. • Signs and symptoms related to mass effects from the neoplasm (particularly HNPGLs), which can compromise cranial nerves (e.g., VII, IX, X, XI) and sympathetic nerves in the head and neck area, leading to hoarseness, dysphagia, soft palate paresis, Horner syndrome, and/or tinnitus. • Incidentally discovered mass on MRI/CT performed for other reasons • Screening of at-risk relatives • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methoxytyramine • Paragangliomas can be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the para-aortic sympathetic chain, as well as some other visceral locations. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall. • PGL/PCCs usually exhibit high signal intensity on T • Multiple tumors can be present. • Digital subtraction angiography (DSA) is sensitive for the detection of small paragangliomas and can be diagnostically definitive. DSA is essential if preoperative embolization or carotid artery occlusion is to be performed. • Some experts suggest using • Other tumors including papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors have been described in individuals with ## Clinical Description In individuals with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, tumors arise within the paraganglia – collections of neural crest cells distributed along the paravertebral axis from the base of the skull to the pelvis – as well as in some visceral locations. The 2022 World Health Organization (WHO) Classification of Endocrine Tumours classifies paragangliomas by location and (directly or indirectly) secretory status (adrenal paraganglioma [called pheochromocytoma], sympathetic abdominal paraganglioma, sympathetic head and neck paraganglioma, and parasympathetic paraganglioma) [ Signs and symptoms of catecholamine excess, including episodic or sustained elevations in blood pressure and pulse, headaches, palpitations (perceived episodic, forceful, often rapid heartbeat), arrhythmias, excessive sweating, pallor, apprehension, and anxiety. Nausea, emesis, fatigue, sudden alteration in glycemic control, and weight loss can also be seen. Paroxysmal symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in individuals with urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria. Signs and symptoms related to mass effects from the neoplasm (particularly HNPGLs), which can compromise cranial nerves (e.g., VII, IX, X, XI) and sympathetic nerves in the head and neck area, leading to hoarseness, dysphagia, soft palate paresis, Horner syndrome, and/or tinnitus. Incidentally discovered mass on MRI/CT performed for other reasons Screening of at-risk relatives Metanephrine or its precursor epinephrine (adrenaline) Normetanephrine or its precursor norepinephrine (noradrenaline) Dopamine and its major metabolite 3-methoxytyramine Note: Plasma chromogranin A is not a catecholamine but is a protein often secreted by PGL/PCCs and can suggest a diagnosis of a PGL/PCC. However, elevation of plasma chromogranin A is not specific, as many other medical conditions (e.g., liver and kidney disease; gastrointestinal conditions such as atrophic gastritis, irritable bowel syndrome, and colon cancer; other malignancies and neuroendocrine tumors) and medications (e.g., proton pump inhibitors) can cause elevated plasma chromogranin A levels. Therefore, it is not recommended to measure plasma chromogranin A in those with suspected PGL/PCC. Paragangliomas can be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the para-aortic sympathetic chain, as well as some other visceral locations. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall. PGL/PCCs usually exhibit high signal intensity on T Multiple tumors can be present. Digital subtraction angiography (DSA) is sensitive for the detection of small paragangliomas and can be diagnostically definitive. DSA is essential if preoperative embolization or carotid artery occlusion is to be performed. Some experts suggest using The most common sites of PGL/PCC metastases are bone, lung, liver, and lymph nodes. For PGL/PCCs that have not metastasized, operative treatment can be curative. However, once metastases have occurred there is no cure, with a five-year survival rate of 50%-69% [ Other tumors including papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors have been described in individuals with • Signs and symptoms of catecholamine excess, including episodic or sustained elevations in blood pressure and pulse, headaches, palpitations (perceived episodic, forceful, often rapid heartbeat), arrhythmias, excessive sweating, pallor, apprehension, and anxiety. Nausea, emesis, fatigue, sudden alteration in glycemic control, and weight loss can also be seen. Paroxysmal symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in individuals with urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria. • Signs and symptoms related to mass effects from the neoplasm (particularly HNPGLs), which can compromise cranial nerves (e.g., VII, IX, X, XI) and sympathetic nerves in the head and neck area, leading to hoarseness, dysphagia, soft palate paresis, Horner syndrome, and/or tinnitus. • Incidentally discovered mass on MRI/CT performed for other reasons • Screening of at-risk relatives • Metanephrine or its precursor epinephrine (adrenaline) • Normetanephrine or its precursor norepinephrine (noradrenaline) • Dopamine and its major metabolite 3-methoxytyramine • Paragangliomas can be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the para-aortic sympathetic chain, as well as some other visceral locations. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall. • PGL/PCCs usually exhibit high signal intensity on T • Multiple tumors can be present. • Digital subtraction angiography (DSA) is sensitive for the detection of small paragangliomas and can be diagnostically definitive. DSA is essential if preoperative embolization or carotid artery occlusion is to be performed. • Some experts suggest using • Other tumors including papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors have been described in individuals with ## Phenotype Correlations by Gene Although persons with Distinguishing Clinical Features of Hereditary PGL/PCC Syndromes by Genetic Etiology AD = autosomal dominant; MOI = mode of inheritance; PCC = pheochromocytoma; PGL = paraganglioma General rules of thumb; exceptions exist. Mode of inheritance is likely paternal; only a few pedigrees have been described. Phenotype is not well described as only a few families have been reported. Maternal transmission has been rarely reported. ## Genotype-Phenotype Correlations No consistent genotype-phenotype correlations have been identified. ## Penetrance Estimated Penetrance for PCC = pheochromocytoma; PGL = paraganglioma This estimate is higher than expected based on clinical experience. ## Nomenclature The hereditary PGL/PCC syndromes were initially referred to as the hereditary paraganglioma syndromes before the discovery of their association with pheochromocytomas. Hereditary paragangliomas of the head and neck have also been referred to as familial glomus tumors and familial nonchromaffin paragangliomas. Prior to the identification of the genes underlying hereditary PGL/PCC syndrome loci, the syndromes were referred to by their locus (i.e., PGL1, PGL2, PGL3, PGL4, and PGL5). A dyadic gene and phenotype-based naming approach is now preferred (e.g., In 2017 WHO replaced the term "malignant pheochromocytoma" with "metastatic pheochromocytoma" to avoid confusion in the definition. PGL/PCCs are now considered localized or metastatic, not benign or malignant. Carney-Stratakis syndrome (OMIM Pheochromocytomas are tumors of the adrenal medulla, which is a specialized paraganglion. Paragangliomas arise from paraganglial tissue anywhere in the body, usually as head and neck paragangliomas (HNPGLs; e.g., carotid body tumor, glomus jugulare tumor, glomus tympanicum tumor, glomus vagale tumor), as thoracic paragangliomas either arising from paraganglia associated with the large arteries or the paraspinal sympathetic chain, or as abdominal paragangliomas (e.g., organ of Zuckerkandl, para-adrenal, bladder wall). The term "chromaffin" tumor is largely historical and refers to positive staining by chromium salts, which react with catecholamines. Therefore, usually only catecholamine-secreting tumors, such as pheochromocytomas and sympathetic paragangliomas, are truly chromaffin, while most parasympathetic tumors are silent. ## Prevalence The incidence of hereditary PGL/PCC syndromes is not precisely known. The incidence of pheochromocytoma is approximately 0.6 in 100,000 per year [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Disorders AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance ## Differential Diagnosis The differential diagnosis of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes includes sporadic pheochromocytoma and sporadic paraganglioma or other syndromes that predispose to pheochromocytomas or paragangliomas. Several genetic disorders (see Disorders to Consider in the Differential Diagnosis of Hereditary Paraganglioma-Pheochromocytoma Syndromes Mainly in females Polycythemia Somatostatinoma Cutaneous & uterine leiomyomas Other types of renal carcinoma Parathyroid tumors Pituitary tumors Foregut neuroendocrine tumors, incl pancreatic, lung, & duodenal neuroendocrine tumors Adrenocortical adenomas PCC that secrete epinephrine &/or norepinephrine PGL are rare. Café au lait macules Axillary & inguinal freckling Neurofibromas (cutaneous & plexiform) Long bone dysplasia Optic glioma PCC that secrete epinephrine/metanephrine &/or norepinephrine/normetanephrine PGL are rare. Medullary thyroid carcinoma Hyperparathyroidism Medullary thyroid carcinoma Mucocutaneous neuromas Ganglioneuromatosis Slender body habitus Joint laxity Skeletal malformations PCC that secrete norepinephrine/normetanephrine PGL are infrequent. Clear cell renal cell carcinoma CNS hemangioblastomas Renal, pancreatic, epididymal, & broad ligament cysts Pancreatic neuroendocrine tumors Endolymphatic sac tumors AD = autosomal dominant; CNS = central nervous system; MOI = mode of inheritance; PCC = pheochromocytoma; PGL = paraganglioma To date, the majority of reported individuals with polycythemia-paraganglioma-somatostatinoma syndrome have the disorder as the result of a somatic mosaic pathogenic variant (i.e., a pathogenic variant not inherited from a parent). • Mainly in females • Polycythemia • Somatostatinoma • Cutaneous & uterine leiomyomas • Other types of renal carcinoma • Parathyroid tumors • Pituitary tumors • Foregut neuroendocrine tumors, incl pancreatic, lung, & duodenal neuroendocrine tumors • Adrenocortical adenomas • PCC that secrete epinephrine &/or norepinephrine • PGL are rare. • Café au lait macules • Axillary & inguinal freckling • Neurofibromas (cutaneous & plexiform) • Long bone dysplasia • Optic glioma • PCC that secrete epinephrine/metanephrine &/or norepinephrine/normetanephrine • PGL are rare. • Medullary thyroid carcinoma • Hyperparathyroidism • Medullary thyroid carcinoma • Mucocutaneous neuromas • Ganglioneuromatosis • Slender body habitus • Joint laxity • Skeletal malformations • PCC that secrete norepinephrine/normetanephrine • PGL are infrequent. • Clear cell renal cell carcinoma • CNS hemangioblastomas • Renal, pancreatic, epididymal, & broad ligament cysts • Pancreatic neuroendocrine tumors • Endolymphatic sac tumors ## Management Clinical practice guidelines for the management of individuals with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes due to To establish the extent of disease and needs in an individual diagnosed with a hereditary PGL/PCC syndrome, the evaluations summarized in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Recommended Evaluations Following Initial Diagnosis Cross-sectional imaging (CT/MRI) is preferred method to define tumor extent. Functional studies, such as somatostatin receptor-based imaging (e.g., HNPGLs are often best characterized by MRI. Thoracic PGLs are best characterized by CT. Abdominal tumors by either MRI or CT Plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines (optional dopamine or 3-methoxytyramine) to screen for secreting PGL/PCC Whole-body MRI for PGL, PCC, renal cell carcinoma, & GIST EGD = esophagogastroduodenoscopy; GI = gastrointestinal; GIST = gastrointestinal stromal tumor; HNPGL = head and neck paraganglioma; MOI = mode of inheritance; PCC = pheochromocytoma; PGL = paraganglioma Medical geneticist, certified genetic counselor, certified advanced genetic nurse The management of tumors in individuals with hereditary PGL/PCC syndromes resembles management of sporadic tumors; however, persons with hereditary PGL/PCC syndromes are more likely to have multiple tumors and multifocal and/or metastatic disease than are those with sporadic tumors [ Hereditary Paraganglioma-Pheochromocytoma Syndromes: Treatment of Manifestations Surgical resection is recommended due to risk for metastases. Prompt resection is particularly important for extra-adrenal sympathetic PGLs because of their tendency to metastasize. Perioperative alpha-adrenergic blockade is typically required. Active observation Surgical resection Radiation therapy Active observation Surgical resection Radiation Surgical resection Active observation Radiation therapy or stereotactic radiosurgery in selected persons Small tumors may potentially be removed w/o complications or permanent nerve injuries. Resection of larger tumors is often assoc w/CSF leak, meningitis, stroke, hearing loss, cranial nerve palsy, or even death. Close observation w/symptomatically guided surgery may be prudent. Gamma knife stereotactic surgery is a good option to prevent morbidity from resection. Alpha-adrenergic blockade (w/prazosin/doxazosin) starting ≥7-10 days preoperatively to normalize BP & allow volume expansion. The dose of the α-blocker is adjusted for a low-normal systolic BP for age. Calcium channel blockers (e.g., amlodipine, nicardipine) as needed for second-line treatment of BP control A liberal sodium diet & fluid intake to allow for plasma volume expansion. Once adequate α-adrenergic blockade or BP control w/calcium channel blockers is achieved, initiation of beta-adrenergic blockade may be required to control reflex tachycardia. The dose of the β-blocker is adjusted for a target heart rate of 80 beats per minute. ~2-8 wks after surgery, assess 24-hour urine fractionated metanephrines &/or plasma-free metanephrines. If the levels are normal, resection of the biochemically active PCC should be considered complete. If the levels are ↑, an unresected 2nd tumor &/or occult metastases should be suspected. BP control w/α-blocker to ↓ symptoms from high catecholamine levels in persons w/sympathetic tumors Surgical debulking to ↓ tumor burden due to mass effect or catecholamine secretion Active observation for nonprogressing, nonsecreting disease Radiation therapy, esp for bony lesions Liver-directed therapy Systemic therapy w/chemotherapy (e.g., cyclophosphamide, vincristine, dacarbazine) I-131-MIBG therapy Surgical resection of localized disease, particularly if tumor is bleeding, causing obstruction, >2 cm, or ↑ in size Tyrosine kinase inhibitor (TKI) for adjuvant therapy after surgical resection or as first-line therapy in those w/metastatic disease. However, SDH-deficient GISTs are largely resistant to TKIs. Early surgical intervention Partial nephrectomy in persons w/solitary tumor at early stage Standard treatment for metastatic disease BP = blood pressure; CSF = cerebrospinal fluid; MIBG = metaiodobenzylguanidine; PCC = pheochromocytoma; PGL = paraganglioma Individuals known to have a hereditary PGL/PCC syndrome and relatives at risk based on family history who have not undergone DNA-based testing need regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes. Although no clear data regarding when to start, best method, and how frequent biochemical studies and imaging should be done in at-risk individuals exist, it is reasonable to consider surveillance for all at-risk individuals [ Hereditary Paraganglioma-Pheochromocytoma Syndromes: Surveillance for Individuals at Risk and Affected Individuals Whole-body MRI for PGL, PCC, RCC, & GIST Note: Some also suggest PET-CT, preferably w/radiolabeled somatostatin analogues. Whole-body MRI for PGL, PCC, RCC, & GIST Note: Current guidelines do not provide surveillance recommendations for at-risk persons w/ EGD = esophagogastroduodenoscopy; GI = gastrointestinal; GIST = gastrointestinal stromal tumor; PCC = pheochromocytoma; PGL = paraganglioma; RCC = renal cell carcinoma The wide age range of when to initiate these recommendations is due to multiple consensus guidelines [ Recommendations apply to individuals with a paternally inherited pathogenic variant in these genes. Although some guidelines suggest using PET-CT in combination with MRI as first-line imaging for tumor screening, there is little data for its use in screening (as opposed to defining suspected tumors), and cost and radiation exposure must be considered. Activities such as cigarette smoking that predispose to chronic lung disease should be discouraged. There is some limited evidence that the penetrance of hereditary PGL/PCC syndromes may be increased in those who live in high altitudes or are chronically exposed to hypoxic conditions [ Evaluation of apparently asymptomatic older and younger at-risk relatives of an individual with hereditary PGL/PCC syndrome is recommended. Identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited a pathogenic variant. Early detection of tumors can facilitate surgical removal, decrease related morbidity, and potentially result in removal prior to the development of metastatic disease. Evaluations can include the following: Pathogenic variants in See There are no published consensus management guidelines for the diagnosis and management of hereditary PGL/PCC syndromes during pregnancy. A high index of suspicion for these tumors in pregnant women is indicated, since there are other more common causes of hypertension during pregnancy (e.g., preeclampsia). Secretory PGL/PCCs are more likely to present at any time during pregnancy (whereas preeclampsia is more common in the second or third trimester) and are typically not associated with weight gain, edema, proteinuria, or thrombocytopenia. Individuals with PGL/PCCs are more likely to present with palpitations, sweating, pallor, orthostatic hypotension, and glucosuria, and the hypertension may be episodic. A retrospective multicenter cohort study of pregnancy outcomes in women with PGL/PCCs showed better outcomes for the woman and the fetus in women treated with alpha-adrenergic blockade [ Every individual with a hereditary PGL/PCC syndrome should be evaluated for an active catecholamine-secreting tumor prior to planned pregnancy or as soon as pregnancy is known. This evaluation can be done by measurement of fractionated metanephrines and catecholamines in a 24-hour urine sample or measurement of plasma-free metanephrines. There is no consensus regarding the frequency of follow-up biochemical evaluation during pregnancy, but obtaining levels during the second trimester (preferred window for surgery) and prior to delivery should be considered. The retrospective multicenter cohort study did not show improved outcomes with surgery in the second trimester compared to medical therapy with alpha-adrenergic blockade [ Surgery is the definitive treatment for these tumors, with appropriate alpha-adrenergic and (if needed) subsequent beta-adrenergic blockade to prevent a hypertensive crisis. For intra-abdominal PGL/PCCs, a laparoscopic surgical approach is ideal if the tumor size allows. After 24 weeks' gestation, surgery may need to be delayed until fetal maturity is reached (~34 weeks) because of issues with tumor accessibility. An open surgical approach combined with elective cesarean section may be necessary in these situations. A good outcome with vaginal delivery has only been described in those with appropriate alpha-adrenergic blockade [ See For metastatic PGL/PCC, several therapies are under investigation. Preliminary studies with peptide receptor radionuclide therapy (PRRT) have shown clinical and biochemical responses that suggest increased survival [ Search • Cross-sectional imaging (CT/MRI) is preferred method to define tumor extent. • Functional studies, such as somatostatin receptor-based imaging (e.g., • HNPGLs are often best characterized by MRI. • Thoracic PGLs are best characterized by CT. • Abdominal tumors by either MRI or CT • Plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines (optional dopamine or 3-methoxytyramine) to screen for secreting PGL/PCC • Whole-body MRI for PGL, PCC, renal cell carcinoma, & GIST • Surgical resection is recommended due to risk for metastases. Prompt resection is particularly important for extra-adrenal sympathetic PGLs because of their tendency to metastasize. • Perioperative alpha-adrenergic blockade is typically required. • Active observation • Surgical resection • Radiation therapy • Active observation • Surgical resection • Radiation • Surgical resection • Active observation • Radiation therapy or stereotactic radiosurgery in selected persons • Small tumors may potentially be removed w/o complications or permanent nerve injuries. • Resection of larger tumors is often assoc w/CSF leak, meningitis, stroke, hearing loss, cranial nerve palsy, or even death. • Close observation w/symptomatically guided surgery may be prudent. • Gamma knife stereotactic surgery is a good option to prevent morbidity from resection. • Alpha-adrenergic blockade (w/prazosin/doxazosin) starting ≥7-10 days preoperatively to normalize BP & allow volume expansion. The dose of the α-blocker is adjusted for a low-normal systolic BP for age. • Calcium channel blockers (e.g., amlodipine, nicardipine) as needed for second-line treatment of BP control • A liberal sodium diet & fluid intake to allow for plasma volume expansion. • Once adequate α-adrenergic blockade or BP control w/calcium channel blockers is achieved, initiation of beta-adrenergic blockade may be required to control reflex tachycardia. The dose of the β-blocker is adjusted for a target heart rate of 80 beats per minute. • ~2-8 wks after surgery, assess 24-hour urine fractionated metanephrines &/or plasma-free metanephrines. • If the levels are normal, resection of the biochemically active PCC should be considered complete. • If the levels are ↑, an unresected 2nd tumor &/or occult metastases should be suspected. • BP control w/α-blocker to ↓ symptoms from high catecholamine levels in persons w/sympathetic tumors • Surgical debulking to ↓ tumor burden due to mass effect or catecholamine secretion • Active observation for nonprogressing, nonsecreting disease • Radiation therapy, esp for bony lesions • Liver-directed therapy • Systemic therapy w/chemotherapy (e.g., cyclophosphamide, vincristine, dacarbazine) • I-131-MIBG therapy • Surgical resection of localized disease, particularly if tumor is bleeding, causing obstruction, >2 cm, or ↑ in size • Tyrosine kinase inhibitor (TKI) for adjuvant therapy after surgical resection or as first-line therapy in those w/metastatic disease. However, SDH-deficient GISTs are largely resistant to TKIs. • Early surgical intervention • Partial nephrectomy in persons w/solitary tumor at early stage • Standard treatment for metastatic disease • Whole-body MRI for PGL, PCC, RCC, & GIST • Note: Some also suggest PET-CT, preferably w/radiolabeled somatostatin analogues. • Whole-body MRI for PGL, PCC, RCC, & GIST • Note: Current guidelines do not provide surveillance recommendations for at-risk persons w/ • Pathogenic variants in ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a hereditary PGL/PCC syndrome, the evaluations summarized in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Recommended Evaluations Following Initial Diagnosis Cross-sectional imaging (CT/MRI) is preferred method to define tumor extent. Functional studies, such as somatostatin receptor-based imaging (e.g., HNPGLs are often best characterized by MRI. Thoracic PGLs are best characterized by CT. Abdominal tumors by either MRI or CT Plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines (optional dopamine or 3-methoxytyramine) to screen for secreting PGL/PCC Whole-body MRI for PGL, PCC, renal cell carcinoma, & GIST EGD = esophagogastroduodenoscopy; GI = gastrointestinal; GIST = gastrointestinal stromal tumor; HNPGL = head and neck paraganglioma; MOI = mode of inheritance; PCC = pheochromocytoma; PGL = paraganglioma Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Cross-sectional imaging (CT/MRI) is preferred method to define tumor extent. • Functional studies, such as somatostatin receptor-based imaging (e.g., • HNPGLs are often best characterized by MRI. • Thoracic PGLs are best characterized by CT. • Abdominal tumors by either MRI or CT • Plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines (optional dopamine or 3-methoxytyramine) to screen for secreting PGL/PCC • Whole-body MRI for PGL, PCC, renal cell carcinoma, & GIST ## Treatment of Manifestations The management of tumors in individuals with hereditary PGL/PCC syndromes resembles management of sporadic tumors; however, persons with hereditary PGL/PCC syndromes are more likely to have multiple tumors and multifocal and/or metastatic disease than are those with sporadic tumors [ Hereditary Paraganglioma-Pheochromocytoma Syndromes: Treatment of Manifestations Surgical resection is recommended due to risk for metastases. Prompt resection is particularly important for extra-adrenal sympathetic PGLs because of their tendency to metastasize. Perioperative alpha-adrenergic blockade is typically required. Active observation Surgical resection Radiation therapy Active observation Surgical resection Radiation Surgical resection Active observation Radiation therapy or stereotactic radiosurgery in selected persons Small tumors may potentially be removed w/o complications or permanent nerve injuries. Resection of larger tumors is often assoc w/CSF leak, meningitis, stroke, hearing loss, cranial nerve palsy, or even death. Close observation w/symptomatically guided surgery may be prudent. Gamma knife stereotactic surgery is a good option to prevent morbidity from resection. Alpha-adrenergic blockade (w/prazosin/doxazosin) starting ≥7-10 days preoperatively to normalize BP & allow volume expansion. The dose of the α-blocker is adjusted for a low-normal systolic BP for age. Calcium channel blockers (e.g., amlodipine, nicardipine) as needed for second-line treatment of BP control A liberal sodium diet & fluid intake to allow for plasma volume expansion. Once adequate α-adrenergic blockade or BP control w/calcium channel blockers is achieved, initiation of beta-adrenergic blockade may be required to control reflex tachycardia. The dose of the β-blocker is adjusted for a target heart rate of 80 beats per minute. ~2-8 wks after surgery, assess 24-hour urine fractionated metanephrines &/or plasma-free metanephrines. If the levels are normal, resection of the biochemically active PCC should be considered complete. If the levels are ↑, an unresected 2nd tumor &/or occult metastases should be suspected. BP control w/α-blocker to ↓ symptoms from high catecholamine levels in persons w/sympathetic tumors Surgical debulking to ↓ tumor burden due to mass effect or catecholamine secretion Active observation for nonprogressing, nonsecreting disease Radiation therapy, esp for bony lesions Liver-directed therapy Systemic therapy w/chemotherapy (e.g., cyclophosphamide, vincristine, dacarbazine) I-131-MIBG therapy Surgical resection of localized disease, particularly if tumor is bleeding, causing obstruction, >2 cm, or ↑ in size Tyrosine kinase inhibitor (TKI) for adjuvant therapy after surgical resection or as first-line therapy in those w/metastatic disease. However, SDH-deficient GISTs are largely resistant to TKIs. Early surgical intervention Partial nephrectomy in persons w/solitary tumor at early stage Standard treatment for metastatic disease BP = blood pressure; CSF = cerebrospinal fluid; MIBG = metaiodobenzylguanidine; PCC = pheochromocytoma; PGL = paraganglioma • Surgical resection is recommended due to risk for metastases. Prompt resection is particularly important for extra-adrenal sympathetic PGLs because of their tendency to metastasize. • Perioperative alpha-adrenergic blockade is typically required. • Active observation • Surgical resection • Radiation therapy • Active observation • Surgical resection • Radiation • Surgical resection • Active observation • Radiation therapy or stereotactic radiosurgery in selected persons • Small tumors may potentially be removed w/o complications or permanent nerve injuries. • Resection of larger tumors is often assoc w/CSF leak, meningitis, stroke, hearing loss, cranial nerve palsy, or even death. • Close observation w/symptomatically guided surgery may be prudent. • Gamma knife stereotactic surgery is a good option to prevent morbidity from resection. • Alpha-adrenergic blockade (w/prazosin/doxazosin) starting ≥7-10 days preoperatively to normalize BP & allow volume expansion. The dose of the α-blocker is adjusted for a low-normal systolic BP for age. • Calcium channel blockers (e.g., amlodipine, nicardipine) as needed for second-line treatment of BP control • A liberal sodium diet & fluid intake to allow for plasma volume expansion. • Once adequate α-adrenergic blockade or BP control w/calcium channel blockers is achieved, initiation of beta-adrenergic blockade may be required to control reflex tachycardia. The dose of the β-blocker is adjusted for a target heart rate of 80 beats per minute. • ~2-8 wks after surgery, assess 24-hour urine fractionated metanephrines &/or plasma-free metanephrines. • If the levels are normal, resection of the biochemically active PCC should be considered complete. • If the levels are ↑, an unresected 2nd tumor &/or occult metastases should be suspected. • BP control w/α-blocker to ↓ symptoms from high catecholamine levels in persons w/sympathetic tumors • Surgical debulking to ↓ tumor burden due to mass effect or catecholamine secretion • Active observation for nonprogressing, nonsecreting disease • Radiation therapy, esp for bony lesions • Liver-directed therapy • Systemic therapy w/chemotherapy (e.g., cyclophosphamide, vincristine, dacarbazine) • I-131-MIBG therapy • Surgical resection of localized disease, particularly if tumor is bleeding, causing obstruction, >2 cm, or ↑ in size • Tyrosine kinase inhibitor (TKI) for adjuvant therapy after surgical resection or as first-line therapy in those w/metastatic disease. However, SDH-deficient GISTs are largely resistant to TKIs. • Early surgical intervention • Partial nephrectomy in persons w/solitary tumor at early stage • Standard treatment for metastatic disease ## Surveillance Individuals known to have a hereditary PGL/PCC syndrome and relatives at risk based on family history who have not undergone DNA-based testing need regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes. Although no clear data regarding when to start, best method, and how frequent biochemical studies and imaging should be done in at-risk individuals exist, it is reasonable to consider surveillance for all at-risk individuals [ Hereditary Paraganglioma-Pheochromocytoma Syndromes: Surveillance for Individuals at Risk and Affected Individuals Whole-body MRI for PGL, PCC, RCC, & GIST Note: Some also suggest PET-CT, preferably w/radiolabeled somatostatin analogues. Whole-body MRI for PGL, PCC, RCC, & GIST Note: Current guidelines do not provide surveillance recommendations for at-risk persons w/ EGD = esophagogastroduodenoscopy; GI = gastrointestinal; GIST = gastrointestinal stromal tumor; PCC = pheochromocytoma; PGL = paraganglioma; RCC = renal cell carcinoma The wide age range of when to initiate these recommendations is due to multiple consensus guidelines [ Recommendations apply to individuals with a paternally inherited pathogenic variant in these genes. Although some guidelines suggest using PET-CT in combination with MRI as first-line imaging for tumor screening, there is little data for its use in screening (as opposed to defining suspected tumors), and cost and radiation exposure must be considered. • Whole-body MRI for PGL, PCC, RCC, & GIST • Note: Some also suggest PET-CT, preferably w/radiolabeled somatostatin analogues. • Whole-body MRI for PGL, PCC, RCC, & GIST • Note: Current guidelines do not provide surveillance recommendations for at-risk persons w/ ## Agents/Circumstances to Avoid Activities such as cigarette smoking that predispose to chronic lung disease should be discouraged. There is some limited evidence that the penetrance of hereditary PGL/PCC syndromes may be increased in those who live in high altitudes or are chronically exposed to hypoxic conditions [ ## Evaluation of Relatives at Risk Evaluation of apparently asymptomatic older and younger at-risk relatives of an individual with hereditary PGL/PCC syndrome is recommended. Identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited a pathogenic variant. Early detection of tumors can facilitate surgical removal, decrease related morbidity, and potentially result in removal prior to the development of metastatic disease. Evaluations can include the following: Pathogenic variants in See • Pathogenic variants in ## Pregnancy Management There are no published consensus management guidelines for the diagnosis and management of hereditary PGL/PCC syndromes during pregnancy. A high index of suspicion for these tumors in pregnant women is indicated, since there are other more common causes of hypertension during pregnancy (e.g., preeclampsia). Secretory PGL/PCCs are more likely to present at any time during pregnancy (whereas preeclampsia is more common in the second or third trimester) and are typically not associated with weight gain, edema, proteinuria, or thrombocytopenia. Individuals with PGL/PCCs are more likely to present with palpitations, sweating, pallor, orthostatic hypotension, and glucosuria, and the hypertension may be episodic. A retrospective multicenter cohort study of pregnancy outcomes in women with PGL/PCCs showed better outcomes for the woman and the fetus in women treated with alpha-adrenergic blockade [ Every individual with a hereditary PGL/PCC syndrome should be evaluated for an active catecholamine-secreting tumor prior to planned pregnancy or as soon as pregnancy is known. This evaluation can be done by measurement of fractionated metanephrines and catecholamines in a 24-hour urine sample or measurement of plasma-free metanephrines. There is no consensus regarding the frequency of follow-up biochemical evaluation during pregnancy, but obtaining levels during the second trimester (preferred window for surgery) and prior to delivery should be considered. The retrospective multicenter cohort study did not show improved outcomes with surgery in the second trimester compared to medical therapy with alpha-adrenergic blockade [ Surgery is the definitive treatment for these tumors, with appropriate alpha-adrenergic and (if needed) subsequent beta-adrenergic blockade to prevent a hypertensive crisis. For intra-abdominal PGL/PCCs, a laparoscopic surgical approach is ideal if the tumor size allows. After 24 weeks' gestation, surgery may need to be delayed until fetal maturity is reached (~34 weeks) because of issues with tumor accessibility. An open surgical approach combined with elective cesarean section may be necessary in these situations. A good outcome with vaginal delivery has only been described in those with appropriate alpha-adrenergic blockade [ See ## Therapies Under Investigation For metastatic PGL/PCC, several therapies are under investigation. Preliminary studies with peptide receptor radionuclide therapy (PRRT) have shown clinical and biochemical responses that suggest increased survival [ Search ## Genetic Counseling The hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are inherited in an autosomal dominant manner. Pathogenic variants in Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent. Rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The age-dependent penetrance and variable expressivity of If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs of a proband are still at increased risk for a hereditary PGL/PCC syndrome because of the possibility of (age-related) reduced penetrance in a heterozygous parent or parent-of-origin effects. An individual who inherits an An individual who inherits an It is unclear whether the same parent-of-origin effect holds true for pathogenic variants in The risk to other family members depends on the genetic status of the proband's parents and the biological relationship to the proband. If a parent of the proband is affected and/or has a pathogenic variant, risk can be determined by pedigree analysis and, if the familial pathogenic variant is known, molecular genetic testing. Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a germline PGL/PCC-related pathogenic variant. Because the recommended gene-specific ages for initiation of surveillance is in childhood for all hereditary PGL/PCC-related genes (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. For those with a known hereditary PGL/PCC syndrome, screening for sympathetic PGL/PCC prior to conception is optimal. Otherwise, at a minimum, screening during pregnancy should be done to allow for optimal medical management for both the mother and the fetus (see Once the PGL/PCC syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent. • Rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The age-dependent penetrance and variable expressivity of • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs of a proband are still at increased risk for a hereditary PGL/PCC syndrome because of the possibility of (age-related) reduced penetrance in a heterozygous parent or parent-of-origin effects. • An individual who inherits an • An individual who inherits an • It is unclear whether the same parent-of-origin effect holds true for pathogenic variants in • The risk to other family members depends on the genetic status of the proband's parents and the biological relationship to the proband. • If a parent of the proband is affected and/or has a pathogenic variant, risk can be determined by pedigree analysis and, if the familial pathogenic variant is known, molecular genetic testing. • Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a germline PGL/PCC-related pathogenic variant. • Because the recommended gene-specific ages for initiation of surveillance is in childhood for all hereditary PGL/PCC-related genes (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • For those with a known hereditary PGL/PCC syndrome, screening for sympathetic PGL/PCC prior to conception is optimal. Otherwise, at a minimum, screening during pregnancy should be done to allow for optimal medical management for both the mother and the fetus (see ## Mode of Inheritance The hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are inherited in an autosomal dominant manner. Pathogenic variants in ## Risk to Family Members Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent. Rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The age-dependent penetrance and variable expressivity of If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs of a proband are still at increased risk for a hereditary PGL/PCC syndrome because of the possibility of (age-related) reduced penetrance in a heterozygous parent or parent-of-origin effects. An individual who inherits an An individual who inherits an It is unclear whether the same parent-of-origin effect holds true for pathogenic variants in The risk to other family members depends on the genetic status of the proband's parents and the biological relationship to the proband. If a parent of the proband is affected and/or has a pathogenic variant, risk can be determined by pedigree analysis and, if the familial pathogenic variant is known, molecular genetic testing. • Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent. • Rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The age-dependent penetrance and variable expressivity of • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs of a proband are still at increased risk for a hereditary PGL/PCC syndrome because of the possibility of (age-related) reduced penetrance in a heterozygous parent or parent-of-origin effects. • An individual who inherits an • An individual who inherits an • It is unclear whether the same parent-of-origin effect holds true for pathogenic variants in • The risk to other family members depends on the genetic status of the proband's parents and the biological relationship to the proband. • If a parent of the proband is affected and/or has a pathogenic variant, risk can be determined by pedigree analysis and, if the familial pathogenic variant is known, molecular genetic testing. ## Related Genetic Counseling Issues Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a germline PGL/PCC-related pathogenic variant. Because the recommended gene-specific ages for initiation of surveillance is in childhood for all hereditary PGL/PCC-related genes (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. For those with a known hereditary PGL/PCC syndrome, screening for sympathetic PGL/PCC prior to conception is optimal. Otherwise, at a minimum, screening during pregnancy should be done to allow for optimal medical management for both the mother and the fetus (see • Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a germline PGL/PCC-related pathogenic variant. • Because the recommended gene-specific ages for initiation of surveillance is in childhood for all hereditary PGL/PCC-related genes (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • For those with a known hereditary PGL/PCC syndrome, screening for sympathetic PGL/PCC prior to conception is optimal. Otherwise, at a minimum, screening during pregnancy should be done to allow for optimal medical management for both the mother and the fetus (see ## Prenatal Testing and Preimplantation Genetic Testing Once the PGL/PCC syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Australia Association for Multiple Endocrine Neoplasia Disorders United Kingdom • • • • • • • • • Australia • • • Association for Multiple Endocrine Neoplasia Disorders • United Kingdom • ## Molecular Genetics Hereditary Paraganglioma-Pheochromocytoma Syndromes: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Paraganglioma-Pheochromocytoma Syndromes ( The common neural crest derivation of skull base and neck paragangliomas, sympathetic extra-adrenal paragangliomas, and pheochromocytomas characterize this syndrome. Inactivation of Much less is known about the role of Hereditary Paraganglioma-Pheochromocytoma Syndromes: Gene-Specific Laboratory Considerations Pathogenic variants in Genes from Hereditary Paraganglioma-Pheochromocytoma Syndromes: Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. • Pathogenic variants in ## Molecular Pathogenesis The common neural crest derivation of skull base and neck paragangliomas, sympathetic extra-adrenal paragangliomas, and pheochromocytomas characterize this syndrome. Inactivation of Much less is known about the role of Hereditary Paraganglioma-Pheochromocytoma Syndromes: Gene-Specific Laboratory Considerations Pathogenic variants in Genes from Hereditary Paraganglioma-Pheochromocytoma Syndromes: Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. • Pathogenic variants in ## Chapter Notes Tobias Else ( Tobias Else ( Tobias Else, MD (2018-present) Lauren Fishbein, MD, PhD, MTR (2018-present) Samantha Greenberg, MS, MPH, CGC (2018-present) Salman Kirmani, MBBS; Aga Khan University, Pakistan (2012-2018) Roger D Klein, MD, JD; Blood Center of Wisconsin (2008-2012) Ricardo V Lloyd, MD, PhD; Mayo Clinic, Rochester (2008-2012) William F Young, MD, MSc; Mayo Clinic, Rochester (2008-2018) 21 September 2023 (sw) Comprehensive update posted live 4 October 2018 (sw) Comprehensive update posted live 6 November 2014 (me) Comprehensive update posted live 30 August 2012 (me) Comprehensive update posted live 21 May 2008 (me) Posted live 14 November 2007 (rdk) Original submission • 21 September 2023 (sw) Comprehensive update posted live • 4 October 2018 (sw) Comprehensive update posted live • 6 November 2014 (me) Comprehensive update posted live • 30 August 2012 (me) Comprehensive update posted live • 21 May 2008 (me) Posted live • 14 November 2007 (rdk) Original submission ## Author Notes Tobias Else ( Tobias Else ( ## Author History Tobias Else, MD (2018-present) Lauren Fishbein, MD, PhD, MTR (2018-present) Samantha Greenberg, MS, MPH, CGC (2018-present) Salman Kirmani, MBBS; Aga Khan University, Pakistan (2012-2018) Roger D Klein, MD, JD; Blood Center of Wisconsin (2008-2012) Ricardo V Lloyd, MD, PhD; Mayo Clinic, Rochester (2008-2012) William F Young, MD, MSc; Mayo Clinic, Rochester (2008-2018) ## Revision History 21 September 2023 (sw) Comprehensive update posted live 4 October 2018 (sw) Comprehensive update posted live 6 November 2014 (me) Comprehensive update posted live 30 August 2012 (me) Comprehensive update posted live 21 May 2008 (me) Posted live 14 November 2007 (rdk) Original submission • 21 September 2023 (sw) Comprehensive update posted live • 4 October 2018 (sw) Comprehensive update posted live • 6 November 2014 (me) Comprehensive update posted live • 30 August 2012 (me) Comprehensive update posted live • 21 May 2008 (me) Posted live • 14 November 2007 (rdk) Original submission ## References Amar L, Pacak K, Steichen O, Akker SA, Aylwin SJB, Baudin E, Buffet A, Burnichon N, Clifton-Bligh RJ, Dahia PLM, Fassnacht M, Grossman AB, Herman P, Hicks RJ, Januszewicz A, Jimenez C, Kunst HPM, Lewis D, Mannelli M, Naruse M, Robledo M, Taïeb D, Taylor DR, Timmers HJLM, Treglia G, Tufton N, Young WF, Lenders JWM, Gimenez-Roqueplo AP, Lussey-Lepoutre C. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol. 2021;17:435-44. [ Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, Dahia PLM, Fraker DL, Goodman KA, Hope TA, Kunz PL, Perez K, Perrier ND, Pryma DA, Ryder M, Sasson AR, Soulen MC, Jimenez C. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021;50:469-93. [ Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, Maher ER; UK Cancer Genetics Centres. UK recommendations for Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915-42. [ Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, Voss SD, Schiffman JD, Wasserman JD. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e68-e75. [ Taïeb D, Wanna GB, Ahmad M, Lussey-Lepoutre C, Perrier ND, Nölting S, Amar L, Timmers HJLM, Schwam ZG, Estrera AL, Lim M, Pollom EL, Vitzthum L, Bourdeau I, Casey RT, Castinetti F, Clifton-Bligh R, Corssmit EPM, de Krijger RR, Del Rivero J, Eisenhofer G, Ghayee HK, Gimenez-Roqueplo AP, Grossman A, Imperiale A, Jansen JC, Jha A, Kerstens MN, Kunst HPM, Liu JK, Maher ER, Marchioni D, Mercado-Asis LB, Mete O, Naruse M, Nilubol N, Pandit-Taskar N, Sebag F, Tanabe A, Widimsky J, Meuter L, Lenders JWM, Pacak K. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023;11:345-61. [ • Amar L, Pacak K, Steichen O, Akker SA, Aylwin SJB, Baudin E, Buffet A, Burnichon N, Clifton-Bligh RJ, Dahia PLM, Fassnacht M, Grossman AB, Herman P, Hicks RJ, Januszewicz A, Jimenez C, Kunst HPM, Lewis D, Mannelli M, Naruse M, Robledo M, Taïeb D, Taylor DR, Timmers HJLM, Treglia G, Tufton N, Young WF, Lenders JWM, Gimenez-Roqueplo AP, Lussey-Lepoutre C. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol. 2021;17:435-44. [ • Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, Dahia PLM, Fraker DL, Goodman KA, Hope TA, Kunz PL, Perez K, Perrier ND, Pryma DA, Ryder M, Sasson AR, Soulen MC, Jimenez C. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021;50:469-93. [ • Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, Maher ER; UK Cancer Genetics Centres. UK recommendations for • Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915-42. [ • Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, Voss SD, Schiffman JD, Wasserman JD. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e68-e75. [ • Taïeb D, Wanna GB, Ahmad M, Lussey-Lepoutre C, Perrier ND, Nölting S, Amar L, Timmers HJLM, Schwam ZG, Estrera AL, Lim M, Pollom EL, Vitzthum L, Bourdeau I, Casey RT, Castinetti F, Clifton-Bligh R, Corssmit EPM, de Krijger RR, Del Rivero J, Eisenhofer G, Ghayee HK, Gimenez-Roqueplo AP, Grossman A, Imperiale A, Jansen JC, Jha A, Kerstens MN, Kunst HPM, Liu JK, Maher ER, Marchioni D, Mercado-Asis LB, Mete O, Naruse M, Nilubol N, Pandit-Taskar N, Sebag F, Tanabe A, Widimsky J, Meuter L, Lenders JWM, Pacak K. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023;11:345-61. [ ## Published Guidelines / Consensus Statements Amar L, Pacak K, Steichen O, Akker SA, Aylwin SJB, Baudin E, Buffet A, Burnichon N, Clifton-Bligh RJ, Dahia PLM, Fassnacht M, Grossman AB, Herman P, Hicks RJ, Januszewicz A, Jimenez C, Kunst HPM, Lewis D, Mannelli M, Naruse M, Robledo M, Taïeb D, Taylor DR, Timmers HJLM, Treglia G, Tufton N, Young WF, Lenders JWM, Gimenez-Roqueplo AP, Lussey-Lepoutre C. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol. 2021;17:435-44. [ Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, Dahia PLM, Fraker DL, Goodman KA, Hope TA, Kunz PL, Perez K, Perrier ND, Pryma DA, Ryder M, Sasson AR, Soulen MC, Jimenez C. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021;50:469-93. [ Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, Maher ER; UK Cancer Genetics Centres. UK recommendations for Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915-42. [ Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, Voss SD, Schiffman JD, Wasserman JD. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e68-e75. [ Taïeb D, Wanna GB, Ahmad M, Lussey-Lepoutre C, Perrier ND, Nölting S, Amar L, Timmers HJLM, Schwam ZG, Estrera AL, Lim M, Pollom EL, Vitzthum L, Bourdeau I, Casey RT, Castinetti F, Clifton-Bligh R, Corssmit EPM, de Krijger RR, Del Rivero J, Eisenhofer G, Ghayee HK, Gimenez-Roqueplo AP, Grossman A, Imperiale A, Jansen JC, Jha A, Kerstens MN, Kunst HPM, Liu JK, Maher ER, Marchioni D, Mercado-Asis LB, Mete O, Naruse M, Nilubol N, Pandit-Taskar N, Sebag F, Tanabe A, Widimsky J, Meuter L, Lenders JWM, Pacak K. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023;11:345-61. [ • Amar L, Pacak K, Steichen O, Akker SA, Aylwin SJB, Baudin E, Buffet A, Burnichon N, Clifton-Bligh RJ, Dahia PLM, Fassnacht M, Grossman AB, Herman P, Hicks RJ, Januszewicz A, Jimenez C, Kunst HPM, Lewis D, Mannelli M, Naruse M, Robledo M, Taïeb D, Taylor DR, Timmers HJLM, Treglia G, Tufton N, Young WF, Lenders JWM, Gimenez-Roqueplo AP, Lussey-Lepoutre C. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol. 2021;17:435-44. [ • Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, Dahia PLM, Fraker DL, Goodman KA, Hope TA, Kunz PL, Perez K, Perrier ND, Pryma DA, Ryder M, Sasson AR, Soulen MC, Jimenez C. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021;50:469-93. [ • Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, Maher ER; UK Cancer Genetics Centres. UK recommendations for • Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915-42. [ • Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, Voss SD, Schiffman JD, Wasserman JD. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e68-e75. [ • Taïeb D, Wanna GB, Ahmad M, Lussey-Lepoutre C, Perrier ND, Nölting S, Amar L, Timmers HJLM, Schwam ZG, Estrera AL, Lim M, Pollom EL, Vitzthum L, Bourdeau I, Casey RT, Castinetti F, Clifton-Bligh R, Corssmit EPM, de Krijger RR, Del Rivero J, Eisenhofer G, Ghayee HK, Gimenez-Roqueplo AP, Grossman A, Imperiale A, Jansen JC, Jha A, Kerstens MN, Kunst HPM, Liu JK, Maher ER, Marchioni D, Mercado-Asis LB, Mete O, Naruse M, Nilubol N, Pandit-Taskar N, Sebag F, Tanabe A, Widimsky J, Meuter L, Lenders JWM, Pacak K. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023;11:345-61. [ ## Literature Cited	[]	21/5/2008	21/9/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
parkinson-overview	parkinson-overview	[ "85/88 kDa calcium-independent phospholipase A2", "Alpha-synuclein", "Auxilin", "E3 ubiquitin-protein ligase parkin", "F-box only protein 7", "Intermembrane lipid transfer protein VPS13C", "Leucine-rich repeat serine/threonine-protein kinase 2", "Parkinson disease protein 7", "Polyamine-transporting ATPase 13A2", "Ras-related protein Rab-32", "Ras-related protein Rab-39B", "Serine/threonine-protein kinase PINK1, mitochondrial", "Synaptojanin-1", "Vacuolar protein sorting-associated protein 35", "ATP13A2", "DNAJC6", "FBXO7", "LRRK2", "PARK7", "PINK1", "PLA2G6", "PRKN", "RAB32", "RAB39B", "SNCA", "SYNJ1", "VPS13C", "VPS35", "Monogenic Parkinson Disease", "Overview" ]	Monogenic Parkinson Disease Overview	Huw Morris, Shen-Yang Lim	Summary The purpose of this overview is to: Describe the Review monogenic Review the Provide an Provide information on Inform	## Clinical Characteristics of Parkinson Disease Parkinson disease (PD), a neurodegenerative disorder, is characterized by slowed movement (bradykinesia), resting tremor, muscle rigidity, and often postural instability, particularly in later stages of the disease [ The clinical diagnosis of PD is based on the clinical findings of bradykinesia plus rest tremor and/or rigidity. An important supportive diagnostic feature is a beneficial response to dopaminergic therapy. Dementia is not an exclusion criterion for diagnosis. Operational clinical research criteria for PD have been defined in the Queen Square Brain Bank and the International Parkinson and Movement Disorder Society (MDS) criteria [ In instances of diagnostic uncertainty, especially in the early stages of PD, neuroimaging such as dopamine transporter single-photon emission computed tomography (DAT-SPECT) or fluorodopa positron emission tomography (PET) can be used to make a more definitive diagnosis of dopaminergic deficit [ Typical PD is associated with brain alpha-synuclein deposition and Lewy body formation at autopsy; however, a clinically similar phenotype can occur without Lewy body formation. This is particularly common in some monogenic forms of PD (e.g., The onset of PD is most commonly around age 68 years but can vary considerably. The following are generally accepted descriptions regarding age of onset [ Juvenile-onset PD: age <21 years Early-onset PD: age 21-50 years Late-onset PD: age ≥50 years Complex parkinsonism may occur in some forms of early-onset and juvenile-onset parkinsonism and may be indicated by additional features such as intellectual disability (which may predate the onset of parkinsonism), early dementia, seizures, spasticity, eye movement abnormalities, severe dystonia, poor or incomplete response to levodopa, and in some individuals brain iron accumulation on brain MRI, overlapping with neurodegeneration with brain iron accumulation (NBIA) disorders. Complex early-onset or juvenile-onset parkinsonism may be caused by biallelic pathogenic variants in • Juvenile-onset PD: age <21 years • Early-onset PD: age 21-50 years • Late-onset PD: age ≥50 years ## Clinical Manifestations of Parkinson Disease Parkinson disease (PD), a neurodegenerative disorder, is characterized by slowed movement (bradykinesia), resting tremor, muscle rigidity, and often postural instability, particularly in later stages of the disease [ The clinical diagnosis of PD is based on the clinical findings of bradykinesia plus rest tremor and/or rigidity. An important supportive diagnostic feature is a beneficial response to dopaminergic therapy. Dementia is not an exclusion criterion for diagnosis. Operational clinical research criteria for PD have been defined in the Queen Square Brain Bank and the International Parkinson and Movement Disorder Society (MDS) criteria [ In instances of diagnostic uncertainty, especially in the early stages of PD, neuroimaging such as dopamine transporter single-photon emission computed tomography (DAT-SPECT) or fluorodopa positron emission tomography (PET) can be used to make a more definitive diagnosis of dopaminergic deficit [ Typical PD is associated with brain alpha-synuclein deposition and Lewy body formation at autopsy; however, a clinically similar phenotype can occur without Lewy body formation. This is particularly common in some monogenic forms of PD (e.g., The onset of PD is most commonly around age 68 years but can vary considerably. The following are generally accepted descriptions regarding age of onset [ Juvenile-onset PD: age <21 years Early-onset PD: age 21-50 years Late-onset PD: age ≥50 years Complex parkinsonism may occur in some forms of early-onset and juvenile-onset parkinsonism and may be indicated by additional features such as intellectual disability (which may predate the onset of parkinsonism), early dementia, seizures, spasticity, eye movement abnormalities, severe dystonia, poor or incomplete response to levodopa, and in some individuals brain iron accumulation on brain MRI, overlapping with neurodegeneration with brain iron accumulation (NBIA) disorders. Complex early-onset or juvenile-onset parkinsonism may be caused by biallelic pathogenic variants in • Juvenile-onset PD: age <21 years • Early-onset PD: age 21-50 years • Late-onset PD: age ≥50 years ## Monogenic Causes of Parkinson Disease An estimated 5%-10% of all Parkinson disease (PD) is attributed to pathogenic variants in single genes (monogenic PD) (see Early-Onset and Late-Onset Parkinson Disease: Monogenic Causes Classic manifestations w/fewer non-motor involvement & cognitive impairment Variable penetrance dependent on age, genotype, & ethnicity Classic PD Age at onset may be <50 years. Cognitive, psychiatric, & autonomic features such as orthostatic hypotension more likely High penetrance; penetrance affected by genotype; >80% penetrance between age 45-65 yrs Classic PD Fewer non-motor manifestations To date, data are too limited to allow quantification of penetrance. Early-onset presentation: onset of PD in 3rd to 4th decade; slower progression than juvenile-onset presentation (see PVs w/milder effect on protein function may cause early-onset PD w/few other features Reported phenotype similar to PARK- Atypical motor features, ID, & seizures occasionally reported Risk to heterozygotes unknown Phenotype similar to PARK- Non-motor manifestations incl psychiatric features more common Usual onset <35 years Slow progression Can have lower limb dystonia, levodopa-induced dyskinesias (although this likely reflects young onset & long disease duration), hyperreflexia Relatively milder non-motor manifestations Early-onset PD w/very rapid progression Truncating variants cause severe disease. Has been described w/PSP-like & DLB-like phenotypes Onset <60 years May have mild ID Overlap w/Waisman syndrome (OMIM AD = autosomal dominant; AJ = Ashkenazi Jewish; AR = autosomal recessive; DD = developmental delay; DLB = dementia with Lewy body disease; ID = intellectual disability; MOI = mode of inheritance; PD = Parkinson disease; PSP = progressive supranuclear palsy; PV = pathogenic variant; XL = X-linked Genes are listed in alphabetical order. Nomenclature based on See Pathogenic variants in several genes have been associated with juvenile-onset monogenic PD (i.e., onset age generally <21 years but can vary) (see Juvenile-Onset Parkinson Disease: Monogenic Causes Triad of spasticity, supranuclear gaze palsy, & dementia Wide variability Also referred to as Kufor-Rakeb syndrome or juvenile-onset atypical PD Juvenile-onset presentation: onset of PD typically late 1st or early 2nd decade; rapid progression & neurologic regression after onset of PD; loss of ambulation; less responsive to levodopa; additional features often precede PD (DD, ID, seizures, other movement disorders, & neuropsychiatric features) Juvenile or early onset; rapidly progressive; may have corticospinal signs Early-onset parkinsonism w/bradykinesia in some persons Parkinsonism w/juvenile or early onset Assoc w/dystonia, pyramidal signs, myoclonus, early levodopa-induced dyskinesia, & cerebellar atrophy Variants in SAC1-like domain cause juvenile-onset dystonia w/dyskinesia. 1 family w/early-onset PD reported Parkinsonism, tremor, seizures AR = autosomal recessive; DD = developmental delay; DYT = dystonia; ID = intellectual disability; MOI = mode of inheritance; PD = Parkinson disease Genes are listed in alphabetical order. Nomenclature based on Allelic disorder: developmental and epileptic encephalopathy 53 (OMIM Additional studies are needed to confirm and clarify the role of pathogenic variants in these genes in PD causation. While these genes may appear on PD multigene testing panels, it is suggested that they not be included in diagnostic testing because of their currently uncertain role (see • Classic manifestations w/fewer non-motor involvement & cognitive impairment • Variable penetrance dependent on age, genotype, & ethnicity • Classic PD • Age at onset may be <50 years. • Cognitive, psychiatric, & autonomic features such as orthostatic hypotension more likely • High penetrance; penetrance affected by genotype; >80% penetrance between age 45-65 yrs • Classic PD • Fewer non-motor manifestations • To date, data are too limited to allow quantification of penetrance. • Early-onset presentation: onset of PD in 3rd to 4th decade; slower progression than juvenile-onset presentation (see • PVs w/milder effect on protein function may cause early-onset PD w/few other features • Reported phenotype similar to PARK- • Atypical motor features, ID, & seizures occasionally reported • Risk to heterozygotes unknown • Phenotype similar to PARK- • Non-motor manifestations incl psychiatric features more common • Usual onset <35 years • Slow progression • Can have lower limb dystonia, levodopa-induced dyskinesias (although this likely reflects young onset & long disease duration), hyperreflexia • Relatively milder non-motor manifestations • Early-onset PD w/very rapid progression • Truncating variants cause severe disease. • Has been described w/PSP-like & DLB-like phenotypes • Onset <60 years • May have mild ID • Overlap w/Waisman syndrome (OMIM • Triad of spasticity, supranuclear gaze palsy, & dementia • Wide variability • Also referred to as Kufor-Rakeb syndrome or juvenile-onset atypical PD • Juvenile-onset presentation: onset of PD typically late 1st or early 2nd decade; rapid progression & neurologic regression after onset of PD; loss of ambulation; less responsive to levodopa; additional features often precede PD (DD, ID, seizures, other movement disorders, & neuropsychiatric features) • Juvenile or early onset; rapidly progressive; may have corticospinal signs • Early-onset parkinsonism w/bradykinesia in some persons • Parkinsonism w/juvenile or early onset • Assoc w/dystonia, pyramidal signs, myoclonus, early levodopa-induced dyskinesia, & cerebellar atrophy • Variants in SAC1-like domain cause juvenile-onset dystonia w/dyskinesia. • 1 family w/early-onset PD reported • Parkinsonism, tremor, seizures ## Adult-Onset Monogenic PD Early-Onset and Late-Onset Parkinson Disease: Monogenic Causes Classic manifestations w/fewer non-motor involvement & cognitive impairment Variable penetrance dependent on age, genotype, & ethnicity Classic PD Age at onset may be <50 years. Cognitive, psychiatric, & autonomic features such as orthostatic hypotension more likely High penetrance; penetrance affected by genotype; >80% penetrance between age 45-65 yrs Classic PD Fewer non-motor manifestations To date, data are too limited to allow quantification of penetrance. Early-onset presentation: onset of PD in 3rd to 4th decade; slower progression than juvenile-onset presentation (see PVs w/milder effect on protein function may cause early-onset PD w/few other features Reported phenotype similar to PARK- Atypical motor features, ID, & seizures occasionally reported Risk to heterozygotes unknown Phenotype similar to PARK- Non-motor manifestations incl psychiatric features more common Usual onset <35 years Slow progression Can have lower limb dystonia, levodopa-induced dyskinesias (although this likely reflects young onset & long disease duration), hyperreflexia Relatively milder non-motor manifestations Early-onset PD w/very rapid progression Truncating variants cause severe disease. Has been described w/PSP-like & DLB-like phenotypes Onset <60 years May have mild ID Overlap w/Waisman syndrome (OMIM AD = autosomal dominant; AJ = Ashkenazi Jewish; AR = autosomal recessive; DD = developmental delay; DLB = dementia with Lewy body disease; ID = intellectual disability; MOI = mode of inheritance; PD = Parkinson disease; PSP = progressive supranuclear palsy; PV = pathogenic variant; XL = X-linked Genes are listed in alphabetical order. Nomenclature based on See • Classic manifestations w/fewer non-motor involvement & cognitive impairment • Variable penetrance dependent on age, genotype, & ethnicity • Classic PD • Age at onset may be <50 years. • Cognitive, psychiatric, & autonomic features such as orthostatic hypotension more likely • High penetrance; penetrance affected by genotype; >80% penetrance between age 45-65 yrs • Classic PD • Fewer non-motor manifestations • To date, data are too limited to allow quantification of penetrance. • Early-onset presentation: onset of PD in 3rd to 4th decade; slower progression than juvenile-onset presentation (see • PVs w/milder effect on protein function may cause early-onset PD w/few other features • Reported phenotype similar to PARK- • Atypical motor features, ID, & seizures occasionally reported • Risk to heterozygotes unknown • Phenotype similar to PARK- • Non-motor manifestations incl psychiatric features more common • Usual onset <35 years • Slow progression • Can have lower limb dystonia, levodopa-induced dyskinesias (although this likely reflects young onset & long disease duration), hyperreflexia • Relatively milder non-motor manifestations • Early-onset PD w/very rapid progression • Truncating variants cause severe disease. • Has been described w/PSP-like & DLB-like phenotypes • Onset <60 years • May have mild ID • Overlap w/Waisman syndrome (OMIM ## Juvenile-Onset Monogenic PD Pathogenic variants in several genes have been associated with juvenile-onset monogenic PD (i.e., onset age generally <21 years but can vary) (see Juvenile-Onset Parkinson Disease: Monogenic Causes Triad of spasticity, supranuclear gaze palsy, & dementia Wide variability Also referred to as Kufor-Rakeb syndrome or juvenile-onset atypical PD Juvenile-onset presentation: onset of PD typically late 1st or early 2nd decade; rapid progression & neurologic regression after onset of PD; loss of ambulation; less responsive to levodopa; additional features often precede PD (DD, ID, seizures, other movement disorders, & neuropsychiatric features) Juvenile or early onset; rapidly progressive; may have corticospinal signs Early-onset parkinsonism w/bradykinesia in some persons Parkinsonism w/juvenile or early onset Assoc w/dystonia, pyramidal signs, myoclonus, early levodopa-induced dyskinesia, & cerebellar atrophy Variants in SAC1-like domain cause juvenile-onset dystonia w/dyskinesia. 1 family w/early-onset PD reported Parkinsonism, tremor, seizures AR = autosomal recessive; DD = developmental delay; DYT = dystonia; ID = intellectual disability; MOI = mode of inheritance; PD = Parkinson disease Genes are listed in alphabetical order. Nomenclature based on Allelic disorder: developmental and epileptic encephalopathy 53 (OMIM Additional studies are needed to confirm and clarify the role of pathogenic variants in these genes in PD causation. While these genes may appear on PD multigene testing panels, it is suggested that they not be included in diagnostic testing because of their currently uncertain role (see • Triad of spasticity, supranuclear gaze palsy, & dementia • Wide variability • Also referred to as Kufor-Rakeb syndrome or juvenile-onset atypical PD • Juvenile-onset presentation: onset of PD typically late 1st or early 2nd decade; rapid progression & neurologic regression after onset of PD; loss of ambulation; less responsive to levodopa; additional features often precede PD (DD, ID, seizures, other movement disorders, & neuropsychiatric features) • Juvenile or early onset; rapidly progressive; may have corticospinal signs • Early-onset parkinsonism w/bradykinesia in some persons • Parkinsonism w/juvenile or early onset • Assoc w/dystonia, pyramidal signs, myoclonus, early levodopa-induced dyskinesia, & cerebellar atrophy • Variants in SAC1-like domain cause juvenile-onset dystonia w/dyskinesia. • 1 family w/early-onset PD reported • Parkinsonism, tremor, seizures ## Differential Diagnosis of Monogenic Parkinson Disease One of the most important non-genetic factors contributing to PD risk is advancing age. Epidemiologic studies have shown possible association of PD with environmental factors including pesticide and other toxin exposure, head injury, and infectious agents. Environmental factors that may be associated with a lower risk for PD include tobacco smoking, caffeine consumption, use of nonsteroidal anti-inflammatory drugs (NSAIDs), high blood urate levels, and physical activity [ Dopa-responsive dystonia (e.g., Parkinson-plus syndromes (degenerative conditions in which parkinsonism is a major finding, such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies) Spinocerebellar ataxia (SCA) (see Frontotemporal dementia (e.g., Infantile disorders of dopamine transport or metabolism (e.g., Drug-induced parkinsonism and other toxin-induced parkinsonism Normal pressure hydrocephalus Vascular disorders Viral/prion disease Autoimmune disorders • • Dopa-responsive dystonia (e.g., • Parkinson-plus syndromes (degenerative conditions in which parkinsonism is a major finding, such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies) • Spinocerebellar ataxia (SCA) (see • Frontotemporal dementia (e.g., • Infantile disorders of dopamine transport or metabolism (e.g., • Drug-induced parkinsonism and other toxin-induced parkinsonism • Normal pressure hydrocephalus • Vascular disorders • Viral/prion disease • Autoimmune disorders ## Evaluation Strategies to Identify the Genetic Cause of Parkinson Disease in a Proband Establishing a specific genetic cause of Parkinson disease (PD): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, cognitive assessment, family history, additional clinical investigations, and molecular genetic testing. Physical examination may provide important clues, particularly in complex parkinsonism. The inheritance pattern and the age of onset/diagnosis of disease, which may help distinguish autosomal dominant from autosomal recessive monogenic PD (see Age (or age at death), which will help distinguish unaffected individuals from individuals whose clinical status cannot be determined, as they are younger than the typical age of onset for PD Details of genetic testing of relatives Ancestry, as some populations are more likely to have certain causative pathogenic variants (see Evaluation by a neurologist (preferably one specializing in movement disorders) of first-degree relatives who have findings concerning for PD For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, cognitive assessment, family history, additional clinical investigations, and molecular genetic testing. Physical examination may provide important clues, particularly in complex parkinsonism. • The inheritance pattern and the age of onset/diagnosis of disease, which may help distinguish autosomal dominant from autosomal recessive monogenic PD (see • Age (or age at death), which will help distinguish unaffected individuals from individuals whose clinical status cannot be determined, as they are younger than the typical age of onset for PD • Details of genetic testing of relatives • Ancestry, as some populations are more likely to have certain causative pathogenic variants (see • Evaluation by a neurologist (preferably one specializing in movement disorders) of first-degree relatives who have findings concerning for PD • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Participation in Targeted Therapeutic Clinical Trials Several gene-targeted therapies for Parkinson disease (PD) are currently in development [ ## Genetic Counseling Monogenic Parkinson disease (PD) is inherited in an autosomal dominant ( Almost all individuals diagnosed with autosomal dominant PD inherited a monogenic PD-related pathogenic variant from a parent, who may or not be affected. In very rare instances, an individual diagnosed with autosomal dominant PD has the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), predictive molecular genetic testing may be considered for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, variable expression, or (especially in PARK- If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is known to have the autosomal dominant PD-related pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%. While all sibs who inherit a familial pathogenic variant will be at increased risk for PD, not all heterozygous sibs will manifest the disease. Reduced, age-related penetrance is well recognized, particularly in PARK- PARK- If the monogenic PD-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents have not been tested for the monogenic PD-related pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for PD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. Each child of an individual with an autosomal dominant PD-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. The probability that offspring who inherit a pathogenic variant will manifest PD increases with advancing age. The parents of an individual with autosomal recessive PD are presumed to be heterozygous for a monogenic PD-related pathogenic variant. Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a monogenic PD-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. The risk to heterozygotes of developing PD is not yet determined. Individuals who are heterozygous for a pathogenic variant in No increased risk of PD has been shown in recent large studies of individuals with single heterozygous If both parents are known to be heterozygous for a monogenic PD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. The risk to heterozygotes of developing PD is not yet determined. Individuals who are heterozygous for a pathogenic variant in No increased risk of PD has been shown in recent large studies of individuals with single heterozygous The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has a Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. If the proband represents a simplex case and if the If the mother of the proband has a If the father of the proband has a If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Hemizygous males transmit the Women with a Predictive testing for relatives at risk for Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Note: In a family with an established diagnosis of monogenic PD, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having monogenic PD-related pathogenic variant(s). Once the monogenic PD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate. • Almost all individuals diagnosed with autosomal dominant PD inherited a monogenic PD-related pathogenic variant from a parent, who may or not be affected. • In very rare instances, an individual diagnosed with autosomal dominant PD has the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), predictive molecular genetic testing may be considered for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, variable expression, or (especially in PARK- • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is known to have the autosomal dominant PD-related pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%. • While all sibs who inherit a familial pathogenic variant will be at increased risk for PD, not all heterozygous sibs will manifest the disease. Reduced, age-related penetrance is well recognized, particularly in PARK- • PARK- • If the monogenic PD-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents have not been tested for the monogenic PD-related pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for PD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • Each child of an individual with an autosomal dominant PD-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. • The probability that offspring who inherit a pathogenic variant will manifest PD increases with advancing age. • The parents of an individual with autosomal recessive PD are presumed to be heterozygous for a monogenic PD-related pathogenic variant. • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a monogenic PD-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • The risk to heterozygotes of developing PD is not yet determined. • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • If both parents are known to be heterozygous for a monogenic PD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • The risk to heterozygotes of developing PD is not yet determined. • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. • If the mother of the proband has a • If the father of the proband has a • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Hemizygous males transmit the • Women with a • Predictive testing for relatives at risk for • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having monogenic PD-related pathogenic variant(s). ## Mode of Inheritance Monogenic Parkinson disease (PD) is inherited in an autosomal dominant ( ## Autosomal Dominant Inheritance – Risk to Family Members Almost all individuals diagnosed with autosomal dominant PD inherited a monogenic PD-related pathogenic variant from a parent, who may or not be affected. In very rare instances, an individual diagnosed with autosomal dominant PD has the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), predictive molecular genetic testing may be considered for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, variable expression, or (especially in PARK- If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is known to have the autosomal dominant PD-related pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%. While all sibs who inherit a familial pathogenic variant will be at increased risk for PD, not all heterozygous sibs will manifest the disease. Reduced, age-related penetrance is well recognized, particularly in PARK- PARK- If the monogenic PD-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents have not been tested for the monogenic PD-related pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for PD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. Each child of an individual with an autosomal dominant PD-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. The probability that offspring who inherit a pathogenic variant will manifest PD increases with advancing age. • Almost all individuals diagnosed with autosomal dominant PD inherited a monogenic PD-related pathogenic variant from a parent, who may or not be affected. • In very rare instances, an individual diagnosed with autosomal dominant PD has the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), predictive molecular genetic testing may be considered for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, variable expression, or (especially in PARK- • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is known to have the autosomal dominant PD-related pathogenic variant identified in the proband, the risk to each sib of inheriting the pathogenic variant is 50%. • While all sibs who inherit a familial pathogenic variant will be at increased risk for PD, not all heterozygous sibs will manifest the disease. Reduced, age-related penetrance is well recognized, particularly in PARK- • PARK- • If the monogenic PD-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents have not been tested for the monogenic PD-related pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for PD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • Each child of an individual with an autosomal dominant PD-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. • The probability that offspring who inherit a pathogenic variant will manifest PD increases with advancing age. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an individual with autosomal recessive PD are presumed to be heterozygous for a monogenic PD-related pathogenic variant. Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a monogenic PD-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. The risk to heterozygotes of developing PD is not yet determined. Individuals who are heterozygous for a pathogenic variant in No increased risk of PD has been shown in recent large studies of individuals with single heterozygous If both parents are known to be heterozygous for a monogenic PD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. The risk to heterozygotes of developing PD is not yet determined. Individuals who are heterozygous for a pathogenic variant in No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • The parents of an individual with autosomal recessive PD are presumed to be heterozygous for a monogenic PD-related pathogenic variant. • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a monogenic PD-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • The risk to heterozygotes of developing PD is not yet determined. • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • If both parents are known to be heterozygous for a monogenic PD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • The risk to heterozygotes of developing PD is not yet determined. • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous • Individuals who are heterozygous for a pathogenic variant in • No increased risk of PD has been shown in recent large studies of individuals with single heterozygous ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has a Males who inherit the pathogenic variant will be affected; Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. If the proband represents a simplex case and if the If the mother of the proband has a If the father of the proband has a If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Hemizygous males transmit the Women with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygotes and their risk of developing PD is unknown. • If the mother of the proband has a • If the father of the proband has a • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Hemizygous males transmit the • Women with a ## Related Genetic Counseling Issues Predictive testing for relatives at risk for Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Note: In a family with an established diagnosis of monogenic PD, it is appropriate to consider testing of symptomatic individuals regardless of age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having monogenic PD-related pathogenic variant(s). • Predictive testing for relatives at risk for • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having monogenic PD-related pathogenic variant(s). ## Prenatal Testing and Preimplantation Genetic Testing Once the monogenic PD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate. ## Resources United Kingdom • • • • • • • • • • • • United Kingdom • • • ## Chapter Notes The Dr Morris acknowledges support from Parkinson's UK, Cure Parkinson's Trust, Progressive Supranuclear Palsy Association, CBD Solutions, Medical Research Council – Rare Disease Research Platform (MR/Y008219/1), Janet Owens Bequest, and Michael J Fox Foundation for the investigations of the genetic basis of familial and early-onset PD and related disorders. Janice Farlow, BS, BA; Indiana University School of Medicine (2014-2025)Tatiana Foroud, PhD; Indiana University School of Medicine (2004-2025)Shen-Yang Lim, MD, FRACP (2025-present)Huw Morris, PhD, FRCP (2025-present)Nathan D Pankratz, PhD; University of Minnesota (2004-2025)Lola Cook Shukla, MS; Indiana University School of Medicine (2019-2025)Jeanine Schulze, MS; Indiana University School of Medicine (2019-2025)Joanne Wojcieszek, MD; Indiana University School of Medicine (2004-2025) 15 May 2025 (sw) Comprehensive update posted live 25 July 2019 (bp) Comprehensive update posted live 27 February 2014 (me) Comprehensive update posted live 16 October 2006 (me) Comprehensive update posted live 25 May 2004 (me) Overview posted live 12 November 2003 (tmf) Original submission • 15 May 2025 (sw) Comprehensive update posted live • 25 July 2019 (bp) Comprehensive update posted live • 27 February 2014 (me) Comprehensive update posted live • 16 October 2006 (me) Comprehensive update posted live • 25 May 2004 (me) Overview posted live • 12 November 2003 (tmf) Original submission ## Author Notes The ## Acknowledgments Dr Morris acknowledges support from Parkinson's UK, Cure Parkinson's Trust, Progressive Supranuclear Palsy Association, CBD Solutions, Medical Research Council – Rare Disease Research Platform (MR/Y008219/1), Janet Owens Bequest, and Michael J Fox Foundation for the investigations of the genetic basis of familial and early-onset PD and related disorders. ## Author History Janice Farlow, BS, BA; Indiana University School of Medicine (2014-2025)Tatiana Foroud, PhD; Indiana University School of Medicine (2004-2025)Shen-Yang Lim, MD, FRACP (2025-present)Huw Morris, PhD, FRCP (2025-present)Nathan D Pankratz, PhD; University of Minnesota (2004-2025)Lola Cook Shukla, MS; Indiana University School of Medicine (2019-2025)Jeanine Schulze, MS; Indiana University School of Medicine (2019-2025)Joanne Wojcieszek, MD; Indiana University School of Medicine (2004-2025) ## Revision History 15 May 2025 (sw) Comprehensive update posted live 25 July 2019 (bp) Comprehensive update posted live 27 February 2014 (me) Comprehensive update posted live 16 October 2006 (me) Comprehensive update posted live 25 May 2004 (me) Overview posted live 12 November 2003 (tmf) Original submission • 15 May 2025 (sw) Comprehensive update posted live • 25 July 2019 (bp) Comprehensive update posted live • 27 February 2014 (me) Comprehensive update posted live • 16 October 2006 (me) Comprehensive update posted live • 25 May 2004 (me) Overview posted live • 12 November 2003 (tmf) Original submission ## References ## Literature Cited	[]	25/5/2004	15/5/2025	9/7/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pbd	pbd	[ "ZSD", "Intermediate/Milder Zellweger Spectrum Disorder (Neonatal Adrenoleukodystrophy, Infantile Refsum Disease, Heimler Syndrome)", "Severe Zellweger Spectrum Disorder (Zellweger Syndrome)", "Peroxisomal ATPase PEX1", "Peroxisomal ATPase PEX6", "Peroxisomal biogenesis factor 19", "Peroxisomal biogenesis factor 3", "Peroxisomal membrane protein 11B", "Peroxisomal membrane protein PEX13", "Peroxisomal membrane protein PEX14", "Peroxisomal membrane protein PEX16", "Peroxisomal targeting signal 1 receptor", "Peroxisome assembly protein 12", "Peroxisome assembly protein 26", "Peroxisome biogenesis factor 10", "Peroxisome biogenesis factor 2", "PEX1", "PEX10", "PEX11B", "PEX12", "PEX13", "PEX14", "PEX16", "PEX19", "PEX2", "PEX26", "PEX3", "PEX5", "PEX6", "Zellweger Spectrum Disorder (ZSD)" ]	Zellweger Spectrum Disorder	Steven J Steinberg, Gerald V Raymond, Nancy E Braverman, Ann B Moser	Summary Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth. The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes. One ZSD is typically inherited in an autosomal recessive manner (one	Severe ZSD (previously called Zellweger syndrome) Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy, infantile Refsum disease, or Heimler syndrome) For synonyms and outdated names see • Severe ZSD (previously called Zellweger syndrome) • Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy, infantile Refsum disease, or Heimler syndrome) ## Diagnosis Zellweger spectrum disorder (ZSD) In newborns: Hypotonia Poor feeding Distinctive facies Brain malformations Seizures Renal cysts Hepatomegaly, cholestasis, and hepatic dysfunction Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones In older infants and children: Developmental delays with or without hypotonia (Note: Intellect can be normal.) Failure to thrive Hearing loss Vision impairment Liver dysfunction Adrenal dysfunction Leukodystrophy Peripheral neuropathy and ataxia The screening assays for ZSD are summarized in Screening Assays for Zellweger Spectrum Disorder DHCA = dihydroxycholestanoic acid; LPC = lysophosphatidylcholine; THCA = trihydroxycholestanoic acid; VLCFA = very-long-chain fatty acids C26:0-LPC is measured in dried blood spots (DBS) in newborn screening programs for Low plasma concentration of LDL and HDL can cause false negative results. In a person with low plasma concentrations of LDL and HDL without a defect in peroxisomal fatty acid metabolism, the plasma concentration of specific fatty acids (e.g., C22:0, C24:0, C26:0) are significantly lower than normal control levels. Persons with defects in peroxisomal fatty acid metabolism and very low LDL and HDL concentrations do not have significant elevations in C26:0 and C26:1, but do have modest elevations in the ratios of C24/C22 and C26/C22. This analysis is usually included in VLCFA measurement. Pipecolic acid measurement is an adjunct to more definitive biomarkers such as plasma VLCFA and erythrocyte plasmalogen levels. Elevations in pipecolic acid can also occur in The diagnosis of ZSD Note: (1) One Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the suggestive clinical and biochemical findings of ZSD described in For an introduction to multigene panels click When the clinical and laboratory findings in an affected individual do not lead to consideration of ZSD, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Zellweger Spectrum Disorder (ZSD) Genes are listed from most frequent to least frequent genetic cause of ZSD. See Based on complementation studies using somatic cell hybridization and/or cDNA complementation analysis in 810 individuals with biochemical confirmation of ZSD (197 at Kennedy Krieger Institute [unpublished] and 613 reported by See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click An estimate, based on the assumption that large deletions or promoter and deep intronic pathogenic variants would be missed; however, these types of variants do not appear to be common in ZSD. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. This estimate is based on the number of individuals identified with a Based on One No data on detection rate of gene-targeted deletion/duplication analysis are available. • Hypotonia • Poor feeding • Distinctive facies • Brain malformations • Seizures • Renal cysts • Hepatomegaly, cholestasis, and hepatic dysfunction • Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones • Developmental delays with or without hypotonia (Note: Intellect can be normal.) • Failure to thrive • Hearing loss • Vision impairment • Liver dysfunction • Adrenal dysfunction • Leukodystrophy • Peripheral neuropathy and ataxia ## Suggestive Findings Zellweger spectrum disorder (ZSD) In newborns: Hypotonia Poor feeding Distinctive facies Brain malformations Seizures Renal cysts Hepatomegaly, cholestasis, and hepatic dysfunction Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones In older infants and children: Developmental delays with or without hypotonia (Note: Intellect can be normal.) Failure to thrive Hearing loss Vision impairment Liver dysfunction Adrenal dysfunction Leukodystrophy Peripheral neuropathy and ataxia The screening assays for ZSD are summarized in Screening Assays for Zellweger Spectrum Disorder DHCA = dihydroxycholestanoic acid; LPC = lysophosphatidylcholine; THCA = trihydroxycholestanoic acid; VLCFA = very-long-chain fatty acids C26:0-LPC is measured in dried blood spots (DBS) in newborn screening programs for Low plasma concentration of LDL and HDL can cause false negative results. In a person with low plasma concentrations of LDL and HDL without a defect in peroxisomal fatty acid metabolism, the plasma concentration of specific fatty acids (e.g., C22:0, C24:0, C26:0) are significantly lower than normal control levels. Persons with defects in peroxisomal fatty acid metabolism and very low LDL and HDL concentrations do not have significant elevations in C26:0 and C26:1, but do have modest elevations in the ratios of C24/C22 and C26/C22. This analysis is usually included in VLCFA measurement. Pipecolic acid measurement is an adjunct to more definitive biomarkers such as plasma VLCFA and erythrocyte plasmalogen levels. Elevations in pipecolic acid can also occur in • Hypotonia • Poor feeding • Distinctive facies • Brain malformations • Seizures • Renal cysts • Hepatomegaly, cholestasis, and hepatic dysfunction • Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones • Developmental delays with or without hypotonia (Note: Intellect can be normal.) • Failure to thrive • Hearing loss • Vision impairment • Liver dysfunction • Adrenal dysfunction • Leukodystrophy • Peripheral neuropathy and ataxia ## Clinical Findings In newborns: Hypotonia Poor feeding Distinctive facies Brain malformations Seizures Renal cysts Hepatomegaly, cholestasis, and hepatic dysfunction Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones In older infants and children: Developmental delays with or without hypotonia (Note: Intellect can be normal.) Failure to thrive Hearing loss Vision impairment Liver dysfunction Adrenal dysfunction Leukodystrophy Peripheral neuropathy and ataxia • Hypotonia • Poor feeding • Distinctive facies • Brain malformations • Seizures • Renal cysts • Hepatomegaly, cholestasis, and hepatic dysfunction • Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones • Developmental delays with or without hypotonia (Note: Intellect can be normal.) • Failure to thrive • Hearing loss • Vision impairment • Liver dysfunction • Adrenal dysfunction • Leukodystrophy • Peripheral neuropathy and ataxia ## Laboratory Findings The screening assays for ZSD are summarized in Screening Assays for Zellweger Spectrum Disorder DHCA = dihydroxycholestanoic acid; LPC = lysophosphatidylcholine; THCA = trihydroxycholestanoic acid; VLCFA = very-long-chain fatty acids C26:0-LPC is measured in dried blood spots (DBS) in newborn screening programs for Low plasma concentration of LDL and HDL can cause false negative results. In a person with low plasma concentrations of LDL and HDL without a defect in peroxisomal fatty acid metabolism, the plasma concentration of specific fatty acids (e.g., C22:0, C24:0, C26:0) are significantly lower than normal control levels. Persons with defects in peroxisomal fatty acid metabolism and very low LDL and HDL concentrations do not have significant elevations in C26:0 and C26:1, but do have modest elevations in the ratios of C24/C22 and C26/C22. This analysis is usually included in VLCFA measurement. Pipecolic acid measurement is an adjunct to more definitive biomarkers such as plasma VLCFA and erythrocyte plasmalogen levels. Elevations in pipecolic acid can also occur in ## Establishing the Diagnosis The diagnosis of ZSD Note: (1) One Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the suggestive clinical and biochemical findings of ZSD described in For an introduction to multigene panels click When the clinical and laboratory findings in an affected individual do not lead to consideration of ZSD, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Zellweger Spectrum Disorder (ZSD) Genes are listed from most frequent to least frequent genetic cause of ZSD. See Based on complementation studies using somatic cell hybridization and/or cDNA complementation analysis in 810 individuals with biochemical confirmation of ZSD (197 at Kennedy Krieger Institute [unpublished] and 613 reported by See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click An estimate, based on the assumption that large deletions or promoter and deep intronic pathogenic variants would be missed; however, these types of variants do not appear to be common in ZSD. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. This estimate is based on the number of individuals identified with a Based on One No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Option 1 For an introduction to multigene panels click ## Option 2 When the clinical and laboratory findings in an affected individual do not lead to consideration of ZSD, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Zellweger Spectrum Disorder (ZSD) Genes are listed from most frequent to least frequent genetic cause of ZSD. See Based on complementation studies using somatic cell hybridization and/or cDNA complementation analysis in 810 individuals with biochemical confirmation of ZSD (197 at Kennedy Krieger Institute [unpublished] and 613 reported by See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click An estimate, based on the assumption that large deletions or promoter and deep intronic pathogenic variants would be missed; however, these types of variants do not appear to be common in ZSD. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. This estimate is based on the number of individuals identified with a Based on One No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Zellweger spectrum disorder (ZSD) is defined by a continuum of three phenotypes described before the biochemical and molecular bases of these disorders had been fully determined: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile The ZSD phenotypic spectrum is broad; some affected individuals have mild manifestations, mainly sensory deficits and/or mild developmental delay. Recently, individuals with normal intellect have been identified [ Although the phenotypic designations listed above may be useful when evaluating undiagnosed individuals and counseling their families, one should not place too much emphasis on assigning a phenotypic label to an affected individual given that these phenotypes lie on a continuum. Thus, the terms "severe," "intermediate," and "milder" ZSD are now preferred. Because of the breadth of the phenotypic spectrum, individuals with ZSD mainly come to clinical attention in the newborn period or later in childhood. Occasionally, the subtlety of symptoms delays diagnosis until adulthood. Severe ZSD (previously called Zellweger syndrome [ZS]) typically presents in the neonatal period with profound hypotonia, characteristic facies, gyral malformations, seizures, inability to feed, renal cysts, hepatic dysfunction, and chondrodysplasia punctata. Infants with severe ZSD are significantly impaired and usually die during the first year of life, usually having made no developmental progress. Death is usually secondary to progressive apnea or respiratory compromise from infection. Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy [NALD] and infantile Refsum disease [IRD]) may present in the newborn period, but generally comes to attention later because of developmental delays, hearing loss, and/or visual impairment. Liver dysfunction may lead to a vitamin K-responsive coagulopathy. Children have also come to attention with episodes of hemorrhage; several children have presented in the first year of life with intracranial bleeding. The clinical course is variable: while many children are very hypotonic, many learn to walk and talk. Intermediate/milder ZSD is a progressive disorder with hearing and vision worsening with time. Some individuals may develop progressive degeneration of CNS myelin, a leukodystrophy, which may lead to loss of previously acquired skills and ultimately death. Children who survive the first year and who have a non-progressive course have a 77% probability of reaching school age [ Individuals with atypical ZSD do not show sensory losses but have ataxia and peripheral neuropathy, and may have congenital cataracts (e.g., those with Note that although Heimler syndrome [ MRI may identify cortical gyral abnormalities and germinolytic cysts that are highly suggestive of severe ZSD. Other brain MRI findings have been identified over time in individuals with milder ZSD. In a small number of individuals with ZSD, diffusion-weighted imaging and diffusion tensor imaging can be used to discern white matter damage not detected by standard imaging [ Biallelic pathogenic variants in the two most commonly involved genes, A general relationship appears to exist among the genotype, cellular phenotype (i.e., import of peroxisomal matrix proteins), and clinical phenotype [ Due to the overall rarity of ZSD the opportunities to rigorously assess genotype and phenotype are limited. The Homozygosity for Homozygosity for Peroxisome biogenesis disorders (PBD) can be divided into two subtypes: the Zellweger spectrum disorder (ZSD) and the rhizomelic chondrodysplasia punctata spectrum, of which rhizomelic chondrodysplasia punctata type 1 (RCDP1) is one subtype. RCDP1 is caused by biallelic pathogenic variants in ZSD has also formerly been referred to as cerebrohepatorenal syndrome, generalized peroxisomal disorders, Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease (also known as infantile phytanic acid oxidase deficiency). Some individuals later shown to have ZSD were initially described as having hyperpipecolatemia or Heimler syndrome. The current preferred terminology is ZSD of severe, intermediate, or milder phenotype in order to recognize the common etiology, variations, and atypical presentations now being documented in individuals with biallelic pathogenic variants in any one of the 13 ZSD-PEX genes. Of note, although Heimler syndrome [ Note: ZSD occurs worldwide with varying prevalence. In the past the incidence of ZSD had been estimated at 1:50,000 [ The main diagnostic center for peroxisomal diseases in Japan reported only 31 affected individuals over a 20-year period, with an estimated birth prevalence of 1:500,000 [ • Homozygosity for • Homozygosity for ## Clinical Description Zellweger spectrum disorder (ZSD) is defined by a continuum of three phenotypes described before the biochemical and molecular bases of these disorders had been fully determined: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile The ZSD phenotypic spectrum is broad; some affected individuals have mild manifestations, mainly sensory deficits and/or mild developmental delay. Recently, individuals with normal intellect have been identified [ Although the phenotypic designations listed above may be useful when evaluating undiagnosed individuals and counseling their families, one should not place too much emphasis on assigning a phenotypic label to an affected individual given that these phenotypes lie on a continuum. Thus, the terms "severe," "intermediate," and "milder" ZSD are now preferred. Because of the breadth of the phenotypic spectrum, individuals with ZSD mainly come to clinical attention in the newborn period or later in childhood. Occasionally, the subtlety of symptoms delays diagnosis until adulthood. Severe ZSD (previously called Zellweger syndrome [ZS]) typically presents in the neonatal period with profound hypotonia, characteristic facies, gyral malformations, seizures, inability to feed, renal cysts, hepatic dysfunction, and chondrodysplasia punctata. Infants with severe ZSD are significantly impaired and usually die during the first year of life, usually having made no developmental progress. Death is usually secondary to progressive apnea or respiratory compromise from infection. Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy [NALD] and infantile Refsum disease [IRD]) may present in the newborn period, but generally comes to attention later because of developmental delays, hearing loss, and/or visual impairment. Liver dysfunction may lead to a vitamin K-responsive coagulopathy. Children have also come to attention with episodes of hemorrhage; several children have presented in the first year of life with intracranial bleeding. The clinical course is variable: while many children are very hypotonic, many learn to walk and talk. Intermediate/milder ZSD is a progressive disorder with hearing and vision worsening with time. Some individuals may develop progressive degeneration of CNS myelin, a leukodystrophy, which may lead to loss of previously acquired skills and ultimately death. Children who survive the first year and who have a non-progressive course have a 77% probability of reaching school age [ Individuals with atypical ZSD do not show sensory losses but have ataxia and peripheral neuropathy, and may have congenital cataracts (e.g., those with Note that although Heimler syndrome [ MRI may identify cortical gyral abnormalities and germinolytic cysts that are highly suggestive of severe ZSD. Other brain MRI findings have been identified over time in individuals with milder ZSD. In a small number of individuals with ZSD, diffusion-weighted imaging and diffusion tensor imaging can be used to discern white matter damage not detected by standard imaging [ ## Severe ZSD Severe ZSD (previously called Zellweger syndrome [ZS]) typically presents in the neonatal period with profound hypotonia, characteristic facies, gyral malformations, seizures, inability to feed, renal cysts, hepatic dysfunction, and chondrodysplasia punctata. Infants with severe ZSD are significantly impaired and usually die during the first year of life, usually having made no developmental progress. Death is usually secondary to progressive apnea or respiratory compromise from infection. ## Intermediate/Milder ZSD Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy [NALD] and infantile Refsum disease [IRD]) may present in the newborn period, but generally comes to attention later because of developmental delays, hearing loss, and/or visual impairment. Liver dysfunction may lead to a vitamin K-responsive coagulopathy. Children have also come to attention with episodes of hemorrhage; several children have presented in the first year of life with intracranial bleeding. The clinical course is variable: while many children are very hypotonic, many learn to walk and talk. Intermediate/milder ZSD is a progressive disorder with hearing and vision worsening with time. Some individuals may develop progressive degeneration of CNS myelin, a leukodystrophy, which may lead to loss of previously acquired skills and ultimately death. Children who survive the first year and who have a non-progressive course have a 77% probability of reaching school age [ ## Other Individuals with atypical ZSD do not show sensory losses but have ataxia and peripheral neuropathy, and may have congenital cataracts (e.g., those with Note that although Heimler syndrome [ ## Neuroimaging MRI may identify cortical gyral abnormalities and germinolytic cysts that are highly suggestive of severe ZSD. Other brain MRI findings have been identified over time in individuals with milder ZSD. In a small number of individuals with ZSD, diffusion-weighted imaging and diffusion tensor imaging can be used to discern white matter damage not detected by standard imaging [ ## Phenotype Correlations by Gene Biallelic pathogenic variants in the two most commonly involved genes, ## Genotype-Phenotype Correlations A general relationship appears to exist among the genotype, cellular phenotype (i.e., import of peroxisomal matrix proteins), and clinical phenotype [ Due to the overall rarity of ZSD the opportunities to rigorously assess genotype and phenotype are limited. The Homozygosity for Homozygosity for • Homozygosity for • Homozygosity for ## Nomenclature Peroxisome biogenesis disorders (PBD) can be divided into two subtypes: the Zellweger spectrum disorder (ZSD) and the rhizomelic chondrodysplasia punctata spectrum, of which rhizomelic chondrodysplasia punctata type 1 (RCDP1) is one subtype. RCDP1 is caused by biallelic pathogenic variants in ZSD has also formerly been referred to as cerebrohepatorenal syndrome, generalized peroxisomal disorders, Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease (also known as infantile phytanic acid oxidase deficiency). Some individuals later shown to have ZSD were initially described as having hyperpipecolatemia or Heimler syndrome. The current preferred terminology is ZSD of severe, intermediate, or milder phenotype in order to recognize the common etiology, variations, and atypical presentations now being documented in individuals with biallelic pathogenic variants in any one of the 13 ZSD-PEX genes. Of note, although Heimler syndrome [ Note: ## Prevalence ZSD occurs worldwide with varying prevalence. In the past the incidence of ZSD had been estimated at 1:50,000 [ The main diagnostic center for peroxisomal diseases in Japan reported only 31 affected individuals over a 20-year period, with an estimated birth prevalence of 1:500,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of Zellweger spectrum disorder (ZSD) varies with age at presentation and most prominent feature of the presentation. ZSD in newborns is most often confused with other conditions that result in profound hypotonia including Down syndrome, other chromosome abnormalities, and the disorders summarized in Differential Diagnosis of ZSD in a Newborn with Profound Hypotonia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PWCR = Prader-Willi critical region; XL = X-linked The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region. Approximately 15% of individuals with a ZSD-like clinical phenotype and increased plasma VLCFA concentration actually have a single-enzyme deficiency of peroxisomal β-oxidation (i.e., D-bifunctional enzyme deficiency or acyl-CoA oxidase deficiency) and do not have a pathogenic variant in a PEX gene. Therefore, in children with elevated plasma VLCFA but no additional biochemical evidence of ZSD, a broader peroxisomal multigene panel that includes at least Other differential diagnoses of peroxisomal and non-peroxisomal disorders that do not necessarily present as profound neonatal hypotonia are summarized in Differential Diagnosis of ZSD – Other Peroxisomal Disorders AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DHCA = dihydroxycholestanoic acid; MOI = mode of inheritance; SNHL = sensorineural hearing loss; THCA = trihydroxycholestanoic acid; VLCFA = very-long-chain fatty acid; XL = X-linked; ZSD = Zellweger spectrum disorder See See Differential Diagnosis of ZSD – Non-Peroxisomal Disorders Type 1: Congenital, bilateral, profound SNHL, vestibular areflexia, & RP Type 2: Congenital, bilateral SNHL & RP AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MT = mitochondrial; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; XL = X-linked See See See See See • Type 1: Congenital, bilateral, profound SNHL, vestibular areflexia, & RP • Type 2: Congenital, bilateral SNHL & RP ## Management To establish the extent of disease and needs in an individual diagnosed with ZSD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Zellweger Spectrum Disorder To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Liver function testing (AST, ALT, total & direct bilirubin, PT, PTT, INR) C27 bile acid intermediates (DHCA & THCA) Ultrasound eval &/or liver fibroscan To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Eval of adrenal function (ACTH & cortisol) Consideration of ACTH stimulation test as appropriate Eval of bone density by DXA Consider serum vitamin D level. Community or Social work involvement for parental support; Home nursing referral. DHCA = dihydroxycholestanoic acid; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OCT = optical coherence tomography; THCA = trihydroxycholestanoic acid Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment focuses on symptomatic therapy. Treatment of Manifestations in Individuals with Zellweger Spectrum Disorder Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. No specific metabolic diet recommended Cataract removal to preserve vision Glasses to correct refractive errors Supplementation of vitamin K & other fat-soluble vitamins Cholbam Varices can be treated w/sclerosing therapies. Vitamin D supplementation Consider bisphosphonate. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability A diet low in phytanic acid has been proposed, based mainly on the weak analogy with adult By providing the final C24 bile acid product, the bile acid pathway undergoes feedback inhibition, thus reducing the levels of elevated C27 bile acid intermediates that are thought to be toxic to the liver. Cholic acid therapy does in fact decrease C27 bile acid intermediates (which should be measured), but its clinical effect in ZSD is not yet known. Recommended Surveillance for Individuals with Zellweger Spectrum Disorder Measurement of growth parameters Eval of nutritional status & safety of oral intake Ophthalmologic eval Visual field testing Coagulation factors & other synthetic liver functions (PT, PTT, AST, ALT, total & direct bilirubin) Ultrasound &/or fibroscan to evaluate liver architecture Urine oxalate-to-creatinine ratio Consider kidney imaging when performing liver imaging. When the proband is on the milder end of the ZSD spectrum, it is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs in order to identify as early as possible those who are affected, and thus would benefit from annual hearing and ophthalmologic evaluation and routine monitoring of coagulation factors, adrenal function, and liver function. Note that molecular genetic testing for the pathogenic variants identified in the family is warranted as the results of screening assays ( See Search • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Liver function testing (AST, ALT, total & direct bilirubin, PT, PTT, INR) • C27 bile acid intermediates (DHCA & THCA) • Ultrasound eval &/or liver fibroscan • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Eval of adrenal function (ACTH & cortisol) • Consideration of ACTH stimulation test as appropriate • Eval of bone density by DXA • Consider serum vitamin D level. • Community or • Social work involvement for parental support; • Home nursing referral. • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. • No specific metabolic diet recommended • Cataract removal to preserve vision • Glasses to correct refractive errors • Supplementation of vitamin K & other fat-soluble vitamins • Cholbam • Varices can be treated w/sclerosing therapies. • Vitamin D supplementation • Consider bisphosphonate. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Ophthalmologic eval • Visual field testing • Coagulation factors & other synthetic liver functions (PT, PTT, AST, ALT, total & direct bilirubin) • Ultrasound &/or fibroscan to evaluate liver architecture • Urine oxalate-to-creatinine ratio • Consider kidney imaging when performing liver imaging. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ZSD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Zellweger Spectrum Disorder To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Liver function testing (AST, ALT, total & direct bilirubin, PT, PTT, INR) C27 bile acid intermediates (DHCA & THCA) Ultrasound eval &/or liver fibroscan To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Eval of adrenal function (ACTH & cortisol) Consideration of ACTH stimulation test as appropriate Eval of bone density by DXA Consider serum vitamin D level. Community or Social work involvement for parental support; Home nursing referral. DHCA = dihydroxycholestanoic acid; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OCT = optical coherence tomography; THCA = trihydroxycholestanoic acid Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Liver function testing (AST, ALT, total & direct bilirubin, PT, PTT, INR) • C27 bile acid intermediates (DHCA & THCA) • Ultrasound eval &/or liver fibroscan • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Eval of adrenal function (ACTH & cortisol) • Consideration of ACTH stimulation test as appropriate • Eval of bone density by DXA • Consider serum vitamin D level. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment focuses on symptomatic therapy. Treatment of Manifestations in Individuals with Zellweger Spectrum Disorder Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. No specific metabolic diet recommended Cataract removal to preserve vision Glasses to correct refractive errors Supplementation of vitamin K & other fat-soluble vitamins Cholbam Varices can be treated w/sclerosing therapies. Vitamin D supplementation Consider bisphosphonate. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability A diet low in phytanic acid has been proposed, based mainly on the weak analogy with adult By providing the final C24 bile acid product, the bile acid pathway undergoes feedback inhibition, thus reducing the levels of elevated C27 bile acid intermediates that are thought to be toxic to the liver. Cholic acid therapy does in fact decrease C27 bile acid intermediates (which should be measured), but its clinical effect in ZSD is not yet known. • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. • No specific metabolic diet recommended • Cataract removal to preserve vision • Glasses to correct refractive errors • Supplementation of vitamin K & other fat-soluble vitamins • Cholbam • Varices can be treated w/sclerosing therapies. • Vitamin D supplementation • Consider bisphosphonate. ## Surveillance Recommended Surveillance for Individuals with Zellweger Spectrum Disorder Measurement of growth parameters Eval of nutritional status & safety of oral intake Ophthalmologic eval Visual field testing Coagulation factors & other synthetic liver functions (PT, PTT, AST, ALT, total & direct bilirubin) Ultrasound &/or fibroscan to evaluate liver architecture Urine oxalate-to-creatinine ratio Consider kidney imaging when performing liver imaging. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Ophthalmologic eval • Visual field testing • Coagulation factors & other synthetic liver functions (PT, PTT, AST, ALT, total & direct bilirubin) • Ultrasound &/or fibroscan to evaluate liver architecture • Urine oxalate-to-creatinine ratio • Consider kidney imaging when performing liver imaging. ## Evaluation of Relatives at Risk When the proband is on the milder end of the ZSD spectrum, it is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs in order to identify as early as possible those who are affected, and thus would benefit from annual hearing and ophthalmologic evaluation and routine monitoring of coagulation factors, adrenal function, and liver function. Note that molecular genetic testing for the pathogenic variants identified in the family is warranted as the results of screening assays ( See ## Therapies Under Investigation Search ## Genetic Counseling Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner. Note: One The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ZSD-causing pathogenic variant based on family history). Once the causative pathogenic variants have been identified in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a ZSD-causing pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a ZSD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. In general, greater clinical variation is observed in families in which affected sibs are on the milder end of ZSD. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. In general, affected individuals do not reproduce. Some individuals with milder phenotypes may reproduce; the offspring of such individuals are obligate heterozygotes (carriers of a ZSD-causing pathogenic variant). See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Biochemical testing of cultured amniocytes may also be useful when abnormalities suggestive of ZSD are detected on prenatal ultrasound examination. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ZSD-causing pathogenic variant based on family history). • Once the causative pathogenic variants have been identified in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a ZSD-causing pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a ZSD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • In general, greater clinical variation is observed in families in which affected sibs are on the milder end of ZSD. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • In general, affected individuals do not reproduce. • Some individuals with milder phenotypes may reproduce; the offspring of such individuals are obligate heterozygotes (carriers of a ZSD-causing pathogenic variant). • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner. Note: One ## Risk to Family Members (Autosomal Recessive Inheritance) The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ZSD-causing pathogenic variant based on family history). Once the causative pathogenic variants have been identified in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a ZSD-causing pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a ZSD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. In general, greater clinical variation is observed in families in which affected sibs are on the milder end of ZSD. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. In general, affected individuals do not reproduce. Some individuals with milder phenotypes may reproduce; the offspring of such individuals are obligate heterozygotes (carriers of a ZSD-causing pathogenic variant). • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ZSD-causing pathogenic variant based on family history). • Once the causative pathogenic variants have been identified in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a ZSD-causing pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a ZSD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • In general, greater clinical variation is observed in families in which affected sibs are on the milder end of ZSD. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • In general, affected individuals do not reproduce. • Some individuals with milder phenotypes may reproduce; the offspring of such individuals are obligate heterozygotes (carriers of a ZSD-causing pathogenic variant). ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Biochemical testing of cultured amniocytes may also be useful when abnormalities suggestive of ZSD are detected on prenatal ultrasound examination. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources 5147 South Harvard Avenue Suite 181 Tulsa OK PO Box 5801 Bethesda MD 20824 Health Resources & Services Administration • • 5147 South Harvard Avenue • Suite 181 • Tulsa OK • • • PO Box 5801 • Bethesda MD 20824 • • • • • Health Resources & Services Administration • • • ## Molecular Genetics Zellweger Spectrum Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Zellweger Spectrum Disorder ( Biallelic pathogenic variants in any one of the 13 PEX genes listed in Zellweger Spectrum Disorder: Gene-Specific Laboratory Considerations Genes from Sequences of coding region are identical. See Zellweger Spectrum Disorder: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Variant designation that does not conform to current naming conventions It has been proposed that the two common alleles reside on specific haplotypes and arose as founder variants [ ## Molecular Pathogenesis Biallelic pathogenic variants in any one of the 13 PEX genes listed in Zellweger Spectrum Disorder: Gene-Specific Laboratory Considerations Genes from Sequences of coding region are identical. See Zellweger Spectrum Disorder: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Variant designation that does not conform to current naming conventions It has been proposed that the two common alleles reside on specific haplotypes and arose as founder variants [ ## Chapter Notes Nancy E Braverman, MS, MD (2003–present)Ann B Moser, BA (2003–present)Hugo W Moser, MD (2003–2007)Gerald V Raymond, MD (2003–present)Steven J Steinberg, PhD (2003–present) Hugo W Moser, MD was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy (ALD). Dr Moser died of cancer on January 20, 2007 at age 82. He is greatly missed by his family, friends, colleagues, and patients. 29 October 2020 (sw) Comprehensive update posted live 16 November 2017 (bp) Comprehensive update posted live 18 January 2011 (me) Comprehensive update posted live 26 April 2006 (me) Comprehensive update posted live 12 December 2003 (me) Review posted live 1 August 2003 (sjs) Original submission • 29 October 2020 (sw) Comprehensive update posted live • 16 November 2017 (bp) Comprehensive update posted live • 18 January 2011 (me) Comprehensive update posted live • 26 April 2006 (me) Comprehensive update posted live • 12 December 2003 (me) Review posted live • 1 August 2003 (sjs) Original submission ## Author History Nancy E Braverman, MS, MD (2003–present)Ann B Moser, BA (2003–present)Hugo W Moser, MD (2003–2007)Gerald V Raymond, MD (2003–present)Steven J Steinberg, PhD (2003–present) Hugo W Moser, MD was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy (ALD). Dr Moser died of cancer on January 20, 2007 at age 82. He is greatly missed by his family, friends, colleagues, and patients. ## Revision History 29 October 2020 (sw) Comprehensive update posted live 16 November 2017 (bp) Comprehensive update posted live 18 January 2011 (me) Comprehensive update posted live 26 April 2006 (me) Comprehensive update posted live 12 December 2003 (me) Review posted live 1 August 2003 (sjs) Original submission • 29 October 2020 (sw) Comprehensive update posted live • 16 November 2017 (bp) Comprehensive update posted live • 18 January 2011 (me) Comprehensive update posted live • 26 April 2006 (me) Comprehensive update posted live • 12 December 2003 (me) Review posted live • 1 August 2003 (sjs) Original submission ## References Braverman NE, Raymond GV , Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117:313-21. Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. • Braverman NE, Raymond GV , Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117:313-21. • Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. ## Published Guidelines / Consensus Statements Braverman NE, Raymond GV , Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117:313-21. Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. • Braverman NE, Raymond GV , Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117:313-21. • Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. ## Literature Cited	[]	12/12/2003	29/10/2020	21/12/2017	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pc-hypo-p	pc-hypo-p	[ "Pontocerebellar Hypoplasia Type 5 (PCH5)", "Pontocerebellar Hypoplasia Type 2 (PCH2)", "Pontocerebellar Hypoplasia Type 4 (PCH4)", "tRNA-splicing endonuclease subunit Sen54", "TSEN54", "TSEN54 Pontocerebellar Hypoplasia" ]		Tessa van Dijk, Frank Baas	Summary The diagnosis of	Pontocerebellar hypoplasia type 2 (PCH2) Pontocerebellar hypoplasia type 4 (PCH4) Pontocerebellar hypoplasia type 5 (PCH5) For synonyms and outdated names see For other genetic causes of these phenotypes see • Pontocerebellar hypoplasia type 2 (PCH2) • Pontocerebellar hypoplasia type 4 (PCH4) • Pontocerebellar hypoplasia type 5 (PCH5) ## Diagnosis The phenotypic spectrum of Cerebellar hypoplasia and varying degrees of cerebellar atrophy (more severe in PCH4). Ventral pontine atrophy, present in the majority of cases (more severe in PCH4). Cerebellar hemispheres more affected than cerebellar vermis Cerebral cortical atrophy, progressive with age Pericerebral CSF accumulation and delayed neocortical maturation in PCH4 Striatal hypoplasia or atrophy Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4 Exceptional: cerebellar hemispheric cysts in PCH2 Diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in Note: Targeted analysis for the common For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of the Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Cerebellar hypoplasia and varying degrees of cerebellar atrophy (more severe in PCH4). • Ventral pontine atrophy, present in the majority of cases (more severe in PCH4). • Cerebellar hemispheres more affected than cerebellar vermis • Cerebral cortical atrophy, progressive with age • Pericerebral CSF accumulation and delayed neocortical maturation in PCH4 • Striatal hypoplasia or atrophy • Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4 • Exceptional: cerebellar hemispheric cysts in PCH2 ## Suggestive Findings ## Brain MRI Findings Cerebellar hypoplasia and varying degrees of cerebellar atrophy (more severe in PCH4). Ventral pontine atrophy, present in the majority of cases (more severe in PCH4). Cerebellar hemispheres more affected than cerebellar vermis Cerebral cortical atrophy, progressive with age Pericerebral CSF accumulation and delayed neocortical maturation in PCH4 Striatal hypoplasia or atrophy Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4 Exceptional: cerebellar hemispheric cysts in PCH2 • Cerebellar hypoplasia and varying degrees of cerebellar atrophy (more severe in PCH4). • Ventral pontine atrophy, present in the majority of cases (more severe in PCH4). • Cerebellar hemispheres more affected than cerebellar vermis • Cerebral cortical atrophy, progressive with age • Pericerebral CSF accumulation and delayed neocortical maturation in PCH4 • Striatal hypoplasia or atrophy • Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4 • Exceptional: cerebellar hemispheric cysts in PCH2 ## Establishing the Diagnosis Diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in Note: Targeted analysis for the common For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of the Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Option 1 Note: Targeted analysis for the common For an introduction to multigene panels click ## Option 2 If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of the Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics To date, at least 131 individuals have been identified with The phenotypic spectrum of The following description of the phenotypic features associated with Select Features of Based on 33 individuals homozygous for the common missense variant, p.Ala307Ser, from nonconsanguineous parents surviving until age 11 years [ GERD = gastroesophageal reflux disease Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing Generalized clonus (often described as "jitteriness") present in the majority Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic. Impaired central vision. Note that primary optic nerve atrophy has not been observed. Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed. Prenatal findings include polyhydramnios in many (but not all) pregnancies. Central respiratory impairment (probably the result of brain stem failure) at birth results in prolonged or perpetual dependence on mechanical ventilation. Respiratory complications occur at a later stage when weaning is difficult or plainly impossible. Microcephaly is usually present at birth. About 50% of neonates have contractures (arthrogryposis) at birth. Generalized clonus, provoked by handling or noise, may be extreme. [ Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis Described in only one family, findings of PCH5 are similar to those of PCH4 except that the degenerative process occurs in the cerebellar vermis rather than the cerebellar hemispheres [ The following clinical data, supported by pathogenic data, strongly suggest a genotype-phenotype correlation. The common In general, infants with the PCH4 phenotype who are compound heterozygotes for a pathogenic nonsense or splice site variant and a pathogenic missense variant have poorer survival than children with the PCH2 phenotype who are homozygous for a missense variant [ Pontocerebellar hypoplasia 2 (PCH2) refers to the phenotype; its subtypes are identified by the gene in which causative variants occur: PCH2A ( PCH2B ( PCH2C ( PCH2D ( The prevalence of The carrier frequency of the common Like many autosomal recessive disorders, PCH2 has been reported to be more common in isolated populations or populations with a high rate of consanguinity. PCH2 was originally identified in an isolated population in Volendam, the Netherlands [ • Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing • Generalized clonus (often described as "jitteriness") present in the majority • Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved • Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic. • Impaired central vision. Note that primary optic nerve atrophy has not been observed. • Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed. • • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • PCH2A ( • PCH2B ( • PCH2C ( • PCH2D ( ## Clinical Description To date, at least 131 individuals have been identified with The phenotypic spectrum of The following description of the phenotypic features associated with Select Features of Based on 33 individuals homozygous for the common missense variant, p.Ala307Ser, from nonconsanguineous parents surviving until age 11 years [ GERD = gastroesophageal reflux disease Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing Generalized clonus (often described as "jitteriness") present in the majority Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic. Impaired central vision. Note that primary optic nerve atrophy has not been observed. Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed. Prenatal findings include polyhydramnios in many (but not all) pregnancies. Central respiratory impairment (probably the result of brain stem failure) at birth results in prolonged or perpetual dependence on mechanical ventilation. Respiratory complications occur at a later stage when weaning is difficult or plainly impossible. Microcephaly is usually present at birth. About 50% of neonates have contractures (arthrogryposis) at birth. Generalized clonus, provoked by handling or noise, may be extreme. [ Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis Described in only one family, findings of PCH5 are similar to those of PCH4 except that the degenerative process occurs in the cerebellar vermis rather than the cerebellar hemispheres [ • Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing • Generalized clonus (often described as "jitteriness") present in the majority • Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved • Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic. • Impaired central vision. Note that primary optic nerve atrophy has not been observed. • Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed. • • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis ## Pontocerebellar Hypoplasia Type 2 The following description of the phenotypic features associated with Select Features of Based on 33 individuals homozygous for the common missense variant, p.Ala307Ser, from nonconsanguineous parents surviving until age 11 years [ GERD = gastroesophageal reflux disease Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing Generalized clonus (often described as "jitteriness") present in the majority Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic. Impaired central vision. Note that primary optic nerve atrophy has not been observed. Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed. • Bucco-pharyngeal incoordination with reduced grasping of the nipple and incoordination of sucking and swallowing • Generalized clonus (often described as "jitteriness") present in the majority • Impaired motor and cognitive development: lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping rarely achieved • Severe chorea often developing during the first six months, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic. • Impaired central vision. Note that primary optic nerve atrophy has not been observed. • Epilepsy (in ~50%); usually generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms have been observed. ## Pontocerebellar Hypoplasia Type 4 Prenatal findings include polyhydramnios in many (but not all) pregnancies. Central respiratory impairment (probably the result of brain stem failure) at birth results in prolonged or perpetual dependence on mechanical ventilation. Respiratory complications occur at a later stage when weaning is difficult or plainly impossible. Microcephaly is usually present at birth. About 50% of neonates have contractures (arthrogryposis) at birth. Generalized clonus, provoked by handling or noise, may be extreme. ## Neuropathology of PCH2 and PCH4 [ Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis • Hypoplasia and reduced branching of the folia; segmental degeneration of the cerebellar cortex and dentate nucleus; variable degeneration of Purkinje cells; relative sparing of the flocculus and vermis • PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis ## Pontocerebellar Hypoplasia Type 5 Described in only one family, findings of PCH5 are similar to those of PCH4 except that the degenerative process occurs in the cerebellar vermis rather than the cerebellar hemispheres [ ## Genotype-Phenotype Correlations The following clinical data, supported by pathogenic data, strongly suggest a genotype-phenotype correlation. The common In general, infants with the PCH4 phenotype who are compound heterozygotes for a pathogenic nonsense or splice site variant and a pathogenic missense variant have poorer survival than children with the PCH2 phenotype who are homozygous for a missense variant [ ## Nomenclature Pontocerebellar hypoplasia 2 (PCH2) refers to the phenotype; its subtypes are identified by the gene in which causative variants occur: PCH2A ( PCH2B ( PCH2C ( PCH2D ( • PCH2A ( • PCH2B ( • PCH2C ( • PCH2D ( ## Prevalence The prevalence of The carrier frequency of the common Like many autosomal recessive disorders, PCH2 has been reported to be more common in isolated populations or populations with a high rate of consanguinity. PCH2 was originally identified in an isolated population in Volendam, the Netherlands [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Heterozygous females have severe or profound ID & structural brain anomalies incl mild congenital microcephaly & severe postnatal microcephaly. Hemizygous males are more severely affected. Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked OMIM OMIM Children with PMM2-CDG ( Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [ Pontocerebellar hypoplasia in extremely premature infants (<28 weeks' gestational age); an acquired phenocopy to be considered [ • Heterozygous females have severe or profound ID & structural brain anomalies incl mild congenital microcephaly & severe postnatal microcephaly. • Hemizygous males are more severely affected. • Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth • Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. • Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [ • Pontocerebellar hypoplasia in extremely premature infants (<28 weeks' gestational age); an acquired phenocopy to be considered [ ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of Contractures, clubfoot, & kyphoscoliosis Need for positioning devices Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist Medical geneticist, certified genetic counselor, certified advanced genetic nurse Of note, adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis. Treatment of Manifestations in Individuals with Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. Alternative casting/splinting & stretching NG = nasogastric, OT = occupational therapy, PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. A vision consultant should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Recommended Surveillance for Individuals with Aspiration risk & nutritional status Monitor for constipation. PT/OT eval Assessment for contractures, scoliosis, & foot deformities. Hip/spine x-rays Monitor those w/seizures as clinically indicated. Monitor for dystonia & choreic movements. OT = occupational therapy; PT = physical therapy Although hyperthermic episodes have been documented in individuals with PCH2, no special risk appears to be associated with generalized anesthesia. See Search • Contractures, clubfoot, & kyphoscoliosis • Need for positioning devices • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. • Alternative casting/splinting & stretching • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Aspiration risk & nutritional status • Monitor for constipation. • PT/OT eval • Assessment for contractures, scoliosis, & foot deformities. • Hip/spine x-rays • Monitor those w/seizures as clinically indicated. • Monitor for dystonia & choreic movements. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of Contractures, clubfoot, & kyphoscoliosis Need for positioning devices Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Contractures, clubfoot, & kyphoscoliosis • Need for positioning devices • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations Of note, adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis. Treatment of Manifestations in Individuals with Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. Alternative casting/splinting & stretching NG = nasogastric, OT = occupational therapy, PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. A vision consultant should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. • Alternative casting/splinting & stretching • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. A vision consultant should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • A vision consultant should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance Recommended Surveillance for Individuals with Aspiration risk & nutritional status Monitor for constipation. PT/OT eval Assessment for contractures, scoliosis, & foot deformities. Hip/spine x-rays Monitor those w/seizures as clinically indicated. Monitor for dystonia & choreic movements. OT = occupational therapy; PT = physical therapy • Aspiration risk & nutritional status • Monitor for constipation. • PT/OT eval • Assessment for contractures, scoliosis, & foot deformities. • Hip/spine x-rays • Monitor those w/seizures as clinically indicated. • Monitor for dystonia & choreic movements. ## Agents/Circumstances to Avoid Although hyperthermic episodes have been documented in individuals with PCH2, no special risk appears to be associated with generalized anesthesia. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics TSEN54 Pontocerebellar Hypoplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for TSEN54 Pontocerebellar Hypoplasia ( The genes of the TSEN complex encode subunits of tRNA splicing endonuclease. The tRNA splicing endonuclease (TSEN) complex has a role in RNA processing [ It is involved in tRNA maturation; 6% of human tRNAs carry an intron in a premature state that is spliced out by the TSEN. The TSEN complex is also involved in mRNA 3' end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3' end formation. The TSEN complex comprises four different subunits: two catalytic subunits encoded by Notable Variants listed in the table have been provided by the authors. • It is involved in tRNA maturation; 6% of human tRNAs carry an intron in a premature state that is spliced out by the TSEN. • The TSEN complex is also involved in mRNA 3' end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3' end formation. ## Molecular Pathogenesis The genes of the TSEN complex encode subunits of tRNA splicing endonuclease. The tRNA splicing endonuclease (TSEN) complex has a role in RNA processing [ It is involved in tRNA maturation; 6% of human tRNAs carry an intron in a premature state that is spliced out by the TSEN. The TSEN complex is also involved in mRNA 3' end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3' end formation. The TSEN complex comprises four different subunits: two catalytic subunits encoded by Notable Variants listed in the table have been provided by the authors. • It is involved in tRNA maturation; 6% of human tRNAs carry an intron in a premature state that is spliced out by the TSEN. • The TSEN complex is also involved in mRNA 3' end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3' end formation. ## Chapter Notes Frank Baas, MD, PhD (2009-present)Peter G Barth, MD, PhD; University of Amsterdam (2009-2020)Veerle RC Eggens, MSc; University of Amsterdam (2009-2020)Yasmin Namavar, MSc; University of Amsterdam (2009-2020)Tessa van Dijk, MD (2020-present) 28 May 2020 (bp) Comprehensive update posted live 14 July 2016 (pgb) Revision: clarification of muscle problem in PCH2 18 February 2016 (pgb) Revision: Agents/Circumstances to Avoid 24 October 2013 (me) Comprehensive update posted live 22 September 2009 (cd) Revision: sequence analysis and prenatal testing is available clinically for 8 September 2009 (me) Review posted live 1 May 2009 (fb) Original submission • 28 May 2020 (bp) Comprehensive update posted live • 14 July 2016 (pgb) Revision: clarification of muscle problem in PCH2 • 18 February 2016 (pgb) Revision: Agents/Circumstances to Avoid • 24 October 2013 (me) Comprehensive update posted live • 22 September 2009 (cd) Revision: sequence analysis and prenatal testing is available clinically for • 8 September 2009 (me) Review posted live • 1 May 2009 (fb) Original submission ## Author History Frank Baas, MD, PhD (2009-present)Peter G Barth, MD, PhD; University of Amsterdam (2009-2020)Veerle RC Eggens, MSc; University of Amsterdam (2009-2020)Yasmin Namavar, MSc; University of Amsterdam (2009-2020)Tessa van Dijk, MD (2020-present) ## Revision History 28 May 2020 (bp) Comprehensive update posted live 14 July 2016 (pgb) Revision: clarification of muscle problem in PCH2 18 February 2016 (pgb) Revision: Agents/Circumstances to Avoid 24 October 2013 (me) Comprehensive update posted live 22 September 2009 (cd) Revision: sequence analysis and prenatal testing is available clinically for 8 September 2009 (me) Review posted live 1 May 2009 (fb) Original submission • 28 May 2020 (bp) Comprehensive update posted live • 14 July 2016 (pgb) Revision: clarification of muscle problem in PCH2 • 18 February 2016 (pgb) Revision: Agents/Circumstances to Avoid • 24 October 2013 (me) Comprehensive update posted live • 22 September 2009 (cd) Revision: sequence analysis and prenatal testing is available clinically for • 8 September 2009 (me) Review posted live • 1 May 2009 (fb) Original submission ## References ## Literature Cited MRI of the brain of an infant age two months with PCH2 a. Midsagittal image showing hypoplastic vermis and flat ventral pons (arrow) b. Lateral sagittal image showing hypoplastic cerebellar hemisphere (arrow) leaving empty space in the posterior fossa From	[ "PG Barth, E Aronica, L de Vries, PG Nikkels, W Scheper, JJ Hoozemans, BT Poll-The, D Troost. Pontocerebellar hypoplasia type 2: a neuropathological update.. Acta Neuropathol (Berl) 2007;114:373-86", "PG Barth, G Blennow, HG Lenard, JH Begeer, JM van der Kley, F Hanefeld, ACB Peters, J Valk. The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from ten pedigrees.. Neurology 1995;45:311-7", "BS Budde, Y Namavar, PG Barth, BT Poll-The, G Nürnberg, C Becker, F van Ruissen, MA Weterman, K Fluiter, ET te Beek, E Aronica, MS van der Knaap, W Höhne, MR Toliat, YJ Crow, M Steinling, T Voit, F Roelenso, W Brussel, K Brockmann, M Kyllerman, E Boltshauser, G Hammersen, M Willemsen, L Basel-Vanagaite, I Krägeloh-Mann, LS de Vries, L Sztriha, F Muntoni, CD Ferrie, R Battini, RC Hennekam, E Grillo, FA Beemer, LM Stoets, B Wollnik, P Nürnberg, F Baas. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia.. Nat Genet 2008;40:1113-8", "MS Forman, W Squier, WB Dobyns, JA Golden. Genotypically defined lissencephalies show distinct pathologies.. J Neuropathol Exp Neurol. 2005;64:847-57", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "Y Namavar, PG Barth, PR Kasher, F van Ruissen, K Brockmann, G Bernert, K Writzl, K Ventura, EY Cheng, DM Ferriero, L Basel-Vanagaite, VR Eggens, I Krägeloh-Mann, L De Meirleir, M King, JM Graham, A von Moers, N Knoers, L Sztriha, R Korinthenberg, PCH Consortium, WB Dobyns, F Baas, BT Poll-The. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.. Brain. 2011;134:143-56", "MS Patel, LE Becker, A Toi, DL Armstrong, D Chitayat. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5?. Am J Med Genet A 2006;140:594-603", "SV Paushkin, M Patel, BS Furia, SW Peltz, CR Trotta. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3’end formation.. Cell 2004;117:311-21", "CR Pierson, F Al Sufiani. Preterm birth and cerebellar neuropathology.. Semin Fetal Neonatal Med. 2016;21:305-11", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "I Sánchez-Albisua, S Frölich, PG Barth, M Steinlin, I Krägeloh-Mann. Natural course of pontocerebellar hypoplasia type 2A.. Orphanet J Rare Dis. 2014;9:70", "M Steinlin, A Klein, K Haas-Lude, D Zafeiriou, S Strozzi, T Müller, D Gubser-Mercati, T Schmitt Mechelke, I Krägeloh-Mann, E Boltshauser. Pontocerebellar hypoplasia type 2: variability in clinical and imaging findings.. Eur J Paediatr Neurol 2007;11:146-52", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "CR Trotta, SV Paushkin, M Patel, H Li, SW Peltz. Cleavage of pre-tRNAs by the splicing endonuclease requires a composite active site.. Nature 2006;441:375-7", "T van Dijk, F Baas, PG Barth, BT Poll-The. What's new in pontocerebellar hypoplasia? An update on genes and subtypes.. Orphanet J Rare Dis. 2018;13:92", "JJ Volpe. Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important.. J Child Neurol. 2009;24:1085-104" ]	8/9/2009	28/5/2020	14/7/2016	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pc	pc	[ "Keratin, type I cytoskeletal 16", "Keratin, type I cytoskeletal 17", "Keratin, type II cytoskeletal 6A", "Keratin, type II cytoskeletal 6B", "Keratin, type II cytoskeletal 6C", "KRT16", "KRT17", "KRT6A", "KRT6B", "KRT6C", "Pachyonychia Congenita" ]	Pachyonychia Congenita	Frances JD Smith, C David Hansen, Peter R Hull, Roger L Kaspar, WH Irwin McLean, Edel O’Toole, Eli Sprecher	Summary Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities. PC is diagnosed by clinical findings and/or by the identification of a heterozygous pathogenic variant in one of the five keratin genes known to cause PC: Pachyonychia congenita is inherited in an autosomal dominant manner. Approximately 30% of cases appear to be caused by a	## Diagnosis Clinical diagnostic criteria for pachyonychia congenita (PC) include the triad of toenail thickening, plantar keratoderma, and plantar pain, which are present in 97% of individuals with genetically confirmed PC by age ten years [ Pachyonychia congenita (PC) Plantar keratoderma including callus with underlying blisters Plantar pain Hypertrophic nail dystrophy, which may be limited to the toenails or to a few toenails or fingernails (See Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty and continue throughout adulthood Oral leukokeratosis Follicular keratoses on the trunk and extremities usually present by early childhood Palmoplantar hyperhydrosis (<50%) Natal or prenatal teeth (i.e., present at birth or by age 1 month in some affected individuals) Note: (1) Approximately 70% of individuals with PC, enrolled in the International Pachyonychia Congenita Research Registry, inherited the condition from an affected parent; therefore, lack of a family history of PC does not preclude the diagnosis. (2) If the family history suggests autosomal recessive inheritance, a condition other than PC should be considered (see The diagnosis of PC Note: (1) Histologic, immunohistologic, or electron microscopic examination of the nails or skin from individuals with PC is not helpful in confirming the diagnosis of PC but can be performed to rule out other diagnoses. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For individuals who have focal non-epidermolytic palmoplantar keratoderma (FNEPPK), sequence analysis of For individuals who have steatocystoma multiplex (SM) or a history of natal teeth, sequence analysis of For an introduction to multigene panels click Molecular Genetic Testing Used in Pachyonychia Congenita (PC) See Pathogenic variants in at least 800 individuals have been reported [ The numbers in this table refer only to those individuals enrolled in the See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on gene-targeted del/dup analysis are available. To date all identified pathogenic variants causing steatocystoma multiplex (SM) are in • Plantar keratoderma including callus with underlying blisters • Plantar pain • Hypertrophic nail dystrophy, which may be limited to the toenails or to a few toenails or fingernails (See • Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty and continue throughout adulthood • Oral leukokeratosis • Follicular keratoses on the trunk and extremities usually present by early childhood • Palmoplantar hyperhydrosis (<50%) • Natal or prenatal teeth (i.e., present at birth or by age 1 month in some affected individuals) • For individuals who have focal non-epidermolytic palmoplantar keratoderma (FNEPPK), sequence analysis of • For individuals who have steatocystoma multiplex (SM) or a history of natal teeth, sequence analysis of ## Suggestive Findings Pachyonychia congenita (PC) Plantar keratoderma including callus with underlying blisters Plantar pain Hypertrophic nail dystrophy, which may be limited to the toenails or to a few toenails or fingernails (See Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty and continue throughout adulthood Oral leukokeratosis Follicular keratoses on the trunk and extremities usually present by early childhood Palmoplantar hyperhydrosis (<50%) Natal or prenatal teeth (i.e., present at birth or by age 1 month in some affected individuals) Note: (1) Approximately 70% of individuals with PC, enrolled in the International Pachyonychia Congenita Research Registry, inherited the condition from an affected parent; therefore, lack of a family history of PC does not preclude the diagnosis. (2) If the family history suggests autosomal recessive inheritance, a condition other than PC should be considered (see • Plantar keratoderma including callus with underlying blisters • Plantar pain • Hypertrophic nail dystrophy, which may be limited to the toenails or to a few toenails or fingernails (See • Pilosebaceous cysts including widespread steatocystomas/steatocysts (benign lesions) and vellus hair cysts which usually develop at puberty and continue throughout adulthood • Oral leukokeratosis • Follicular keratoses on the trunk and extremities usually present by early childhood • Palmoplantar hyperhydrosis (<50%) • Natal or prenatal teeth (i.e., present at birth or by age 1 month in some affected individuals) ## Establishing the Diagnosis The diagnosis of PC Note: (1) Histologic, immunohistologic, or electron microscopic examination of the nails or skin from individuals with PC is not helpful in confirming the diagnosis of PC but can be performed to rule out other diagnoses. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For individuals who have focal non-epidermolytic palmoplantar keratoderma (FNEPPK), sequence analysis of For individuals who have steatocystoma multiplex (SM) or a history of natal teeth, sequence analysis of For an introduction to multigene panels click Molecular Genetic Testing Used in Pachyonychia Congenita (PC) See Pathogenic variants in at least 800 individuals have been reported [ The numbers in this table refer only to those individuals enrolled in the See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on gene-targeted del/dup analysis are available. To date all identified pathogenic variants causing steatocystoma multiplex (SM) are in • For individuals who have focal non-epidermolytic palmoplantar keratoderma (FNEPPK), sequence analysis of • For individuals who have steatocystoma multiplex (SM) or a history of natal teeth, sequence analysis of ## Clinical Characteristics In all types of pachyonychia congenita (PC) most characteristics are visible by age ten years [ The severity of findings can differ both within a family and among families with the same pathogenic variant. International Pachyonychia Congenita Research Registry (IPCRR) Data Summary (as of 10 May 2017) Data from 774 individuals enrolled in the International PC Research Registry with genetically confirmed pachyonychia congenita By age ≤10 years Nails that grow to full length and have an upward slant caused by the prominent distal hyperkeratosis (often with an accentuated curvature of the nail) Nails that have a nail plate that terminates prematurely leaving a gently sloping distal region of hyperkeratosis and exposed distal finger tip Focal non-epidermolytic palmoplantar keratoderma (FNEPPK), defined as keratoderma of varying severity that may occur on the palms and soles with no (or very mild) nail dystrophy, was previously thought to be a distinct entity but is now considered part of the spectrum of PC. Steatocystoma multiplex (SM), defined as widespread steatocystomas that can develop at puberty with subtle nail involvement but no palmoplantar keratoderma, occurs in association with heterozygous pathogenic variants in Excessive sweating of the palms and soles (palmoplantar hyperhydrosis), observed in approximately 50% of individuals Axillary and inguinal cyst formation Excessive production of waxy material in the ear Severe and unexplained ear pain Hoarseness (laryngeal involvement), reported primarily in young children. Although rare, laryngeal involvement may cause life-threatening respiratory distress requiring intervention. Angular cheilitis (inflammation and fissuring at the angles of the mouth) which is sometimes secondarily infected Paronychia with pronounced edema (and occasional blister formation) under the nails; may exhibit lymphatic extension and may sometimes be caused by infection Leukokeratosis with laryngeal involvement may be seen in infants and children with PC-K6a (see All cases of "failure to thrive" and poor feeding in infancy have been found to be in individuals with PC-K6a, caused by a heterozygous pathogenic variant in Focal non-epidermolytic palmoplantar keratoderma (FNEPPK) has been described only in individuals who have a heterozygous pathogenic variant in either Steatocystoma multiplex (SM) has been reported only in individuals who have a heterozygous pathogenic variant in Individuals with a history of natal teeth are more likely to have a heterozygous pathogenic variant in Based on data on 774 individuals with PC in the IPCRR, clear genotype-phenotype correlations are evident [ In the following instances, the phenotype may vary among individuals with the same pathogenic variant: The same In a few reports of late-onset PC, pathogenic variants have been identified outside the helix boundary and some have questioned whether the location of the pathogenic variant affects the age at onset. However, the ages in these cases are the expected ages at onset for the particular type of PC and should likely not be referred to as "late-onset." Based on data from the International Pachyonychia Congenita Research Registry (IPCRR), the most recent classification for pachyonychia congenita is by mutated gene [ PC-K6a (caused by pathogenic variants in PC-K6b (caused by pathogenic variants in PC-K6c (caused by pathogenic variants in PC-K16 (caused by pathogenic variants in PC-K17 (caused by pathogenic variants in The classification suggested for PC prior to the identification of the genetic basis of the disease was based solely on clinical findings. Historically, the two major subtypes of PC were based on subtle variable phenotypic features (primarily on the presence or absence of pilosebaceous cysts and natal or prenatal teeth) [ PC-1 (Jadassohn-Lewandowski syndrome) PC-2 (Jackson-Lawler syndrome) With detailed clinical histories and pathogenic variants identified in an increasing number of people with PC, it became clear that the older classification of PC-1 and PC-2 was not applicable to the broader population of individuals with PC. The rarity of PC makes it difficult to accurately assess its prevalence. The • Nails that grow to full length and have an upward slant caused by the prominent distal hyperkeratosis (often with an accentuated curvature of the nail) • Nails that have a nail plate that terminates prematurely leaving a gently sloping distal region of hyperkeratosis and exposed distal finger tip • Focal non-epidermolytic palmoplantar keratoderma (FNEPPK), defined as keratoderma of varying severity that may occur on the palms and soles with no (or very mild) nail dystrophy, was previously thought to be a distinct entity but is now considered part of the spectrum of PC. • Steatocystoma multiplex (SM), defined as widespread steatocystomas that can develop at puberty with subtle nail involvement but no palmoplantar keratoderma, occurs in association with heterozygous pathogenic variants in • Excessive sweating of the palms and soles (palmoplantar hyperhydrosis), observed in approximately 50% of individuals • Axillary and inguinal cyst formation • Excessive production of waxy material in the ear • Severe and unexplained ear pain • Hoarseness (laryngeal involvement), reported primarily in young children. Although rare, laryngeal involvement may cause life-threatening respiratory distress requiring intervention. • Angular cheilitis (inflammation and fissuring at the angles of the mouth) which is sometimes secondarily infected • Paronychia with pronounced edema (and occasional blister formation) under the nails; may exhibit lymphatic extension and may sometimes be caused by infection • The same • In a few reports of late-onset PC, pathogenic variants have been identified outside the helix boundary and some have questioned whether the location of the pathogenic variant affects the age at onset. However, the ages in these cases are the expected ages at onset for the particular type of PC and should likely not be referred to as "late-onset." • PC-K6a (caused by pathogenic variants in • PC-K6b (caused by pathogenic variants in • PC-K6c (caused by pathogenic variants in • PC-K16 (caused by pathogenic variants in • PC-K17 (caused by pathogenic variants in • PC-1 (Jadassohn-Lewandowski syndrome) • PC-2 (Jackson-Lawler syndrome) ## Clinical Description In all types of pachyonychia congenita (PC) most characteristics are visible by age ten years [ The severity of findings can differ both within a family and among families with the same pathogenic variant. International Pachyonychia Congenita Research Registry (IPCRR) Data Summary (as of 10 May 2017) Data from 774 individuals enrolled in the International PC Research Registry with genetically confirmed pachyonychia congenita By age ≤10 years Nails that grow to full length and have an upward slant caused by the prominent distal hyperkeratosis (often with an accentuated curvature of the nail) Nails that have a nail plate that terminates prematurely leaving a gently sloping distal region of hyperkeratosis and exposed distal finger tip Focal non-epidermolytic palmoplantar keratoderma (FNEPPK), defined as keratoderma of varying severity that may occur on the palms and soles with no (or very mild) nail dystrophy, was previously thought to be a distinct entity but is now considered part of the spectrum of PC. Steatocystoma multiplex (SM), defined as widespread steatocystomas that can develop at puberty with subtle nail involvement but no palmoplantar keratoderma, occurs in association with heterozygous pathogenic variants in Excessive sweating of the palms and soles (palmoplantar hyperhydrosis), observed in approximately 50% of individuals Axillary and inguinal cyst formation Excessive production of waxy material in the ear Severe and unexplained ear pain Hoarseness (laryngeal involvement), reported primarily in young children. Although rare, laryngeal involvement may cause life-threatening respiratory distress requiring intervention. Angular cheilitis (inflammation and fissuring at the angles of the mouth) which is sometimes secondarily infected Paronychia with pronounced edema (and occasional blister formation) under the nails; may exhibit lymphatic extension and may sometimes be caused by infection • Nails that grow to full length and have an upward slant caused by the prominent distal hyperkeratosis (often with an accentuated curvature of the nail) • Nails that have a nail plate that terminates prematurely leaving a gently sloping distal region of hyperkeratosis and exposed distal finger tip • Focal non-epidermolytic palmoplantar keratoderma (FNEPPK), defined as keratoderma of varying severity that may occur on the palms and soles with no (or very mild) nail dystrophy, was previously thought to be a distinct entity but is now considered part of the spectrum of PC. • Steatocystoma multiplex (SM), defined as widespread steatocystomas that can develop at puberty with subtle nail involvement but no palmoplantar keratoderma, occurs in association with heterozygous pathogenic variants in • Excessive sweating of the palms and soles (palmoplantar hyperhydrosis), observed in approximately 50% of individuals • Axillary and inguinal cyst formation • Excessive production of waxy material in the ear • Severe and unexplained ear pain • Hoarseness (laryngeal involvement), reported primarily in young children. Although rare, laryngeal involvement may cause life-threatening respiratory distress requiring intervention. • Angular cheilitis (inflammation and fissuring at the angles of the mouth) which is sometimes secondarily infected • Paronychia with pronounced edema (and occasional blister formation) under the nails; may exhibit lymphatic extension and may sometimes be caused by infection ## Phenotype Correlations by Gene Leukokeratosis with laryngeal involvement may be seen in infants and children with PC-K6a (see All cases of "failure to thrive" and poor feeding in infancy have been found to be in individuals with PC-K6a, caused by a heterozygous pathogenic variant in Focal non-epidermolytic palmoplantar keratoderma (FNEPPK) has been described only in individuals who have a heterozygous pathogenic variant in either Steatocystoma multiplex (SM) has been reported only in individuals who have a heterozygous pathogenic variant in Individuals with a history of natal teeth are more likely to have a heterozygous pathogenic variant in ## Genotype-Phenotype Correlations Based on data on 774 individuals with PC in the IPCRR, clear genotype-phenotype correlations are evident [ In the following instances, the phenotype may vary among individuals with the same pathogenic variant: The same In a few reports of late-onset PC, pathogenic variants have been identified outside the helix boundary and some have questioned whether the location of the pathogenic variant affects the age at onset. However, the ages in these cases are the expected ages at onset for the particular type of PC and should likely not be referred to as "late-onset." • The same • In a few reports of late-onset PC, pathogenic variants have been identified outside the helix boundary and some have questioned whether the location of the pathogenic variant affects the age at onset. However, the ages in these cases are the expected ages at onset for the particular type of PC and should likely not be referred to as "late-onset." ## Nomenclature Based on data from the International Pachyonychia Congenita Research Registry (IPCRR), the most recent classification for pachyonychia congenita is by mutated gene [ PC-K6a (caused by pathogenic variants in PC-K6b (caused by pathogenic variants in PC-K6c (caused by pathogenic variants in PC-K16 (caused by pathogenic variants in PC-K17 (caused by pathogenic variants in The classification suggested for PC prior to the identification of the genetic basis of the disease was based solely on clinical findings. Historically, the two major subtypes of PC were based on subtle variable phenotypic features (primarily on the presence or absence of pilosebaceous cysts and natal or prenatal teeth) [ PC-1 (Jadassohn-Lewandowski syndrome) PC-2 (Jackson-Lawler syndrome) With detailed clinical histories and pathogenic variants identified in an increasing number of people with PC, it became clear that the older classification of PC-1 and PC-2 was not applicable to the broader population of individuals with PC. • PC-K6a (caused by pathogenic variants in • PC-K6b (caused by pathogenic variants in • PC-K6c (caused by pathogenic variants in • PC-K16 (caused by pathogenic variants in • PC-K17 (caused by pathogenic variants in • PC-1 (Jadassohn-Lewandowski syndrome) • PC-2 (Jackson-Lawler syndrome) ## Prevalence The rarity of PC makes it difficult to accurately assess its prevalence. The ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Note: EBS may be incorrectly diagnosed in young children with PC because they have a greater tendency toward blister formation and lesser tendency toward keratoderma. ## Management To establish the extent of disease and needs in an individual diagnosed with pachyonychia congenita, the following evaluations are recommended: Thorough clinical examination to assess each affected area. These will vary based on the specific gene involved (see Consultation with a clinical geneticist and/or genetic counselor Preliminary treatment guidelines have been published [ The current treatment modalities primarily center on symptomatic relief of pain, hygienic grooming practices including paring of hyperkeratotic areas, treatment of secondary infection when indicated, and use of various walking aids including wheelchairs, crutches, and canes. Topical therapies to remove the hyperkeratosis: Special orthotics or insoles, wicking socks, ventilated footwear or cushioned footwear can help to lessen the pain although pain varies from day to day and at times can be intense even at rest. Maintaining ideal body weight can be a factor in reducing the hyperkeratosis and pain. Limiting walking or standing can help to reduce trauma and slightly diminish the resulting blisters, callus, and pain. The origin, nature, and underlying mechanism of plantar pain in individuals with PC is poorly understood. Several recent studies suggest that neuropathic pain treatments may be useful in individuals with PC who experience plantar pain [ If bacterial or fungal infections occur, systemic antibiotics or antifungals are indicated. Particularly troublesome nails can be successfully removed surgically; however, few affected individuals have had this procedure and in many cases – regardless of the specific pathogenic variant – the nails have regrown [ Some individuals have reported reduction of the leukokeratosis in response to oral antibiotics, suggesting a possible bacterial contribution; more likely, improvement may be a response to the anti-inflammatory properties of the antibiotics. Infection of the skin and nails following grooming or trauma is the most common secondary complication seen in PC. Pre- and post-grooming hygiene and use of clean instruments minimizes this complication. Antibiotics may be indicated when infection occurs. A simple "bleach bath" regimen using a mild bleach solution can help prevent infections. In general, individuals with PC have no known associated systemic diseases or predispositions that require routine surveillance. Some report that higher temperatures and higher humidity worsen the condition. Molecular genetic testing of at-risk relatives in a family with PC is not indicated because the phenotype is readily observed from a young age and no interventions can prevent the development of manifestations or reduce their severity. See For a pregnant woman with PC, weight gain (increasing stress on the plantar surface) or altered hormonal environment during pregnancy may worsen the painful plantar keratoderma. In 2014, a Phase 1b clinical trial sponsored by PC Project and TransDerm was performed using topical sirolimus. This study included 15 affected individuals and was conducted by Dr Joyce Teng at Stanford University. Background research for this trial was previously published [ Short interfering RNA (siRNA) can selectively block expression of a specific K6a-causing pathogenic variant [ Botulinum toxin has been used to treat pain in several affected individuals, with promising results [ Several persons have been treated with statins. The results from studies are mixed. Further research is being conducted and additional animal testing is proposed [ Other therapies currently under investigation include anti-TNF biologics, duloxetine or duloxetine and a tricyclic combination, gabapentin, topical gabapentin, and capsaicin injections. Search • Thorough clinical examination to assess each affected area. These will vary based on the specific gene involved (see • Consultation with a clinical geneticist and/or genetic counselor • Pre- and post-grooming hygiene and use of clean instruments minimizes this complication. • Antibiotics may be indicated when infection occurs. • A simple "bleach bath" regimen using a mild bleach solution can help prevent infections. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with pachyonychia congenita, the following evaluations are recommended: Thorough clinical examination to assess each affected area. These will vary based on the specific gene involved (see Consultation with a clinical geneticist and/or genetic counselor • Thorough clinical examination to assess each affected area. These will vary based on the specific gene involved (see • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Preliminary treatment guidelines have been published [ The current treatment modalities primarily center on symptomatic relief of pain, hygienic grooming practices including paring of hyperkeratotic areas, treatment of secondary infection when indicated, and use of various walking aids including wheelchairs, crutches, and canes. Topical therapies to remove the hyperkeratosis: Special orthotics or insoles, wicking socks, ventilated footwear or cushioned footwear can help to lessen the pain although pain varies from day to day and at times can be intense even at rest. Maintaining ideal body weight can be a factor in reducing the hyperkeratosis and pain. Limiting walking or standing can help to reduce trauma and slightly diminish the resulting blisters, callus, and pain. The origin, nature, and underlying mechanism of plantar pain in individuals with PC is poorly understood. Several recent studies suggest that neuropathic pain treatments may be useful in individuals with PC who experience plantar pain [ If bacterial or fungal infections occur, systemic antibiotics or antifungals are indicated. Particularly troublesome nails can be successfully removed surgically; however, few affected individuals have had this procedure and in many cases – regardless of the specific pathogenic variant – the nails have regrown [ Some individuals have reported reduction of the leukokeratosis in response to oral antibiotics, suggesting a possible bacterial contribution; more likely, improvement may be a response to the anti-inflammatory properties of the antibiotics. ## Prevention of Secondary Complications Infection of the skin and nails following grooming or trauma is the most common secondary complication seen in PC. Pre- and post-grooming hygiene and use of clean instruments minimizes this complication. Antibiotics may be indicated when infection occurs. A simple "bleach bath" regimen using a mild bleach solution can help prevent infections. • Pre- and post-grooming hygiene and use of clean instruments minimizes this complication. • Antibiotics may be indicated when infection occurs. • A simple "bleach bath" regimen using a mild bleach solution can help prevent infections. ## Surveillance In general, individuals with PC have no known associated systemic diseases or predispositions that require routine surveillance. ## Agents/Circumstances to Avoid Some report that higher temperatures and higher humidity worsen the condition. ## Evaluation of Relatives at Risk Molecular genetic testing of at-risk relatives in a family with PC is not indicated because the phenotype is readily observed from a young age and no interventions can prevent the development of manifestations or reduce their severity. See ## Pregnancy Management For a pregnant woman with PC, weight gain (increasing stress on the plantar surface) or altered hormonal environment during pregnancy may worsen the painful plantar keratoderma. ## Therapies Under Investigation In 2014, a Phase 1b clinical trial sponsored by PC Project and TransDerm was performed using topical sirolimus. This study included 15 affected individuals and was conducted by Dr Joyce Teng at Stanford University. Background research for this trial was previously published [ Short interfering RNA (siRNA) can selectively block expression of a specific K6a-causing pathogenic variant [ Botulinum toxin has been used to treat pain in several affected individuals, with promising results [ Several persons have been treated with statins. The results from studies are mixed. Further research is being conducted and additional animal testing is proposed [ Other therapies currently under investigation include anti-TNF biologics, duloxetine or duloxetine and a tricyclic combination, gabapentin, topical gabapentin, and capsaicin injections. Search ## Genetic Counseling Pachyonychia congenita (PC) is inherited in an autosomal dominant manner. Up to 70% of individuals diagnosed with pachyonychia congenita have an affected parent. A proband with pachyonychia congenita may have the disorder as the result of a Complete clinical examination by a dermatologist to confirm the absence of phenotype is recommended for the evaluation of parents of a proband with an apparent If a parent of the proband is affected, the risk to the sibs is 50%. If the parents are clinically unaffected, the risk to the sibs of a proband is low, but slightly greater than that of the general population because of the possibility of germline mosaicism. The incidence of germline mosaicism is not known. It is extremely rare: of 774 cases, a single case of germline mosaicism (0.13%) has been reported for PC [ Because PC is a very rare disorder, affected individuals and families often feel completely isolated. Connecting affected individuals and families to the PC patient advocacy group (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. • Up to 70% of individuals diagnosed with pachyonychia congenita have an affected parent. • A proband with pachyonychia congenita may have the disorder as the result of a • Complete clinical examination by a dermatologist to confirm the absence of phenotype is recommended for the evaluation of parents of a proband with an apparent • If a parent of the proband is affected, the risk to the sibs is 50%. • If the parents are clinically unaffected, the risk to the sibs of a proband is low, but slightly greater than that of the general population because of the possibility of germline mosaicism. • The incidence of germline mosaicism is not known. It is extremely rare: of 774 cases, a single case of germline mosaicism (0.13%) has been reported for PC [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Pachyonychia congenita (PC) is inherited in an autosomal dominant manner. ## Risk to Family Members Up to 70% of individuals diagnosed with pachyonychia congenita have an affected parent. A proband with pachyonychia congenita may have the disorder as the result of a Complete clinical examination by a dermatologist to confirm the absence of phenotype is recommended for the evaluation of parents of a proband with an apparent If a parent of the proband is affected, the risk to the sibs is 50%. If the parents are clinically unaffected, the risk to the sibs of a proband is low, but slightly greater than that of the general population because of the possibility of germline mosaicism. The incidence of germline mosaicism is not known. It is extremely rare: of 774 cases, a single case of germline mosaicism (0.13%) has been reported for PC [ • Up to 70% of individuals diagnosed with pachyonychia congenita have an affected parent. • A proband with pachyonychia congenita may have the disorder as the result of a • Complete clinical examination by a dermatologist to confirm the absence of phenotype is recommended for the evaluation of parents of a proband with an apparent • If a parent of the proband is affected, the risk to the sibs is 50%. • If the parents are clinically unaffected, the risk to the sibs of a proband is low, but slightly greater than that of the general population because of the possibility of germline mosaicism. • The incidence of germline mosaicism is not known. It is extremely rare: of 774 cases, a single case of germline mosaicism (0.13%) has been reported for PC [ ## Related Genetic Counseling Issues Because PC is a very rare disorder, affected individuals and families often feel completely isolated. Connecting affected individuals and families to the PC patient advocacy group (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. ## Resources PC Project P.O. Box 17850 Holladay UT 84117 • • PC Project • P.O. Box 17850 • Holladay UT 84117 • • • ## Molecular Genetics Pachyonychia Congenita: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pachyonychia Congenita ( Keratins form a cytoskeletal intermediate filament network within all epithelial cells. Epithelia in different body regions utilize a range of different keratins. Keratins associated with PC are constitutively expressed in the nail, palmoplantar skin, oral mucosa, and hair. Thus, pathogenic variants in the genes encoding these keratins lead to pathology in these major body sites. Pathogenic variants in at least 400 families have been reported to date [ Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Selected Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Keratins form a cytoskeletal intermediate filament network within all epithelial cells. Epithelia in different body regions utilize a range of different keratins. Keratins associated with PC are constitutively expressed in the nail, palmoplantar skin, oral mucosa, and hair. Thus, pathogenic variants in the genes encoding these keratins lead to pathology in these major body sites. Pathogenic variants in at least 400 families have been reported to date [ Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Selected Variants listed in the table have been provided by the authors. ## Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## ## ## ## Selected Variants listed in the table have been provided by the authors. ## Chapter Notes We thank the many affected individuals and the clinicians without whose input our work into the genetic basis of PC would not have been possible. Thanks to Holly Evans of PC Project for helping with IPCRR data preparation. Research into the genetic basis and treatment of keratin disorders in the WHIM lab has been supported by The Wellcome Trust, DEBRA UK, and The PC Project. C David Hansen, MD (2011-present)Peter R Hull, MD, PhD, FRCPC (2011-present)Roger L Kaspar, PhD (2006-present)Sancy A Leachman, MD, PhD; University of Utah (2006-2014)WH Irwin McLean, DSc, FRSE (2006-present)Leonard M Milstone, MD; Yale University (2011-2017)Edel O'Toole, MD, PhD, FRCPI, FRCP (2014-present)Mary E Schwartz, LLD; PC Project (2006-2017)Frances JD Smith, PhD (2006-present)Eli Sprecher, MD, PhD (2011-present)Maurice van Steensel, MD, PhD; University Hospital Maastricht (2014-2017) 30 November 2017 (ma) Comprehensive update posted live 24 July 2014 (me) Comprehensive updated posted live 1 December 2011 (me) Comprehensive update posted live 25 June 2009 (me) Comprehensive update posted live 6 December 2007 (cd) Revision: clarification of PC phenotypes 27 January 2006 (me) Review posted live 14 July 2005 (rlk) Original submission • 30 November 2017 (ma) Comprehensive update posted live • 24 July 2014 (me) Comprehensive updated posted live • 1 December 2011 (me) Comprehensive update posted live • 25 June 2009 (me) Comprehensive update posted live • 6 December 2007 (cd) Revision: clarification of PC phenotypes • 27 January 2006 (me) Review posted live • 14 July 2005 (rlk) Original submission ## Author Notes ## Acknowledgments We thank the many affected individuals and the clinicians without whose input our work into the genetic basis of PC would not have been possible. Thanks to Holly Evans of PC Project for helping with IPCRR data preparation. Research into the genetic basis and treatment of keratin disorders in the WHIM lab has been supported by The Wellcome Trust, DEBRA UK, and The PC Project. ## Author History C David Hansen, MD (2011-present)Peter R Hull, MD, PhD, FRCPC (2011-present)Roger L Kaspar, PhD (2006-present)Sancy A Leachman, MD, PhD; University of Utah (2006-2014)WH Irwin McLean, DSc, FRSE (2006-present)Leonard M Milstone, MD; Yale University (2011-2017)Edel O'Toole, MD, PhD, FRCPI, FRCP (2014-present)Mary E Schwartz, LLD; PC Project (2006-2017)Frances JD Smith, PhD (2006-present)Eli Sprecher, MD, PhD (2011-present)Maurice van Steensel, MD, PhD; University Hospital Maastricht (2014-2017) ## Revision History 30 November 2017 (ma) Comprehensive update posted live 24 July 2014 (me) Comprehensive updated posted live 1 December 2011 (me) Comprehensive update posted live 25 June 2009 (me) Comprehensive update posted live 6 December 2007 (cd) Revision: clarification of PC phenotypes 27 January 2006 (me) Review posted live 14 July 2005 (rlk) Original submission • 30 November 2017 (ma) Comprehensive update posted live • 24 July 2014 (me) Comprehensive updated posted live • 1 December 2011 (me) Comprehensive update posted live • 25 June 2009 (me) Comprehensive update posted live • 6 December 2007 (cd) Revision: clarification of PC phenotypes • 27 January 2006 (me) Review posted live • 14 July 2005 (rlk) Original submission ## References ## Literature Cited Common findings of pachyonychia congenita include: thickened and dystrophic nails (both fingernails and toenails) (a-c); bullae (usually on the pressure points of the heels and soles); hyperkeratosis (d-e); cysts (f); and oral leukokeratosis (g). Schematic diagram showing the basic protein structure of a keratin filament. The α-helical rod domain is divided into four domains: 1A, 1B, 2A, and 2B, connected by non-helical linkers L1, L12, and L2. At the ends of the rod domain are the helix initiation motif (shaded red) and helix termination motif (shaded red) that are highly conserved in sequence between keratins. The majority of pathogenic variants found in PC in	[ "SP Covello, FJD Smith, JH Sillevis Smitt, AS Paller, CS Munro, MF Jonkman, J Uitto, WHI McLean. Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2.. Br J Dermatol 1998;139:475-80", "CMC DeKlotz, ME Schwartz, LM Milstone. Nail removal in pachyonychia congenita: patient-reported survey outcomes.. J Am Acad Dermatol. 2017;76:990-2", "S Duchatelet, L Guibbal, S de Veer, S Fraitag, P Nitschké, M Zarhrate, C Bodemer, A Hovnanian. 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pcd	pcd	[ "Immotile Cilia Syndrome", "Kartagener Syndrome", "Immotile Cilia Syndrome", "Kartagener Syndrome", "Calaxin", "Centriole and centriolar satellite protein OFD1", "Cilia- and flagella-associated protein 221", "Cilia- and flagella-associated protein 298", "Cilia- and flagella-associated protein 300", "Cilia- and flagella-associated protein 54", "Cilia- and flagella-associated protein 57", "Cilia- and flagella-associated protein 74", "Coiled-coil domain-containing protein 39", "Coiled-coil domain-containing protein 40", "Cyclin-O", "DnaJ homolog subfamily B member 13", "Dynein assembly factor 5, axonemal", "Dynein axonemal assembly factor 1", "Dynein axonemal assembly factor 11", "Dynein axonemal assembly factor 19", "Dynein axonemal assembly factor 3", "Dynein axonemal assembly factor 4", "Dynein axonemal assembly factor 6", "Dynein axonemal heavy chain 1", "Dynein axonemal heavy chain 10", "Dynein axonemal heavy chain 11", "Dynein axonemal heavy chain 5", "Dynein axonemal heavy chain 7", "Dynein axonemal heavy chain 9", "Dynein axonemal intermediate chain 1", "Dynein axonemal intermediate chain 2", "Dynein axonemal light chain 1", "Dynein regulatory complex protein 1", "Dynein regulatory complex subunit 2", "Dynein regulatory complex subunit 4", "Forkhead box protein J1", "GAS2-like protein 2", "Hydrocephalus-inducing protein homolog", "Intraflagellar transport protein 74 homolog", "Leucine-rich repeat-containing protein 56", "Multicilin", "Nucleoside diphosphate kinase homolog 5", "Outer dynein arm-docking complex subunit 1", "Outer dynein arm-docking complex subunit 2", "Outer dynein arm-docking complex subunit 3", "Outer dynein arm-docking complex subunit 4", "Protein kintoun", "Protein TALPID3", "Radial spoke head 1 homolog", "Radial spoke head protein 3 homolog", "Radial spoke head protein 4 homolog A", "Radial spoke head protein 9 homolog", "Serine/threonine-protein kinase 36", "Serine/threonine-protein kinase Nek10", "Sperm flagellar protein 2", "Sperm-associated antigen 1", "Tetratricopeptide repeat protein 12", "Thioredoxin domain-containing protein 3", "Tubulin beta-4B chain", "Tumor protein p73", "X-linked retinitis pigmentosa GTPase regulator", "Zinc finger MYND domain-containing protein 10", "CCDC39", "CCDC40", "CCNO", "CFAP221", "CFAP298", "CFAP300", "CFAP54", "CFAP57", "CFAP74", "CLXN", "DNAAF1", "DNAAF11", "DNAAF19", "DNAAF2", "DNAAF3", "DNAAF4", "DNAAF5", "DNAAF6", "DNAH1", "DNAH10", "DNAH11", "DNAH5", "DNAH7", "DNAH9", "DNAI1", "DNAI2", "DNAJB13", "DNAL1", "DRC1", "DRC2", "DRC4", "FOXJ1", "GAS2L2", "HYDIN", "IFT74", "KIAA0586", "LRRC56", "MCIDAS", "NEK10", "NME5", "NME8", "ODAD1", "ODAD2", "ODAD3", "ODAD4", "OFD1", "RPGR", "RSPH1", "RSPH3", "RSPH4A", "RSPH9", "SPAG1", "SPEF2", "STK36", "TP73", "TTC12", "TUBB4B", "ZMYND10", "Primary Ciliary Dyskinesia", "Overview" ]	Primary Ciliary Dyskinesia	Maimoona A Zariwala, Katherine A Despotes, Stephanie D Davis	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform	## Clinical Characteristics of Primary Ciliary Dyskinesia Primary ciliary dyskinesia (PCD) is associated with: Abnormal ciliary structure and function and biogenesis defects that result in retention of mucus and bacteria in the respiratory tract, leading to chronic otosinopulmonary disease; Defective flagellar structure resulting in abnormal sperm motility. The progression and severity of lung disease varies among individuals, and emerging genotype-phenotype associations are being described [ Chronic airway symptoms are apparent in early childhood. Most children have chronic year-round wet cough, sputum production, and chronic rhonchi that begin during infancy. Lung function test results are consistent with obstructive lung disease. Airway infection and inflammation begin at an early age. Sputum cultures typically yield oropharyngeal flora, Chronic airway infection and inflammation coupled with impaired mucociliary clearance leads to bronchiectasis, which may be apparent in some young children and is almost uniformly present in adulthood on chest CT examination [ A subset of adults with chronic airway infection have calcium deposition in the lung and, as a result, expectorate small calcium stones (lithoptysis) [ Chronic sinusitis and nasal congestion (frequently with mucostasis and prominent nasal drainage) begin in the first months of life, often at birth. Sinus infections and chronic nasal symptoms persist through adulthood [ Chronic/recurrent ear infections are apparent in most young children with PCD, with frequent tympanostomy tube placement [ Subfertility is common among males with PCD as a result of abnormal sperm motility due to shared structural and functional features between the flagellum and motile cilia [ Some females with PCD have normal fertility; others have reduced fertility because of impaired ciliary function in the oviduct [ In affected individuals with heterotaxy, congenital cardiovascular malformations are common and complex, and often the cause of death. Specific cardiovascular defects associated with heterotaxy include atrial isomerism, transposition of the great vessels, double outlet right ventricle, anomalous venous return, interrupted inferior vena cava, and bilateral superior vena cava [ Pulmonary isomerism, usually asymptomatic, can be right isomerism (a trilobed pulmonary anatomy bilaterally with bilateral eparterial bronchi) or left isomerism (both lungs have the lobar and hilar anatomy characteristic of a normal left lung). The stomach may be displaced to the right; the liver may be midline, or the left and right lobes may be reversed. Abnormal rotation of the intestinal loop can result in obstruction or volvulus (vascular obstruction). Central nervous system, skeletal, and genitourinary malformations may also be seen. Hydrocephalus may occur on rare occasion in individuals with PCD (especially those with pathogenic variants in Published consensus recommendations [ Clinical Characteristics to Identify Primary Ciliary Dyskinesia Adapted from The diagnosis of PCD is highly likely if two or more of these key clinical features are present [ • Abnormal ciliary structure and function and biogenesis defects that result in retention of mucus and bacteria in the respiratory tract, leading to chronic otosinopulmonary disease; • Defective flagellar structure resulting in abnormal sperm motility. ## Clinical Manifestations of PCD The progression and severity of lung disease varies among individuals, and emerging genotype-phenotype associations are being described [ Chronic airway symptoms are apparent in early childhood. Most children have chronic year-round wet cough, sputum production, and chronic rhonchi that begin during infancy. Lung function test results are consistent with obstructive lung disease. Airway infection and inflammation begin at an early age. Sputum cultures typically yield oropharyngeal flora, Chronic airway infection and inflammation coupled with impaired mucociliary clearance leads to bronchiectasis, which may be apparent in some young children and is almost uniformly present in adulthood on chest CT examination [ A subset of adults with chronic airway infection have calcium deposition in the lung and, as a result, expectorate small calcium stones (lithoptysis) [ Chronic sinusitis and nasal congestion (frequently with mucostasis and prominent nasal drainage) begin in the first months of life, often at birth. Sinus infections and chronic nasal symptoms persist through adulthood [ Chronic/recurrent ear infections are apparent in most young children with PCD, with frequent tympanostomy tube placement [ Subfertility is common among males with PCD as a result of abnormal sperm motility due to shared structural and functional features between the flagellum and motile cilia [ Some females with PCD have normal fertility; others have reduced fertility because of impaired ciliary function in the oviduct [ In affected individuals with heterotaxy, congenital cardiovascular malformations are common and complex, and often the cause of death. Specific cardiovascular defects associated with heterotaxy include atrial isomerism, transposition of the great vessels, double outlet right ventricle, anomalous venous return, interrupted inferior vena cava, and bilateral superior vena cava [ Pulmonary isomerism, usually asymptomatic, can be right isomerism (a trilobed pulmonary anatomy bilaterally with bilateral eparterial bronchi) or left isomerism (both lungs have the lobar and hilar anatomy characteristic of a normal left lung). The stomach may be displaced to the right; the liver may be midline, or the left and right lobes may be reversed. Abnormal rotation of the intestinal loop can result in obstruction or volvulus (vascular obstruction). Central nervous system, skeletal, and genitourinary malformations may also be seen. Hydrocephalus may occur on rare occasion in individuals with PCD (especially those with pathogenic variants in ## Pulmonary Disease The progression and severity of lung disease varies among individuals, and emerging genotype-phenotype associations are being described [ Chronic airway symptoms are apparent in early childhood. Most children have chronic year-round wet cough, sputum production, and chronic rhonchi that begin during infancy. Lung function test results are consistent with obstructive lung disease. Airway infection and inflammation begin at an early age. Sputum cultures typically yield oropharyngeal flora, Chronic airway infection and inflammation coupled with impaired mucociliary clearance leads to bronchiectasis, which may be apparent in some young children and is almost uniformly present in adulthood on chest CT examination [ A subset of adults with chronic airway infection have calcium deposition in the lung and, as a result, expectorate small calcium stones (lithoptysis) [ ## Nasal Congestion and Sinus Infections Chronic sinusitis and nasal congestion (frequently with mucostasis and prominent nasal drainage) begin in the first months of life, often at birth. Sinus infections and chronic nasal symptoms persist through adulthood [ ## Chronic/Recurrent Ear Infections Chronic/recurrent ear infections are apparent in most young children with PCD, with frequent tympanostomy tube placement [ ## Infertility Subfertility is common among males with PCD as a result of abnormal sperm motility due to shared structural and functional features between the flagellum and motile cilia [ Some females with PCD have normal fertility; others have reduced fertility because of impaired ciliary function in the oviduct [ ## Situs Abnormalities In affected individuals with heterotaxy, congenital cardiovascular malformations are common and complex, and often the cause of death. Specific cardiovascular defects associated with heterotaxy include atrial isomerism, transposition of the great vessels, double outlet right ventricle, anomalous venous return, interrupted inferior vena cava, and bilateral superior vena cava [ Pulmonary isomerism, usually asymptomatic, can be right isomerism (a trilobed pulmonary anatomy bilaterally with bilateral eparterial bronchi) or left isomerism (both lungs have the lobar and hilar anatomy characteristic of a normal left lung). The stomach may be displaced to the right; the liver may be midline, or the left and right lobes may be reversed. Abnormal rotation of the intestinal loop can result in obstruction or volvulus (vascular obstruction). Central nervous system, skeletal, and genitourinary malformations may also be seen. ## Other Hydrocephalus may occur on rare occasion in individuals with PCD (especially those with pathogenic variants in ## Establishing the Clinical Diagnosis of Primary Ciliary Dyskinesia Published consensus recommendations [ Clinical Characteristics to Identify Primary Ciliary Dyskinesia Adapted from The diagnosis of PCD is highly likely if two or more of these key clinical features are present [ ## Causes of Primary Ciliary Dyskinesia To date, pathogenic variants in more than 50 genes are known to cause primary ciliary dyskinesia (PCD) [ Molecular Genetics of Primary Ciliary Dyskinesia AD = autosomal dominant; CP = central pair; IDA = inner dynein arm; MOI = mode of inheritance; MTD = microtubular disorganization; ODA = outer dynein arm; PCD = primary ciliary dyskinesia; XL = X-linked Genes are listed in alphabetical order. Rare = pathogenic variants in this gene reported in <1% of individuals with PCD Low levels of nasal nitric oxide ≤77 nL/min [ From a large study consisting of 1,236 individuals [ Hypomorphic pathogenic variants result in outer dynein arm defect. Not included in Most cilia may appear normal. ## Differential Diagnosis of Primary Ciliary Dyskinesia Inborn errors of immunity. Overlap is likely if associated with respiratory manifestations. Immunodeficiencies such as immunoglobulin G (IgG) subclass deficiency [ Bronchiectasis and nasal polyposis (OMIM Mucin deficiency due to biallelic loss of Asthma and/or allergic rhinitis Gastroesophageal reflux disease Wegener granulomatosis (upper- and lower-airway disease) • • Inborn errors of immunity. Overlap is likely if associated with respiratory manifestations. Immunodeficiencies such as immunoglobulin G (IgG) subclass deficiency [ • • • • • • • • • Bronchiectasis and nasal polyposis (OMIM • Mucin deficiency due to biallelic loss of • Asthma and/or allergic rhinitis • Gastroesophageal reflux disease • Wegener granulomatosis (upper- and lower-airway disease) • • • • ## Evaluation Strategy to Identify the Genetic Cause of Primary Ciliary Dyskinesia The diagnosis of a specific mendelian form of primary ciliary dyskinesia (PCD) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of PCD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Transmission electron microscopy (TEM) to identify ciliary ultrastructural defects requires a biopsy of the respiratory epithelium, typically obtained by brushing or scraping the inferior surface of the nasal turbinate or brushing the bronchial surface via bronchoscopy [ The dynein arm defects are often specific for the mutated gene (see Shortening and/or absence of outer dynein arms alone (26%-59% of all PCD) Shortening or absence of both outer and inner dynein arms (6%-39% of all PCD) Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (6%-16% of all PCD) Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (1%-19% of all PCD) Shortening and/or absence of inner dynein arms alone (rare) Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare) Note: Expertise in evaluation of ciliary ultrastructure is needed to distinguish primary (genetic) defects from acquired defects that result from exposure to different environmental and infectious agents [ Nitric oxide (NO), produced by the respiratory cells (airway epithelial cells), is present in much higher concentrations in the upper airway than in the lower airway. Individuals with PCD have very low nasal NO levels that are approximately one tenth of control values, though the mechanisms for this finding are not fully understood [ • Shortening and/or absence of outer dynein arms alone (26%-59% of all PCD) • Shortening or absence of both outer and inner dynein arms (6%-39% of all PCD) • Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (6%-16% of all PCD) • Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (1%-19% of all PCD) • Shortening and/or absence of inner dynein arms alone (rare) • Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare) ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of PCD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of PCD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click ## Other Testing Transmission electron microscopy (TEM) to identify ciliary ultrastructural defects requires a biopsy of the respiratory epithelium, typically obtained by brushing or scraping the inferior surface of the nasal turbinate or brushing the bronchial surface via bronchoscopy [ The dynein arm defects are often specific for the mutated gene (see Shortening and/or absence of outer dynein arms alone (26%-59% of all PCD) Shortening or absence of both outer and inner dynein arms (6%-39% of all PCD) Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (6%-16% of all PCD) Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (1%-19% of all PCD) Shortening and/or absence of inner dynein arms alone (rare) Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare) Note: Expertise in evaluation of ciliary ultrastructure is needed to distinguish primary (genetic) defects from acquired defects that result from exposure to different environmental and infectious agents [ Nitric oxide (NO), produced by the respiratory cells (airway epithelial cells), is present in much higher concentrations in the upper airway than in the lower airway. Individuals with PCD have very low nasal NO levels that are approximately one tenth of control values, though the mechanisms for this finding are not fully understood [ • Shortening and/or absence of outer dynein arms alone (26%-59% of all PCD) • Shortening or absence of both outer and inner dynein arms (6%-39% of all PCD) • Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (6%-16% of all PCD) • Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (1%-19% of all PCD) • Shortening and/or absence of inner dynein arms alone (rare) • Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare) ## Ciliary Ultrastructural Analysis Transmission electron microscopy (TEM) to identify ciliary ultrastructural defects requires a biopsy of the respiratory epithelium, typically obtained by brushing or scraping the inferior surface of the nasal turbinate or brushing the bronchial surface via bronchoscopy [ The dynein arm defects are often specific for the mutated gene (see Shortening and/or absence of outer dynein arms alone (26%-59% of all PCD) Shortening or absence of both outer and inner dynein arms (6%-39% of all PCD) Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (6%-16% of all PCD) Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (1%-19% of all PCD) Shortening and/or absence of inner dynein arms alone (rare) Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare) Note: Expertise in evaluation of ciliary ultrastructure is needed to distinguish primary (genetic) defects from acquired defects that result from exposure to different environmental and infectious agents [ • Shortening and/or absence of outer dynein arms alone (26%-59% of all PCD) • Shortening or absence of both outer and inner dynein arms (6%-39% of all PCD) • Microtubular (axonemal) disorganization associated with absence of the inner dynein arm and central apparatus defect (6%-16% of all PCD) • Absence or disruption of the central apparatus (central microtubule pair and/or radial spokes) (1%-19% of all PCD) • Shortening and/or absence of inner dynein arms alone (rare) • Oligocilia (presence of only few cilia) with or without normal ultrastructure (rare) ## Nasal Nitric Oxide Measurement Nitric oxide (NO), produced by the respiratory cells (airway epithelial cells), is present in much higher concentrations in the upper airway than in the lower airway. Individuals with PCD have very low nasal NO levels that are approximately one tenth of control values, though the mechanisms for this finding are not fully understood [ ## Other Tests Under Evaluation as Supportive Tests for PCD ## Management Limited clinical practice guidelines for primary ciliary dyskinesia (PCD) exist, and are largely based on small observational studies, expert opinion, and from data in similar conditions such as cystic fibrosis. The PCD Foundation and the European Respiratory Society (ERS) have published consensus recommendations for evaluation and treatment of PCD [ To establish the extent of disease in an individual diagnosed with PCD, the evaluations summarized in Primary Ciliary Dyskinesia: Recommended Evaluations Following Initial Diagnosis Respiratory cultures (typically sputum cultures) to identify infecting organisms & direct antimicrobial therapy Chest radiographs &/or chest CT to define distribution & severity of airway disease & bronchiectasis Pulmonary function tests (spirometry) to define severity of obstructive impairment Pulse oximetry, w/overnight saturation studies if borderline Risk of subfertility should be discussed for males & females. Semen analysis should be performed to guide counseling for males. Risk of ectopic pregnancy should be discussed w/females. Refer to an infertility specialist as needed. Echocardiogram Abdominal ultrasound for polysplenia, asplenia, & abdominal situs inversus MOI = mode of inheritance; PCD = primary ciliary dyskinesia Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) To date, no specific therapies can correct ciliary dysfunction, though this is an active area of research (e.g., mRNA therapies) [ Primary Ciliary Dyskinesia: Treatment of Manifestations Chest percussion Postural drainage Oscillatory vest Breathing maneuvers to facilitate clearance of distal airways Coughing & activities that promote deep breathing & cough (e.g., vigorous exercise) Hydrator therapies are often used as an adjunct despite limited efficacy reported. Pertussis Haemophilus influenzae type b Pneumococcal Influenza For those w/localized bronchiectasis, lobectomy has been performed to ↓ infection of remaining lung. This approach is controversial & multidisciplinary consultation w/experts in PCD is important. Lung transplantation has been performed in persons w/end-stage lung disease. Treatment of congenital heart disease per cardiologist/cardiac surgeon For splenic dysfunction, prophylactic antimicrobial therapy may be indicated. ICSI = intracytoplasmic sperm injection; IUI = intrauterine insemination; PCD = primary ciliary dyskinesia; PE = pressure equalizing To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Primary Ciliary Dyskinesia: Recommended Surveillance Pulmonary visits 2-4x/yr Spirometry 2-4x/yr Surveillance sputum cultures or oropharyngeal swabs 2-4x/yr Imaging as clinically indicated during exacerbations Typically, ear disease improves in later childhood, but hearing loss can persist into adulthood [ Cough suppressants should not be used because cough is critical for clearing secretions. Exposure to respiratory pathogens, tobacco smoke, and other pollutants and irritants that may damage airway mucosa and stimulate mucus secretion should be avoided [ It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment of pulmonary disease and recurrent infections and preventive measures. If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variant(s) in the family are not known, a rigorous clinical history and physical examination accompanied by chest imaging, See For a woman with PCD, any pulmonary infections and pulmonary function status should be rigorously evaluated by an expert in PCD (or cystic fibrosis) to define the risk associated with childbearing. • Respiratory cultures (typically sputum cultures) to identify infecting organisms & direct antimicrobial therapy • Chest radiographs &/or chest CT to define distribution & severity of airway disease & bronchiectasis • Pulmonary function tests (spirometry) to define severity of obstructive impairment • Pulse oximetry, w/overnight saturation studies if borderline • Risk of subfertility should be discussed for males & females. • Semen analysis should be performed to guide counseling for males. • Risk of ectopic pregnancy should be discussed w/females. • Refer to an infertility specialist as needed. • Echocardiogram • Abdominal ultrasound for polysplenia, asplenia, & abdominal situs inversus • Chest percussion • Postural drainage • Oscillatory vest • Breathing maneuvers to facilitate clearance of distal airways • Coughing & activities that promote deep breathing & cough (e.g., vigorous exercise) • Hydrator therapies are often used as an adjunct despite limited efficacy reported. • Pertussis • Haemophilus influenzae type b • Pneumococcal • Influenza • For those w/localized bronchiectasis, lobectomy has been performed to ↓ infection of remaining lung. This approach is controversial & multidisciplinary consultation w/experts in PCD is important. • Lung transplantation has been performed in persons w/end-stage lung disease. • Treatment of congenital heart disease per cardiologist/cardiac surgeon • For splenic dysfunction, prophylactic antimicrobial therapy may be indicated. • Pulmonary visits 2-4x/yr • Spirometry 2-4x/yr • Surveillance sputum cultures or oropharyngeal swabs 2-4x/yr • Imaging as clinically indicated during exacerbations • If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variant(s) in the family are not known, a rigorous clinical history and physical examination accompanied by chest imaging, ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with PCD, the evaluations summarized in Primary Ciliary Dyskinesia: Recommended Evaluations Following Initial Diagnosis Respiratory cultures (typically sputum cultures) to identify infecting organisms & direct antimicrobial therapy Chest radiographs &/or chest CT to define distribution & severity of airway disease & bronchiectasis Pulmonary function tests (spirometry) to define severity of obstructive impairment Pulse oximetry, w/overnight saturation studies if borderline Risk of subfertility should be discussed for males & females. Semen analysis should be performed to guide counseling for males. Risk of ectopic pregnancy should be discussed w/females. Refer to an infertility specialist as needed. Echocardiogram Abdominal ultrasound for polysplenia, asplenia, & abdominal situs inversus MOI = mode of inheritance; PCD = primary ciliary dyskinesia Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Respiratory cultures (typically sputum cultures) to identify infecting organisms & direct antimicrobial therapy • Chest radiographs &/or chest CT to define distribution & severity of airway disease & bronchiectasis • Pulmonary function tests (spirometry) to define severity of obstructive impairment • Pulse oximetry, w/overnight saturation studies if borderline • Risk of subfertility should be discussed for males & females. • Semen analysis should be performed to guide counseling for males. • Risk of ectopic pregnancy should be discussed w/females. • Refer to an infertility specialist as needed. • Echocardiogram • Abdominal ultrasound for polysplenia, asplenia, & abdominal situs inversus ## Treatment of Manifestations To date, no specific therapies can correct ciliary dysfunction, though this is an active area of research (e.g., mRNA therapies) [ Primary Ciliary Dyskinesia: Treatment of Manifestations Chest percussion Postural drainage Oscillatory vest Breathing maneuvers to facilitate clearance of distal airways Coughing & activities that promote deep breathing & cough (e.g., vigorous exercise) Hydrator therapies are often used as an adjunct despite limited efficacy reported. Pertussis Haemophilus influenzae type b Pneumococcal Influenza For those w/localized bronchiectasis, lobectomy has been performed to ↓ infection of remaining lung. This approach is controversial & multidisciplinary consultation w/experts in PCD is important. Lung transplantation has been performed in persons w/end-stage lung disease. Treatment of congenital heart disease per cardiologist/cardiac surgeon For splenic dysfunction, prophylactic antimicrobial therapy may be indicated. ICSI = intracytoplasmic sperm injection; IUI = intrauterine insemination; PCD = primary ciliary dyskinesia; PE = pressure equalizing • Chest percussion • Postural drainage • Oscillatory vest • Breathing maneuvers to facilitate clearance of distal airways • Coughing & activities that promote deep breathing & cough (e.g., vigorous exercise) • Hydrator therapies are often used as an adjunct despite limited efficacy reported. • Pertussis • Haemophilus influenzae type b • Pneumococcal • Influenza • For those w/localized bronchiectasis, lobectomy has been performed to ↓ infection of remaining lung. This approach is controversial & multidisciplinary consultation w/experts in PCD is important. • Lung transplantation has been performed in persons w/end-stage lung disease. • Treatment of congenital heart disease per cardiologist/cardiac surgeon • For splenic dysfunction, prophylactic antimicrobial therapy may be indicated. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Primary Ciliary Dyskinesia: Recommended Surveillance Pulmonary visits 2-4x/yr Spirometry 2-4x/yr Surveillance sputum cultures or oropharyngeal swabs 2-4x/yr Imaging as clinically indicated during exacerbations Typically, ear disease improves in later childhood, but hearing loss can persist into adulthood [ • Pulmonary visits 2-4x/yr • Spirometry 2-4x/yr • Surveillance sputum cultures or oropharyngeal swabs 2-4x/yr • Imaging as clinically indicated during exacerbations ## Agents/Circumstances to Avoid Cough suppressants should not be used because cough is critical for clearing secretions. Exposure to respiratory pathogens, tobacco smoke, and other pollutants and irritants that may damage airway mucosa and stimulate mucus secretion should be avoided [ ## Evaluation of Relatives at Risk It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment of pulmonary disease and recurrent infections and preventive measures. If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variant(s) in the family are not known, a rigorous clinical history and physical examination accompanied by chest imaging, See • If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variant(s) in the family are not known, a rigorous clinical history and physical examination accompanied by chest imaging, ## Pregnancy Management For a woman with PCD, any pulmonary infections and pulmonary function status should be rigorously evaluated by an expert in PCD (or cystic fibrosis) to define the risk associated with childbearing. ## Genetic Counseling of Family Members of an Individual with Primary Ciliary Dyskinesia Primary ciliary dyskinesia (PCD) is usually inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for an autosomal recessive PCD-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PCD-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive PCD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and the PCD-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ If the proband represents a simplex case (i.e., a single occurrence in a family) and the PCD-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism. All of their daughters, who will be heterozygotes; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the Female relatives of an affected male who are heterozygous are usually not affected but may develop manifestations of the disorder due to skewed X-chromosome inactivation [ To date, all individuals with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for autosomal dominant PCD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a PCD-related pathogenic variant. Once the PCD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an autosomal recessive PCD-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PCD-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive PCD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and the PCD-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ • If the proband represents a simplex case (i.e., a single occurrence in a family) and the PCD-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism. • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ • All of their daughters, who will be heterozygotes; • None of their sons. • Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the • Female relatives of an affected male who are heterozygous are usually not affected but may develop manifestations of the disorder due to skewed X-chromosome inactivation [ • To date, all individuals with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for autosomal dominant PCD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a PCD-related pathogenic variant. ## Mode of Inheritance Primary ciliary dyskinesia (PCD) is usually inherited in an autosomal recessive manner. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an autosomal recessive PCD-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PCD-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an autosomal recessive PCD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are presumed to be heterozygous for an autosomal recessive PCD-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a PCD-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an autosomal recessive PCD-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and the PCD-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ If the proband represents a simplex case (i.e., a single occurrence in a family) and the PCD-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism. All of their daughters, who will be heterozygotes; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the Female relatives of an affected male who are heterozygous are usually not affected but may develop manifestations of the disorder due to skewed X-chromosome inactivation [ • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and the PCD-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ • If the proband represents a simplex case (i.e., a single occurrence in a family) and the PCD-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism. • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Although heterozygous females are usually not affected, females with skewed X-chromosome inactivation may develop manifestations of the disorder [ • All of their daughters, who will be heterozygotes; • None of their sons. • Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the • Female relatives of an affected male who are heterozygous are usually not affected but may develop manifestations of the disorder due to skewed X-chromosome inactivation [ ## Autosomal Dominant Inheritance – Risk to Family Members To date, all individuals with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for autosomal dominant PCD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • To date, all individuals with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [ • If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for autosomal dominant PCD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a PCD-related pathogenic variant. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a PCD-related pathogenic variant. ## Prenatal Testing and Preimplantation Genetic Testing Once the PCD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Germany United Kingdom United Kingdom • • • • Germany • • • • • United Kingdom • • • • • • • United Kingdom • • • ## Chapter Notes Websites: Stephanie D Davis ( Drs Davis, Zariwala, and Despotes are also interested in hearing from clinicians treating families affected by PCD in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Zariwala to inquire about review of variants of uncertain significance. We are grateful to the patients and their families for their participation. We also thank the US PCD foundation. We would like to thank Dr Johnny Carson for the assistance with the figure. NIH/NHLBI U54 HL096458 NIH/NHLBI R01 HL071798 NIH/NHLBI R01 HL117836 The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. Stephanie D Davis, MD (2025-present)Katherine A Despotes, MD (2025-present)Michael R Knowles, MD; University of North Carolina at Chapel Hill (2007-2025)Margaret W Leigh, MD; University of North Carolina at Chapel Hill (2007-2025)Maimoona A Zariwala, MSc, PhD, FACMG (2007-present) 22 May 2025 (sw) Comprehensive update posted live 5 December 2019 (sw) Comprehensive update posted live; scope change to overview 3 September 2015 (me) Comprehensive update posted live 15 September 2011 (me) Comprehensive update posted live 6 October 2009 (me) Comprehensive update posted live 24 January 2007 (me) Review posted live 19 July 2006 (mbz) Original submission • NIH/NHLBI U54 HL096458 • NIH/NHLBI R01 HL071798 • NIH/NHLBI R01 HL117836 • 22 May 2025 (sw) Comprehensive update posted live • 5 December 2019 (sw) Comprehensive update posted live; scope change to overview • 3 September 2015 (me) Comprehensive update posted live • 15 September 2011 (me) Comprehensive update posted live • 6 October 2009 (me) Comprehensive update posted live • 24 January 2007 (me) Review posted live • 19 July 2006 (mbz) Original submission ## Author Notes Websites: Stephanie D Davis ( Drs Davis, Zariwala, and Despotes are also interested in hearing from clinicians treating families affected by PCD in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Zariwala to inquire about review of variants of uncertain significance. ## Acknowledgments We are grateful to the patients and their families for their participation. We also thank the US PCD foundation. We would like to thank Dr Johnny Carson for the assistance with the figure. NIH/NHLBI U54 HL096458 NIH/NHLBI R01 HL071798 NIH/NHLBI R01 HL117836 The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. • NIH/NHLBI U54 HL096458 • NIH/NHLBI R01 HL071798 • NIH/NHLBI R01 HL117836 ## Author History Stephanie D Davis, MD (2025-present)Katherine A Despotes, MD (2025-present)Michael R Knowles, MD; University of North Carolina at Chapel Hill (2007-2025)Margaret W Leigh, MD; University of North Carolina at Chapel Hill (2007-2025)Maimoona A Zariwala, MSc, PhD, FACMG (2007-present) ## Revision History 22 May 2025 (sw) Comprehensive update posted live 5 December 2019 (sw) Comprehensive update posted live; scope change to overview 3 September 2015 (me) Comprehensive update posted live 15 September 2011 (me) Comprehensive update posted live 6 October 2009 (me) Comprehensive update posted live 24 January 2007 (me) Review posted live 19 July 2006 (mbz) Original submission • 22 May 2025 (sw) Comprehensive update posted live • 5 December 2019 (sw) Comprehensive update posted live; scope change to overview • 3 September 2015 (me) Comprehensive update posted live • 15 September 2011 (me) Comprehensive update posted live • 6 October 2009 (me) Comprehensive update posted live • 24 January 2007 (me) Review posted live • 19 July 2006 (mbz) Original submission ## References ## Literature Cited Cross section of the cilia A. Schematic diagram of a cilium revealing "9+2" arrangement of nine peripheral microtubule doublets surrounding a central microtubule pair B. Representative electron microscopic image of a normal cilium from the nasal epithelium of a control. "O" represents the outer dynein arm (open arrow) and "I" represents the inner dynein arm (solid arrow). The central pair and radial spokes are also visible. C. Representative electron microscopic image of a cilium from the nasal epithelium of an individual with PCD demonstrating absence of dynein arms.	[]	24/1/2007	22/5/2025	28/2/2013	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pdc	pdc	[ "Pyruvate Carboxylase Deficiency Type A", "Pyruvate Carboxylase Deficiency Type B", "Pyruvate Carboxylase Deficiency Type C", "Pyruvate carboxylase, mitochondrial", "PC", "Pyruvate Carboxylase Deficiency" ]	Pyruvate Carboxylase Deficiency	Maria Laura Duque Lasio, April N Lehman, Ayesha Ahmad, Jirair K Bedoyan	Summary Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to gain weight and/or linear growth failure, developmental delay, epilepsy, and metabolic acidosis. Three clinical phenotypes are recognized. The diagnosis of PC deficiency is established in a proband whose newborn screening or biochemical findings suggest PC deficiency based on identification of either (1) biallelic pathogenic variants in PC deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	Pyruvate Carboxylase Deficiency: Included Phenotypes ## Diagnosis In some newborns and states in the United States, pyruvate carboxylase (PC) deficiency can be suspected on the basis of elevated levels of citrulline during newborn screening. Since citrulline elevation is not specific to PC deficiency, it is critical to perform additional testing to identify the etiology of the citrulline elevation (see Pyruvate carboxylase (PC) deficiency Poor feeding, vomiting, failure to gain weight, linear growth failure Respiratory distress/failure, tachypnea, Kussmaul breathing Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria Developmental delay Hepatomegaly (or hepatosplenomegaly) Poor feeding, vomiting, failure to gain weight Respiratory distress/failure, tachypnea Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy Hepatomegaly Relatively normal or mildly delayed motor development; intellectual disability and autism Respiratory distress, tachypnea, Kussmaul breathing Episodic vomiting Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis Hepatomegaly Pyruvate Carboxylase Deficiency: Supportive Biochemical Laboratory Findings in Blood by Phenotype ↑ alanine & proline NL or intermittent ↑ citrulline ↑ alanine, citrulline, lysine, & proline ↓ glutamine ↑ alanine, lysine, & proline NL citrulline NL = normal Similar abnormalities of lactate and pyruvate and amino acids are seen in urine and cerebrospinal fluid (CSF) [ In the North American Indigenous populations homozygous for the Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. The The Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Of note, the turnaround time in receiving test results, which varies among laboratories, should be considered when determining the order of testing. Frequently, both types of testing are ordered together or sequentially, especially if one of the test results is ambiguous or insufficient to establish the diagnosis. In individuals with PC deficiency, cultured fibroblast- or lymphocyte-based PC enzyme activity is usually less than 10% of that observed in controls [ Molecular genetic testing approaches can include a combination of A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pyruvate Carboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Several pathogenic splicing variants outside the canonical splice junction, deep intronic variants, and structural variants involving Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. One structural variant (a reciprocal translocation between chromosomes 11 and 1) disrupting • Poor feeding, vomiting, failure to gain weight, linear growth failure • Respiratory distress/failure, tachypnea, Kussmaul breathing • Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria • Developmental delay • Hepatomegaly (or hepatosplenomegaly) • Poor feeding, vomiting, failure to gain weight • Respiratory distress/failure, tachypnea • Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy • Hepatomegaly • Relatively normal or mildly delayed motor development; intellectual disability and autism • Respiratory distress, tachypnea, Kussmaul breathing • Episodic vomiting • Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis • Hepatomegaly • ↑ alanine & proline • NL or intermittent ↑ citrulline • ↑ alanine, citrulline, lysine, & proline • ↓ glutamine • ↑ alanine, lysine, & proline • NL citrulline ## Suggestive Findings Pyruvate carboxylase (PC) deficiency Poor feeding, vomiting, failure to gain weight, linear growth failure Respiratory distress/failure, tachypnea, Kussmaul breathing Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria Developmental delay Hepatomegaly (or hepatosplenomegaly) Poor feeding, vomiting, failure to gain weight Respiratory distress/failure, tachypnea Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy Hepatomegaly Relatively normal or mildly delayed motor development; intellectual disability and autism Respiratory distress, tachypnea, Kussmaul breathing Episodic vomiting Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis Hepatomegaly Pyruvate Carboxylase Deficiency: Supportive Biochemical Laboratory Findings in Blood by Phenotype ↑ alanine & proline NL or intermittent ↑ citrulline ↑ alanine, citrulline, lysine, & proline ↓ glutamine ↑ alanine, lysine, & proline NL citrulline NL = normal Similar abnormalities of lactate and pyruvate and amino acids are seen in urine and cerebrospinal fluid (CSF) [ In the North American Indigenous populations homozygous for the Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. • Poor feeding, vomiting, failure to gain weight, linear growth failure • Respiratory distress/failure, tachypnea, Kussmaul breathing • Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria • Developmental delay • Hepatomegaly (or hepatosplenomegaly) • Poor feeding, vomiting, failure to gain weight • Respiratory distress/failure, tachypnea • Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy • Hepatomegaly • Relatively normal or mildly delayed motor development; intellectual disability and autism • Respiratory distress, tachypnea, Kussmaul breathing • Episodic vomiting • Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis • Hepatomegaly • ↑ alanine & proline • NL or intermittent ↑ citrulline • ↑ alanine, citrulline, lysine, & proline • ↓ glutamine • ↑ alanine, lysine, & proline • NL citrulline ## Clinical Findings Poor feeding, vomiting, failure to gain weight, linear growth failure Respiratory distress/failure, tachypnea, Kussmaul breathing Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria Developmental delay Hepatomegaly (or hepatosplenomegaly) Poor feeding, vomiting, failure to gain weight Respiratory distress/failure, tachypnea Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy Hepatomegaly Relatively normal or mildly delayed motor development; intellectual disability and autism Respiratory distress, tachypnea, Kussmaul breathing Episodic vomiting Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis Hepatomegaly • Poor feeding, vomiting, failure to gain weight, linear growth failure • Respiratory distress/failure, tachypnea, Kussmaul breathing • Hypotonia, epilepsy (or epileptic encephalopathy), ataxia, dysarthria • Developmental delay • Hepatomegaly (or hepatosplenomegaly) • Poor feeding, vomiting, failure to gain weight • Respiratory distress/failure, tachypnea • Hypotonia, epilepsy, hyporeflexia, hypothermia, lethargy • Hepatomegaly • Relatively normal or mildly delayed motor development; intellectual disability and autism • Respiratory distress, tachypnea, Kussmaul breathing • Episodic vomiting • Episodic hypotonia, dystonia, ataxia, dysarthria, transient hemiparesis or acute flaccid paralysis • Hepatomegaly ## Supportive Laboratory Findings Pyruvate Carboxylase Deficiency: Supportive Biochemical Laboratory Findings in Blood by Phenotype ↑ alanine & proline NL or intermittent ↑ citrulline ↑ alanine, citrulline, lysine, & proline ↓ glutamine ↑ alanine, lysine, & proline NL citrulline NL = normal Similar abnormalities of lactate and pyruvate and amino acids are seen in urine and cerebrospinal fluid (CSF) [ In the North American Indigenous populations homozygous for the • ↑ alanine & proline • NL or intermittent ↑ citrulline • ↑ alanine, citrulline, lysine, & proline • ↓ glutamine • ↑ alanine, lysine, & proline • NL citrulline ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The The Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Of note, the turnaround time in receiving test results, which varies among laboratories, should be considered when determining the order of testing. Frequently, both types of testing are ordered together or sequentially, especially if one of the test results is ambiguous or insufficient to establish the diagnosis. In individuals with PC deficiency, cultured fibroblast- or lymphocyte-based PC enzyme activity is usually less than 10% of that observed in controls [ Molecular genetic testing approaches can include a combination of A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pyruvate Carboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Several pathogenic splicing variants outside the canonical splice junction, deep intronic variants, and structural variants involving Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. One structural variant (a reciprocal translocation between chromosomes 11 and 1) disrupting ## Biochemical Diagnosis In individuals with PC deficiency, cultured fibroblast- or lymphocyte-based PC enzyme activity is usually less than 10% of that observed in controls [ ## Molecular Genetic Diagnosis Molecular genetic testing approaches can include a combination of A For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pyruvate Carboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Several pathogenic splicing variants outside the canonical splice junction, deep intronic variants, and structural variants involving Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. One structural variant (a reciprocal translocation between chromosomes 11 and 1) disrupting ## A For an introduction to multigene panels click ## For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pyruvate Carboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Several pathogenic splicing variants outside the canonical splice junction, deep intronic variants, and structural variants involving Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. One structural variant (a reciprocal translocation between chromosomes 11 and 1) disrupting ## Clinical Characteristics Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to gain weight and/or linear growth failure, developmental delay, epilepsy, and metabolic acidosis. Historically, three phenotypes of PC deficiency (types A, B, and C) have been recognized based on clinical presentation (see These phenotypes likely represent a continuum ranging from most severe (type B) to least severe (type C) rather than distinct subtypes. Approximately 75 individuals with PC deficiency have been reported to date, with most being either type A or type B; approximately 15 individuals have been reported with type C [ Pyruvate Carboxylase Deficiency: Phenotypes by Select Clinical Features + = present; − = not reported Includes brain anomalies in fetuses homozygous for the North American Indigenous population founder variant p.Ala610Thr [ PC deficiency type A is characterized by infantile onset with metabolic acidosis, lactic acidosis, delayed motor development, intellectual disability, failure to gain weight and/or linear growth failure, apathy, hypotonia, pyramidal tract signs, ataxia, chorea-like movements, nystagmus, and seizures. Episodes of acute vomiting, tachypnea, and lactic acidosis with a compensated metabolic acidosis are usually precipitated by metabolic or infectious stress. Some individuals may require gastrostomy tube placement. PC deficiency type B is characterized by affected neonates and infants presenting with hypothermia (neonates), lethargy, respiratory distress/failure, vomiting, severe lactic acidosis, and hyperammonemia; presenting individuals are likely to develop hypoglycemia. Some affected individuals may require gastrostomy tube placement. Other features include hepatomegaly (or hepatosplenomegaly), epilepsy, and neurologic findings, including hypotonia, pyramidal tract signs, and abnormal movements (including high-amplitude tremor and dyskinesia). Motor development is severely delayed and affected infants have marked developmental delay. In the approximately 15 individuals with PC deficiency type C reported to date, development has ranged from relatively normal (e.g., individuals who walk independently and have some speech and slight cognitive delays) to others with mild developmental delays involving motor skills, speech, and/or cognition; other individuals have had speech delay, a broad-based toe-walking or unsteady gait, and autism spectrum disorder with stereotypic movements (hand flapping) with an otherwise normal neurologic examination [ Other findings reported in some individuals have included exertional dyspnea, seizures, and episodic metabolic acidosis. In one report, the initial clinical presentation mimicked diabetic ketoacidosis [ Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ The pathogenic variant Of note, in general, there is no significant correlation between the clinical phenotype and level of fibroblast- or lymphocyte-based residual PC enzyme activity, although no detectable or low PC activity (<2% of unaffected control mean) is more often associated with PC deficiency type B [ About 75 individuals with PC deficiency have been reported, with most being either type A or type B. Because type C may be under reported, the prevalence of PC deficiency in most populations may be higher. In most populations, the birth incidence of PC deficiency is considered low (1 in 250,000), but prospective studies evaluating the incidence in newborns in most populations have not been completed. In the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada, the carrier frequency of the founder variant PC deficiency type A is also referred to as the infantile or North American form. PC deficiency type B is also referred to as the severe neonatal or French form. PC deficiency type C is also referred to as the intermittent/attenuated form. • • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ ## Clinical Description Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to gain weight and/or linear growth failure, developmental delay, epilepsy, and metabolic acidosis. Historically, three phenotypes of PC deficiency (types A, B, and C) have been recognized based on clinical presentation (see These phenotypes likely represent a continuum ranging from most severe (type B) to least severe (type C) rather than distinct subtypes. Approximately 75 individuals with PC deficiency have been reported to date, with most being either type A or type B; approximately 15 individuals have been reported with type C [ Pyruvate Carboxylase Deficiency: Phenotypes by Select Clinical Features + = present; − = not reported Includes brain anomalies in fetuses homozygous for the North American Indigenous population founder variant p.Ala610Thr [ PC deficiency type A is characterized by infantile onset with metabolic acidosis, lactic acidosis, delayed motor development, intellectual disability, failure to gain weight and/or linear growth failure, apathy, hypotonia, pyramidal tract signs, ataxia, chorea-like movements, nystagmus, and seizures. Episodes of acute vomiting, tachypnea, and lactic acidosis with a compensated metabolic acidosis are usually precipitated by metabolic or infectious stress. Some individuals may require gastrostomy tube placement. PC deficiency type B is characterized by affected neonates and infants presenting with hypothermia (neonates), lethargy, respiratory distress/failure, vomiting, severe lactic acidosis, and hyperammonemia; presenting individuals are likely to develop hypoglycemia. Some affected individuals may require gastrostomy tube placement. Other features include hepatomegaly (or hepatosplenomegaly), epilepsy, and neurologic findings, including hypotonia, pyramidal tract signs, and abnormal movements (including high-amplitude tremor and dyskinesia). Motor development is severely delayed and affected infants have marked developmental delay. In the approximately 15 individuals with PC deficiency type C reported to date, development has ranged from relatively normal (e.g., individuals who walk independently and have some speech and slight cognitive delays) to others with mild developmental delays involving motor skills, speech, and/or cognition; other individuals have had speech delay, a broad-based toe-walking or unsteady gait, and autism spectrum disorder with stereotypic movements (hand flapping) with an otherwise normal neurologic examination [ Other findings reported in some individuals have included exertional dyspnea, seizures, and episodic metabolic acidosis. In one report, the initial clinical presentation mimicked diabetic ketoacidosis [ Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ ## PC Deficiency Type A PC deficiency type A is characterized by infantile onset with metabolic acidosis, lactic acidosis, delayed motor development, intellectual disability, failure to gain weight and/or linear growth failure, apathy, hypotonia, pyramidal tract signs, ataxia, chorea-like movements, nystagmus, and seizures. Episodes of acute vomiting, tachypnea, and lactic acidosis with a compensated metabolic acidosis are usually precipitated by metabolic or infectious stress. Some individuals may require gastrostomy tube placement. ## PC Deficiency Type B PC deficiency type B is characterized by affected neonates and infants presenting with hypothermia (neonates), lethargy, respiratory distress/failure, vomiting, severe lactic acidosis, and hyperammonemia; presenting individuals are likely to develop hypoglycemia. Some affected individuals may require gastrostomy tube placement. Other features include hepatomegaly (or hepatosplenomegaly), epilepsy, and neurologic findings, including hypotonia, pyramidal tract signs, and abnormal movements (including high-amplitude tremor and dyskinesia). Motor development is severely delayed and affected infants have marked developmental delay. ## PC Deficiency Type C In the approximately 15 individuals with PC deficiency type C reported to date, development has ranged from relatively normal (e.g., individuals who walk independently and have some speech and slight cognitive delays) to others with mild developmental delays involving motor skills, speech, and/or cognition; other individuals have had speech delay, a broad-based toe-walking or unsteady gait, and autism spectrum disorder with stereotypic movements (hand flapping) with an otherwise normal neurologic examination [ Other findings reported in some individuals have included exertional dyspnea, seizures, and episodic metabolic acidosis. In one report, the initial clinical presentation mimicked diabetic ketoacidosis [ ## Other Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ • Septated or nonseptated inter- or periventricular or caudothalamic groove cysts [ • Periventricular leukopathy, abnormal diffuse white matter edema involving the frontal temporoparietal, occipital deep, and subcortical white matter, corpus callosum atrophy/agenesis, and brain stem hypoplasia [ • Moderate or severe cortical atrophy, white matter loss, periventricular focal infarctions, ischemic-like brain lesions, subdural hemorrhage / hematomas of differing age, or subarachnoid hemorrhage [ • Abnormal myelination in the cerebral hemispheres, posterior limbs of the internal capsules, cerebral peduncles, midbrain, and cerebellum [ ## Genotype-Phenotype Correlations The pathogenic variant Of note, in general, there is no significant correlation between the clinical phenotype and level of fibroblast- or lymphocyte-based residual PC enzyme activity, although no detectable or low PC activity (<2% of unaffected control mean) is more often associated with PC deficiency type B [ ## Prevalence About 75 individuals with PC deficiency have been reported, with most being either type A or type B. Because type C may be under reported, the prevalence of PC deficiency in most populations may be higher. In most populations, the birth incidence of PC deficiency is considered low (1 in 250,000), but prospective studies evaluating the incidence in newborns in most populations have not been completed. In the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada, the carrier frequency of the founder variant ## Nomenclature PC deficiency type A is also referred to as the infantile or North American form. PC deficiency type B is also referred to as the severe neonatal or French form. PC deficiency type C is also referred to as the intermittent/attenuated form. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Many inborn errors of metabolism have features similar to those of pyruvate carboxylase (PC) deficiency. As listed in Disorders in the Differential Diagnosis of Pyruvate Carboxylase Deficiency Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, seizures w/metabolic acidosis, hearing loss, alopecia, & perioral/facial dermatitis Laboratory findings incl metabolic ketolactic acidosis, organic aciduria, & hyperammonemia If diagnosed through newborn screening, usually asymptomatic w/lifelong treatment of oral biotin Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, encephalopathy, seizure, & metabolic acidosis &/or metabolic stroke Lactic acidemia, hypoglycemia, hyperammonemia, ketosis Multiorgan system involvement Lactic acidemia w/progressive or intermittent neurologic features (poor acquisition or loss of motor milestones, hypotonia, epilepsy, ataxia), nystagmus, & dystonia ↑ blood & CSF lactate concentrations & ↑ blood & CSF concentrations of pyruvate & alanine Blood ketone bodies usually not detectable & normal lactate-to-pyruvate ratio in plasma, unlike PC deficiency Neonatal lactic acidosis ↑ glycine concentration Electron transport chain enzyme activity deficiencies Lactic acidosis ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal) May be assoc w/abnormal acylcarnitine profile &/or ↑ urine organic acid w/marked 2-methyl-2,3-dihydroxybutyric acid Lactic acidosis ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal) May be assoc w/abnormal acylcarnitine profile &/or urine organic acids Lactic acidosis & seizures ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal or elevated) ↑ glycine concentration Electron transport chain enzyme activity deficiencies Neonatal lactic acidosis ↑ 2-hydroxyglutaric acid concentration ↑ lactate & pyruvate concentrations (normal lactate-to-pyruvate ratio) Treatable w/high-dose thiamine ↑ blood lactate, pyruvate, & alanine concentrations w/clinical symptoms Hypoglycemia ↑ ketone bodies ↑ lactate & pyruvate concentrations ↑ lactate-to-pyruvate ratio ↑ fumaric acid or other TCA cycle intermediates Severe ketoacidosis, metabolic acidosis, tachypnea (due to acidosis), vomiting May have seizures May be hypo- or hyperglycemic or have mild hyperammonemia AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; Mat = maternal; MOI = mode of inheritance; PC deficiency = pyruvate carboxylase deficiency; PDCD = pyruvate dehydrogenase complex deficiency; XL = X-linked See • Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, seizures w/metabolic acidosis, hearing loss, alopecia, & perioral/facial dermatitis • Laboratory findings incl metabolic ketolactic acidosis, organic aciduria, & hyperammonemia • If diagnosed through newborn screening, usually asymptomatic w/lifelong treatment of oral biotin • Can present in neonatal period or later in infancy w/neurologic symptoms such as lethargy, encephalopathy, seizure, & metabolic acidosis &/or metabolic stroke • Lactic acidemia, hypoglycemia, hyperammonemia, ketosis • Multiorgan system involvement • Lactic acidemia w/progressive or intermittent neurologic features (poor acquisition or loss of motor milestones, hypotonia, epilepsy, ataxia), nystagmus, & dystonia • ↑ blood & CSF lactate concentrations & ↑ blood & CSF concentrations of pyruvate & alanine • Blood ketone bodies usually not detectable & normal lactate-to-pyruvate ratio in plasma, unlike PC deficiency • Neonatal lactic acidosis • ↑ glycine concentration • Electron transport chain enzyme activity deficiencies • Lactic acidosis • ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal) • May be assoc w/abnormal acylcarnitine profile &/or ↑ urine organic acid w/marked 2-methyl-2,3-dihydroxybutyric acid • Lactic acidosis • ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal) • May be assoc w/abnormal acylcarnitine profile &/or urine organic acids • Lactic acidosis & seizures • ↑ pyruvate concentration (lactate-to-pyruvate ratio may be normal or elevated) • ↑ glycine concentration • Electron transport chain enzyme activity deficiencies • Neonatal lactic acidosis • ↑ 2-hydroxyglutaric acid concentration • ↑ lactate & pyruvate concentrations (normal lactate-to-pyruvate ratio) • Treatable w/high-dose thiamine • ↑ blood lactate, pyruvate, & alanine concentrations w/clinical symptoms • Hypoglycemia • ↑ ketone bodies • ↑ lactate & pyruvate concentrations • ↑ lactate-to-pyruvate ratio • ↑ fumaric acid or other TCA cycle intermediates • Severe ketoacidosis, metabolic acidosis, tachypnea (due to acidosis), vomiting • May have seizures • May be hypo- or hyperglycemic or have mild hyperammonemia ## Management No clinical practice guidelines for pyruvate carboxylase (PC) deficiency have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with PC deficiency, the evaluations summarized in Pyruvate Carboxylase Deficiency: Recommended Evaluations Following Initial Diagnosis in a Neonate/Infant or Child Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended. Hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for metabolic crises) Blood lactate & pyruvate Blood ammonia Blood chemistry panel incl glucose & liver enzymes Arterial or venous blood gas Beta-hydroxybutyrate Blood amino acids Urine organic acids Neurology consultation Brain MRI (and MRS if available) Electroencephalogram Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance; PC deficiency = pyruvate carboxylase deficiency Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for PC deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Pyruvate Carboxylase Deficiency: Treatment of Manifestations Reverse catabolism w/IV dextrose administration. Metabolic acidosis may require IV sodium bicarbonate. Treat precipitating stressors (dehydration, fever, infection, vomiting) Initiate anaplerotic therapy. Provide a high-carbohydrate & high-protein diet w/frequent feedings to help prevent dependence on gluconeogenesis. Ketogenic diet is contraindicated. Feeding therapy Nasogastric tube or gastrostomy tube CNS = central nervous system Liver transplantation between ages 6.5 months and 2.5 years has been tried as a treatment option for PC deficiency types A and B, with long survival reported [ Therapies include pharmacologic doses of cofactors involved in the metabolism of pyruvate and the substitution of the missing end-products. Aspartic acid is needed because in PC deficiency, oxaloacetate biosynthesis and the Krebs cycle are impaired. Depletion of aspartate disrupts the urea cycle; therefore, it is necessary for affected individuals to receive aspartic acid. Thiamine (coenzyme for pyruvate dehydrogenase), biotin (regulator of pyruvate carboxylase activity), and citrate (which reduces acidosis and provides the substrate in the citric acid cycle) are also needed. Studies have suggested that exogenous lipoic acid, while beneficial as an antioxidant and with very low toxicity, is not utilized for mitochondrial lipoylation [ To monitor existing manifestations, the individual's response to treatment, and the emergence of new manifestations, the evaluations summarized in Pyruvate Carboxylase Deficiency: Recommended Surveillance Measurement of growth parameters (incl head circumference) Assessment of feeding skills in infants/toddlers Assessment by metabolic dietitian Plasma ammonia, if clinically warranted Plasma lactic acid Plasma amino acids Comprehensive metabolic panel Liver function tests CBC, ferritin, & urinalysis for ketones EEG MRI Monitor for GI adverse reactions. If receiving via feeding tube, monitor integrity of feeding tube. Monitor plasma acylcarnitine profile. CBC = complete blood count; GI = gastrointestinal Ketogenic diet is contraindicated, as it adds to the metabolic acidosis and ketosis from ketone bodies. Avoid fasting, which induces a catabolic state. It is appropriate to clarify the genetic and/or biochemical status of apparently asymptomatic older and younger at-risk sibs of an affected individual with PC deficiency type C in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. See Pregnancy in a woman with PC deficiency has not been reported. However, should a woman with PC deficiency type C become pregnant, such a pregnancy would be considered high risk and should be closely monitored for any metabolic derangements including dehydration and metabolic acidosis. Search • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended. • Hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for metabolic crises) • Blood lactate & pyruvate • Blood ammonia • Blood chemistry panel incl glucose & liver enzymes • Arterial or venous blood gas • Beta-hydroxybutyrate • Blood amino acids • Urine organic acids • Neurology consultation • Brain MRI (and MRS if available) • Electroencephalogram • Community or • Social work involvement for parental support • Home nursing referral • Reverse catabolism w/IV dextrose administration. • Metabolic acidosis may require IV sodium bicarbonate. • Treat precipitating stressors (dehydration, fever, infection, vomiting) • Initiate anaplerotic therapy. • Provide a high-carbohydrate & high-protein diet w/frequent feedings to help prevent dependence on gluconeogenesis. • Ketogenic diet is contraindicated. • Feeding therapy • Nasogastric tube or gastrostomy tube • Measurement of growth parameters (incl head circumference) • Assessment of feeding skills in infants/toddlers • Assessment by metabolic dietitian • Plasma ammonia, if clinically warranted • Plasma lactic acid • Plasma amino acids • Comprehensive metabolic panel • Liver function tests • CBC, ferritin, & urinalysis for ketones • EEG • MRI • Monitor for GI adverse reactions. • If receiving via feeding tube, monitor integrity of feeding tube. • Monitor plasma acylcarnitine profile. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PC deficiency, the evaluations summarized in Pyruvate Carboxylase Deficiency: Recommended Evaluations Following Initial Diagnosis in a Neonate/Infant or Child Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended. Hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for metabolic crises) Blood lactate & pyruvate Blood ammonia Blood chemistry panel incl glucose & liver enzymes Arterial or venous blood gas Beta-hydroxybutyrate Blood amino acids Urine organic acids Neurology consultation Brain MRI (and MRS if available) Electroencephalogram Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance; PC deficiency = pyruvate carboxylase deficiency Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended. • Hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for metabolic crises) • Blood lactate & pyruvate • Blood ammonia • Blood chemistry panel incl glucose & liver enzymes • Arterial or venous blood gas • Beta-hydroxybutyrate • Blood amino acids • Urine organic acids • Neurology consultation • Brain MRI (and MRS if available) • Electroencephalogram • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for PC deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Pyruvate Carboxylase Deficiency: Treatment of Manifestations Reverse catabolism w/IV dextrose administration. Metabolic acidosis may require IV sodium bicarbonate. Treat precipitating stressors (dehydration, fever, infection, vomiting) Initiate anaplerotic therapy. Provide a high-carbohydrate & high-protein diet w/frequent feedings to help prevent dependence on gluconeogenesis. Ketogenic diet is contraindicated. Feeding therapy Nasogastric tube or gastrostomy tube CNS = central nervous system Liver transplantation between ages 6.5 months and 2.5 years has been tried as a treatment option for PC deficiency types A and B, with long survival reported [ Therapies include pharmacologic doses of cofactors involved in the metabolism of pyruvate and the substitution of the missing end-products. Aspartic acid is needed because in PC deficiency, oxaloacetate biosynthesis and the Krebs cycle are impaired. Depletion of aspartate disrupts the urea cycle; therefore, it is necessary for affected individuals to receive aspartic acid. Thiamine (coenzyme for pyruvate dehydrogenase), biotin (regulator of pyruvate carboxylase activity), and citrate (which reduces acidosis and provides the substrate in the citric acid cycle) are also needed. Studies have suggested that exogenous lipoic acid, while beneficial as an antioxidant and with very low toxicity, is not utilized for mitochondrial lipoylation [ • Reverse catabolism w/IV dextrose administration. • Metabolic acidosis may require IV sodium bicarbonate. • Treat precipitating stressors (dehydration, fever, infection, vomiting) • Initiate anaplerotic therapy. • Provide a high-carbohydrate & high-protein diet w/frequent feedings to help prevent dependence on gluconeogenesis. • Ketogenic diet is contraindicated. • Feeding therapy • Nasogastric tube or gastrostomy tube ## Surveillance To monitor existing manifestations, the individual's response to treatment, and the emergence of new manifestations, the evaluations summarized in Pyruvate Carboxylase Deficiency: Recommended Surveillance Measurement of growth parameters (incl head circumference) Assessment of feeding skills in infants/toddlers Assessment by metabolic dietitian Plasma ammonia, if clinically warranted Plasma lactic acid Plasma amino acids Comprehensive metabolic panel Liver function tests CBC, ferritin, & urinalysis for ketones EEG MRI Monitor for GI adverse reactions. If receiving via feeding tube, monitor integrity of feeding tube. Monitor plasma acylcarnitine profile. CBC = complete blood count; GI = gastrointestinal • Measurement of growth parameters (incl head circumference) • Assessment of feeding skills in infants/toddlers • Assessment by metabolic dietitian • Plasma ammonia, if clinically warranted • Plasma lactic acid • Plasma amino acids • Comprehensive metabolic panel • Liver function tests • CBC, ferritin, & urinalysis for ketones • EEG • MRI • Monitor for GI adverse reactions. • If receiving via feeding tube, monitor integrity of feeding tube. • Monitor plasma acylcarnitine profile. ## Agents/Circumstances to Avoid Ketogenic diet is contraindicated, as it adds to the metabolic acidosis and ketosis from ketone bodies. Avoid fasting, which induces a catabolic state. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic and/or biochemical status of apparently asymptomatic older and younger at-risk sibs of an affected individual with PC deficiency type C in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. See ## Pregnancy Management Pregnancy in a woman with PC deficiency has not been reported. However, should a woman with PC deficiency type C become pregnant, such a pregnancy would be considered high risk and should be closely monitored for any metabolic derangements including dehydration and metabolic acidosis. ## Therapies Under Investigation Search ## Genetic Counseling Pyruvate carboxylase (PC) deficiency is inherited in an autosomal recessive manner. The parents of an affected child are typically heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a postzygotic A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. In the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada, the carrier frequency of the founder variant Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are typically heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a postzygotic • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. In the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada, the carrier frequency of the founder variant ## Mode of Inheritance Pyruvate carboxylase (PC) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are typically heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a postzygotic A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are typically heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a postzygotic • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. In the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada, the carrier frequency of the founder variant • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. In the native North American Ojibwa, Cree, and Mi'kmaq tribes of the Algonquin-speaking peoples in northwestern Ontario and northeastern Manitoba, Canada, the carrier frequency of the founder variant ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • United Kingdom • ## Molecular Genetics Pyruvate Carboxylase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pyruvate Carboxylase Deficiency ( Pyruvate carboxylase (PC) deficiency was first described in 1968 in an individual with Leigh encephalopathy [ PC catalyzes the ATP-dependent irreversible two-step carboxylation of pyruvate to oxaloacetate (see The purpose of aspartate use in management of PC deficiency is to provide oxaloacetate, the missing product of PC (see Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Pyruvate carboxylase (PC) deficiency was first described in 1968 in an individual with Leigh encephalopathy [ PC catalyzes the ATP-dependent irreversible two-step carboxylation of pyruvate to oxaloacetate (see The purpose of aspartate use in management of PC deficiency is to provide oxaloacetate, the missing product of PC (see Variants listed in the table have been provided by the authors. ## Chapter Notes Jirair K Bedoyan ( Dr Bedoyan is also interested in hearing from clinicians treating families affected by various disorders of pyruvate metabolism in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Bedoyan to inquire about review of JKB was supported in part by NIH 2U54NS078059-09 RDCRN NAMDC Project 4 grant. Ayesha Ahmad, MD (2024-present)Jirair K Bedoyan, MD, PhD (2024-present)Darryl De Vivo, MD; Columbia University (2009-2024)Maria Laura Duque Lasio, MD (2024-present)April N Lehman, MD (2024-present)Dong Wang, MD; Georgia Neurodiagnostic & Treatment Center (2009-2024) 30 May 2024 (gf) Comprehensive update posted live 1 March 2018 (sw) Comprehensive update posted live 24 July 2014 (me) Comprehensive update posted live 21 July 2011 (me) Comprehensive update posted live 2 June 2009 (et) Review posted live 7 March 2005 (ddv) Original submission • 30 May 2024 (gf) Comprehensive update posted live • 1 March 2018 (sw) Comprehensive update posted live • 24 July 2014 (me) Comprehensive update posted live • 21 July 2011 (me) Comprehensive update posted live • 2 June 2009 (et) Review posted live • 7 March 2005 (ddv) Original submission ## Author Notes Jirair K Bedoyan ( Dr Bedoyan is also interested in hearing from clinicians treating families affected by various disorders of pyruvate metabolism in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Bedoyan to inquire about review of ## Acknowledgments JKB was supported in part by NIH 2U54NS078059-09 RDCRN NAMDC Project 4 grant. ## Author History Ayesha Ahmad, MD (2024-present)Jirair K Bedoyan, MD, PhD (2024-present)Darryl De Vivo, MD; Columbia University (2009-2024)Maria Laura Duque Lasio, MD (2024-present)April N Lehman, MD (2024-present)Dong Wang, MD; Georgia Neurodiagnostic & Treatment Center (2009-2024) ## Revision History 30 May 2024 (gf) Comprehensive update posted live 1 March 2018 (sw) Comprehensive update posted live 24 July 2014 (me) Comprehensive update posted live 21 July 2011 (me) Comprehensive update posted live 2 June 2009 (et) Review posted live 7 March 2005 (ddv) Original submission • 30 May 2024 (gf) Comprehensive update posted live • 1 March 2018 (sw) Comprehensive update posted live • 24 July 2014 (me) Comprehensive update posted live • 21 July 2011 (me) Comprehensive update posted live • 2 June 2009 (et) Review posted live • 7 March 2005 (ddv) Original submission ## References ## Literature Cited Diagrammatic representation of the metabolic pathways affected by pyruvate carboxylase (PC) deficiency. The PC enzyme is indicated by the red oval; the dotted arrow lines represent absent pathways.	[]	2/6/2009	30/5/2024	30/7/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pdhc-def-ov	pdhc-def-ov	[ "PDH Deficiency (PDHD)", "PDHC Deficiency", "Pyruvate Dehydrogenase Complex Deficiency Disease (PDCDD)", "Pyruvate Dehydrogenase Deficiency", "PDH Deficiency (PDHD)", "PDHC Deficiency", "Pyruvate Dehydrogenase Complex Deficiency Disease (PDCDD)", "Pyruvate Dehydrogenase Deficiency", "[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial", "[Pyruvate dehydrogenase [acetyl-transferring]]-phosphatase 1, mitochondrial", "Dihydrolipoyl dehydrogenase, mitochondrial", "Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial", "Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial", "Pyruvate dehydrogenase E1 component subunit beta, mitochondrial", "Pyruvate dehydrogenase protein X component, mitochondrial", "DLAT", "DLD", "PDHA1", "PDHB", "PDHX", "PDK3", "PDP1", "Primary Pyruvate Dehydrogenase Complex Deficiency", "Overview" ]	Primary Pyruvate Dehydrogenase Complex Deficiency Overview	Rebecca Ganetzky, Elizabeth M McCormick, Marni J Falk	Summary The purpose of this overview is to: Describe the Review the Review the Provide an Inform (when possible) Inform	## Clinical Characteristics of Primary Pyruvate Dehydrogenase Complex Deficiency Primary pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation that mostly affects the brain and leads to decreased ATP production and energy deficit. Primary PDCD most commonly manifests as a syndrome of neurologic signs (congenital microcephaly, hypotonia, epilepsy, and/or ataxia), abnormal brain imaging (dysgenesis of the corpus callosum, Leigh syndrome) and metabolic abnormalities (increased plasma pyruvate, lactic acidemia, and/or metabolic acidosis). Developmental delay is nearly universal [ Developmental delay (majority of individuals) Hypotonia, especially axial (majority of individuals) Epilepsy (occasional) Hypertonia, especially appendicular (occasional) Ataxia (occasional) Peripheral neuropathy (occasional) [ Dystonia – may be episodic, in response to fever, stress or exercise (occasional) [ Spasticity (occasional) Dyskinesia – may be paroxysmal exercise-induced (rare) [ Hemiplegia or episodic limb paralysis (rare) [ Optic atrophy (rare) Nystagmus (rare) Ptosis (rare) or ophthalmoplegia [ Strabismus (rare) Intrauterine growth restriction Shortened long bones (rare) Primary or acquired microcephaly (majority of individuals) Cerebral atrophy (majority of individuals) [ Asymmetric ventriculomegaly (common) Dysgenesis or agenesis of the corpus callosum (common) [ T Periventricular cysts and/or intraventricular septations (occasional) Hyporotation of the hippocampus (rare) Elevated blood lactate with proportional elevation of pyruvate; normal lactate/pyruvate ratio (normal range 10-20). Peak pyruvate is typically >0.2 mmol/L [ Note: Pyruvate may appear artificially low in samples that are collected improperly (e.g., not drawn immediately into a perchloric acid tube, not drawn on ice, or drawn while using a tourniquet). Elevated plasma alanine and proline may also occur. Alanine-to-leucine and proline-to-leucine ratios are highly sensitive but not specific for primary PDCD [ Elevated urine and CSF lactate and pyruvate Low pyruvate dehydrogenase complex (PDC) enzyme activity in cultured fibroblasts, lymphocytes, and/or skeletal muscle (activity levels may vary between tissues in an individual) [ Additional laboratory features variably present in individuals with specific molecular causes of primary PDCD (See Positive newborn screen (limited availability to date). Pilot newborn screening for primary PDCD using dried blood spots to screen for ratio of alanine:leucine >4 and/or proline:leucine >3 was used to identify three neonates with PDCD and two additional neonates with other mitochondrial diseases. This screening had a 2.8% positive predictive value and an 80% sensitivity. Pilot newborn screening is ongoing in the state of Ohio [ • Developmental delay (majority of individuals) • Hypotonia, especially axial (majority of individuals) • Epilepsy (occasional) • Hypertonia, especially appendicular (occasional) • Ataxia (occasional) • Peripheral neuropathy (occasional) [ • Dystonia – may be episodic, in response to fever, stress or exercise (occasional) [ • Spasticity (occasional) • Dyskinesia – may be paroxysmal exercise-induced (rare) [ • Hemiplegia or episodic limb paralysis (rare) [ • Optic atrophy (rare) • Nystagmus (rare) • Ptosis (rare) or ophthalmoplegia [ • Strabismus (rare) • Intrauterine growth restriction • Shortened long bones (rare) • Primary or acquired microcephaly (majority of individuals) • Cerebral atrophy (majority of individuals) [ • Asymmetric ventriculomegaly (common) • Dysgenesis or agenesis of the corpus callosum (common) [ • T • Periventricular cysts and/or intraventricular septations (occasional) • Hyporotation of the hippocampus (rare) • Elevated blood lactate with proportional elevation of pyruvate; normal lactate/pyruvate ratio (normal range 10-20). Peak pyruvate is typically >0.2 mmol/L [ • Note: Pyruvate may appear artificially low in samples that are collected improperly (e.g., not drawn immediately into a perchloric acid tube, not drawn on ice, or drawn while using a tourniquet). • Elevated plasma alanine and proline may also occur. Alanine-to-leucine and proline-to-leucine ratios are highly sensitive but not specific for primary PDCD [ • Elevated urine and CSF lactate and pyruvate • Low pyruvate dehydrogenase complex (PDC) enzyme activity in cultured fibroblasts, lymphocytes, and/or skeletal muscle (activity levels may vary between tissues in an individual) [ • Additional laboratory features variably present in individuals with specific molecular causes of primary PDCD (See • Positive newborn screen (limited availability to date). Pilot newborn screening for primary PDCD using dried blood spots to screen for ratio of alanine:leucine >4 and/or proline:leucine >3 was used to identify three neonates with PDCD and two additional neonates with other mitochondrial diseases. This screening had a 2.8% positive predictive value and an 80% sensitivity. Pilot newborn screening is ongoing in the state of Ohio [ ## Features of Primary PDCD Developmental delay (majority of individuals) Hypotonia, especially axial (majority of individuals) Epilepsy (occasional) Hypertonia, especially appendicular (occasional) Ataxia (occasional) Peripheral neuropathy (occasional) [ Dystonia – may be episodic, in response to fever, stress or exercise (occasional) [ Spasticity (occasional) Dyskinesia – may be paroxysmal exercise-induced (rare) [ Hemiplegia or episodic limb paralysis (rare) [ Optic atrophy (rare) Nystagmus (rare) Ptosis (rare) or ophthalmoplegia [ Strabismus (rare) Intrauterine growth restriction Shortened long bones (rare) Primary or acquired microcephaly (majority of individuals) Cerebral atrophy (majority of individuals) [ Asymmetric ventriculomegaly (common) Dysgenesis or agenesis of the corpus callosum (common) [ T Periventricular cysts and/or intraventricular septations (occasional) Hyporotation of the hippocampus (rare) Elevated blood lactate with proportional elevation of pyruvate; normal lactate/pyruvate ratio (normal range 10-20). Peak pyruvate is typically >0.2 mmol/L [ Note: Pyruvate may appear artificially low in samples that are collected improperly (e.g., not drawn immediately into a perchloric acid tube, not drawn on ice, or drawn while using a tourniquet). Elevated plasma alanine and proline may also occur. Alanine-to-leucine and proline-to-leucine ratios are highly sensitive but not specific for primary PDCD [ Elevated urine and CSF lactate and pyruvate Low pyruvate dehydrogenase complex (PDC) enzyme activity in cultured fibroblasts, lymphocytes, and/or skeletal muscle (activity levels may vary between tissues in an individual) [ Additional laboratory features variably present in individuals with specific molecular causes of primary PDCD (See Positive newborn screen (limited availability to date). Pilot newborn screening for primary PDCD using dried blood spots to screen for ratio of alanine:leucine >4 and/or proline:leucine >3 was used to identify three neonates with PDCD and two additional neonates with other mitochondrial diseases. This screening had a 2.8% positive predictive value and an 80% sensitivity. Pilot newborn screening is ongoing in the state of Ohio [ • Developmental delay (majority of individuals) • Hypotonia, especially axial (majority of individuals) • Epilepsy (occasional) • Hypertonia, especially appendicular (occasional) • Ataxia (occasional) • Peripheral neuropathy (occasional) [ • Dystonia – may be episodic, in response to fever, stress or exercise (occasional) [ • Spasticity (occasional) • Dyskinesia – may be paroxysmal exercise-induced (rare) [ • Hemiplegia or episodic limb paralysis (rare) [ • Optic atrophy (rare) • Nystagmus (rare) • Ptosis (rare) or ophthalmoplegia [ • Strabismus (rare) • Intrauterine growth restriction • Shortened long bones (rare) • Primary or acquired microcephaly (majority of individuals) • Cerebral atrophy (majority of individuals) [ • Asymmetric ventriculomegaly (common) • Dysgenesis or agenesis of the corpus callosum (common) [ • T • Periventricular cysts and/or intraventricular septations (occasional) • Hyporotation of the hippocampus (rare) • Elevated blood lactate with proportional elevation of pyruvate; normal lactate/pyruvate ratio (normal range 10-20). Peak pyruvate is typically >0.2 mmol/L [ • Note: Pyruvate may appear artificially low in samples that are collected improperly (e.g., not drawn immediately into a perchloric acid tube, not drawn on ice, or drawn while using a tourniquet). • Elevated plasma alanine and proline may also occur. Alanine-to-leucine and proline-to-leucine ratios are highly sensitive but not specific for primary PDCD [ • Elevated urine and CSF lactate and pyruvate • Low pyruvate dehydrogenase complex (PDC) enzyme activity in cultured fibroblasts, lymphocytes, and/or skeletal muscle (activity levels may vary between tissues in an individual) [ • Additional laboratory features variably present in individuals with specific molecular causes of primary PDCD (See • Positive newborn screen (limited availability to date). Pilot newborn screening for primary PDCD using dried blood spots to screen for ratio of alanine:leucine >4 and/or proline:leucine >3 was used to identify three neonates with PDCD and two additional neonates with other mitochondrial diseases. This screening had a 2.8% positive predictive value and an 80% sensitivity. Pilot newborn screening is ongoing in the state of Ohio [ ## Causes of Primary Pyruvate Dehydrogenase Complex Deficiency Primary Pyruvate Dehydrogenase Complex Deficiency: Genes and Distinguishing Clinical Features Milder phenotype w/survival into childhood/adulthood Episodic dystonia PDC enzyme activity below reference range but not as low as other forms of PDCD ± abnl brain MRI, globus pallidus lesions (resembles PKAN but w/o "eye of the tiger" MRI sign) Several w/clinical response to lipoic acid, thiamine, &/or ketogenic diet Present w/Leigh syndrome ↑ branched-chain amino acids (i.e., mild-moderate ↑s of leucine, isoleucine & valine w/or w/o alloisoleucine) ↑ citrulline ↑ urine alpha-ketoglutarate Founder variant in Ashkenazi Jewish population Variable phenotype: neonatal lactic acidosis, Leigh syndrome Affected females have most striking abnormalities on brain MRI (e.g., asymmetric ventriculomegaly, corpus callosum dysgenesis). Variable response to ketogenic diet; treatment w/ketogenic diet is assoc w/↑ life span. Typically more severely affected ± structural brain abnormalities & microcephaly Leigh syndrome IUGR Treatment w/ketogenic diet is assoc w/↑ life span. Neonatal lactic acidosis Non-progressive encephalopathy Mild dysmorphic features Founder variant in people of Roma & Moroccan ancestry Cardiomyopathy Neonatal lactic acidosis Clinical response to ketogenic diet Clinical features of CMT incl Childhood/adult onset abnl = abnormal; CMT = Charcot-Marie-Tooth; IUGR = intrauterine growth restriction; PKAN = pantothenate kinase-associated neurodegeneration Genes are listed alphabetically Molecular causes of Leigh syndrome is characterized by decompensation during intercurrent illness, lactic acidosis, and bilateral symmetric T • Milder phenotype w/survival into childhood/adulthood • Episodic dystonia • PDC enzyme activity below reference range but not as low as other forms of PDCD • ± abnl brain MRI, globus pallidus lesions (resembles PKAN but w/o "eye of the tiger" MRI sign) • Several w/clinical response to lipoic acid, thiamine, &/or ketogenic diet • Present w/Leigh syndrome • ↑ branched-chain amino acids (i.e., mild-moderate ↑s of leucine, isoleucine & valine w/or w/o alloisoleucine) • ↑ citrulline • ↑ urine alpha-ketoglutarate • Founder variant in Ashkenazi Jewish population • Variable phenotype: neonatal lactic acidosis, Leigh syndrome • Affected females have most striking abnormalities on brain MRI (e.g., asymmetric ventriculomegaly, corpus callosum dysgenesis). • Variable response to ketogenic diet; treatment w/ketogenic diet is assoc w/↑ life span. • Typically more severely affected • ± structural brain abnormalities & microcephaly • Leigh syndrome • IUGR • Treatment w/ketogenic diet is assoc w/↑ life span. • Neonatal lactic acidosis • Non-progressive encephalopathy • Mild dysmorphic features • Founder variant in people of Roma & Moroccan ancestry • Cardiomyopathy • Neonatal lactic acidosis • Clinical response to ketogenic diet • Clinical features of CMT incl • Childhood/adult onset ## Differential Diagnosis of Primary Pyruvate Dehydrogenase Complex Deficiency Note: Multiple genes, in addition to those listed in Genes of Interest in the Differential Diagnosis of Primary Pyruvate Dehydrogenase Complex Deficiency AD = autosomal dominant; AR = autosomal recessive; MT = mitochondrial; MOI = mode of inheritance; mtDNA = mitochondrial DNA; nl = normal; PDCD = pyruvate dehydrogenase complex deficiency; PDC = pyruvate dehydrogenase complex; XL = X-linked Unlike primary PDCD, fetal alcohol syndrome is associated with normal lactate and pyruvate and a fetal history suggestive of in utero alcohol exposure. In addition, children with fetal alcohol syndrome typically have more advanced development compared to children with primary PDCD. • Unlike primary PDCD, fetal alcohol syndrome is associated with normal lactate and pyruvate and a fetal history suggestive of in utero alcohol exposure. In addition, children with fetal alcohol syndrome typically have more advanced development compared to children with primary PDCD. ## Evaluation Strategies to Identify the Genetic Cause of Primary Pyruvate Dehydrogenase Complex Deficiency in a Proband Establishing a specific genetic cause of primary pyruvate dehydrogenase complex deficiency (PDCD): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management of Pyruvate Dehydrogenase Complex Deficiency Based on Genetic Cause This section provides information regarding recommendations for evaluations following initial diagnosis ( Recommended Evaluations Following Initial Diagnosis in Individuals with Primary Pyruvate Dehydrogenase Complex Deficiency Community or Social work involvement for parental support; Home nursing or therapy (speech, PT &/or OT) referral. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There are no FDA-approved therapies for primary PDCD, thus, treatment recommendations are based on open-label case reports and small trials. Pyruvate Dehydrogenase Complex Deficiency: Management by Genetic Cause Ketogenic diet Thiamine (300-1000 mg/day) has been used w/limited success. Branched-chain amino acid restriction Dextrose-containing IV fluids Riboflavin (220-400 mg/day) Acetaminophen & ethanol are contraindicated. The recommended ratio varies from as low as a 1:1 fat-to-carbohydrate & protein ratio ("modified" ketogenic diet) to as high as a 4:1 ratio. There are no studies that definitively demonstrate the superiority of any particular ratio. The recommended amount of dietary fat can vary widely, from ~55% to 80%, with variable proportions of unsaturated and saturated fats. The best outcomes are associated with maintaining plasma or serum beta-hydroxybutyrate levels at about 3.0-3.5 mEq/L [ Ketogenic diet is the most beneficial in individuals with a milder pre-treatment disease course, disease onset after the neonatal period, higher baseline developmental functioning, and absence of structural brain anomalies [ Treatment of Manifestations in Individuals with Primary Pyruvate Dehydrogenase Complex Deficiency Minimize stressors (e.g., fever). Benzodiazepines Ketogenic diet Standard anti-seizure therapy as needed Nasogastric tube or gastrostomy tube Feeding therapy w/speech therapist OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see For individuals with primary PDCD, comprehensive neurologic examination and developmental assessment are recommended every six to 12 months to assess for new neurologic symptoms and epilepsy control. Repeat brain MRI and EEG are warranted only if new symptoms develop. Individuals may require a physical medicine and rehabilitation specialist to guide their therapy and advise on the use of orthotic devices. Physical examination to assess for neuromuscular scoliosis and acquired hip dysplasia should be performed every six to 12 months, accompanied by radiographic imaging if there is clinical concern. Annual ophthalmologic examination to assess for eye movement and ptosis is recommended. Serum bicarbonate and lactate levels to monitor for acidosis should be performed as needed with illness and metabolic stressors, as well as with initiation of and modifications in ketogenic diet regimen. Beta-hydroxybutyrate levels should be monitored routinely for children on the ketogenic diet, with a goal of maintenance above 3.0-3.5 mmol/L. For individuals with pathogenic variants in Dichloroacetate (DCA) and phenylbutyrate both inhibit pyruvate dehydrogenase kinase 1 (PDK1), which is the major inhibitor of PDC. Inhibition of PDK1 results in enhanced residual PDC enzyme activity. DCA is reportedly a pan PDK inhibitor, although the inhibition varies among isoforms. Clinical trials with DCA are ongoing ( Phenylbutyrate has been shown in vitro to increase PDC enzyme activity in cell lines from individuals with • Community or • Social work involvement for parental support; • Home nursing or therapy (speech, PT &/or OT) referral. • Ketogenic diet • Thiamine (300-1000 mg/day) has been used w/limited success. • Branched-chain amino acid restriction • Dextrose-containing IV fluids • Riboflavin (220-400 mg/day) • Acetaminophen & ethanol are contraindicated. • Minimize stressors (e.g., fever). • Benzodiazepines • Ketogenic diet • Standard anti-seizure therapy as needed • Nasogastric tube or gastrostomy tube • Feeding therapy w/speech therapist ## Evaluations Following Initial Diagnosis Recommended Evaluations Following Initial Diagnosis in Individuals with Primary Pyruvate Dehydrogenase Complex Deficiency Community or Social work involvement for parental support; Home nursing or therapy (speech, PT &/or OT) referral. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Community or • Social work involvement for parental support; • Home nursing or therapy (speech, PT &/or OT) referral. ## Treatment of Manifestations There are no FDA-approved therapies for primary PDCD, thus, treatment recommendations are based on open-label case reports and small trials. Pyruvate Dehydrogenase Complex Deficiency: Management by Genetic Cause Ketogenic diet Thiamine (300-1000 mg/day) has been used w/limited success. Branched-chain amino acid restriction Dextrose-containing IV fluids Riboflavin (220-400 mg/day) Acetaminophen & ethanol are contraindicated. The recommended ratio varies from as low as a 1:1 fat-to-carbohydrate & protein ratio ("modified" ketogenic diet) to as high as a 4:1 ratio. There are no studies that definitively demonstrate the superiority of any particular ratio. The recommended amount of dietary fat can vary widely, from ~55% to 80%, with variable proportions of unsaturated and saturated fats. The best outcomes are associated with maintaining plasma or serum beta-hydroxybutyrate levels at about 3.0-3.5 mEq/L [ Ketogenic diet is the most beneficial in individuals with a milder pre-treatment disease course, disease onset after the neonatal period, higher baseline developmental functioning, and absence of structural brain anomalies [ Treatment of Manifestations in Individuals with Primary Pyruvate Dehydrogenase Complex Deficiency Minimize stressors (e.g., fever). Benzodiazepines Ketogenic diet Standard anti-seizure therapy as needed Nasogastric tube or gastrostomy tube Feeding therapy w/speech therapist OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Ketogenic diet • Thiamine (300-1000 mg/day) has been used w/limited success. • Branched-chain amino acid restriction • Dextrose-containing IV fluids • Riboflavin (220-400 mg/day) • Acetaminophen & ethanol are contraindicated. • Minimize stressors (e.g., fever). • Benzodiazepines • Ketogenic diet • Standard anti-seizure therapy as needed • Nasogastric tube or gastrostomy tube • Feeding therapy w/speech therapist ## Surveillance For individuals with primary PDCD, comprehensive neurologic examination and developmental assessment are recommended every six to 12 months to assess for new neurologic symptoms and epilepsy control. Repeat brain MRI and EEG are warranted only if new symptoms develop. Individuals may require a physical medicine and rehabilitation specialist to guide their therapy and advise on the use of orthotic devices. Physical examination to assess for neuromuscular scoliosis and acquired hip dysplasia should be performed every six to 12 months, accompanied by radiographic imaging if there is clinical concern. Annual ophthalmologic examination to assess for eye movement and ptosis is recommended. Serum bicarbonate and lactate levels to monitor for acidosis should be performed as needed with illness and metabolic stressors, as well as with initiation of and modifications in ketogenic diet regimen. Beta-hydroxybutyrate levels should be monitored routinely for children on the ketogenic diet, with a goal of maintenance above 3.0-3.5 mmol/L. For individuals with pathogenic variants in ## Therapies Under Investigation Dichloroacetate (DCA) and phenylbutyrate both inhibit pyruvate dehydrogenase kinase 1 (PDK1), which is the major inhibitor of PDC. Inhibition of PDK1 results in enhanced residual PDC enzyme activity. DCA is reportedly a pan PDK inhibitor, although the inhibition varies among isoforms. Clinical trials with DCA are ongoing ( Phenylbutyrate has been shown in vitro to increase PDC enzyme activity in cell lines from individuals with ## Genetic Risk Assessment of Family Members of a Proband with Primary Pyruvate Dehydrogenase Complex Deficiency Unlike many X-linked disorders, an equal frequency of clinically affected males and females has been observed in Primary PDCD caused by pathogenic variants in The father of an affected male will not have the disorder nor be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the mother may have somatic/germline mosaicism, or the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. A female proband may have To date, all reported female probands with Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a The risk to sibs of a male proband of inheriting a The risk to sibs of a female proband of inheriting a If the mother of the proband has a If the father of the proband has a The risk that a sib who inherits a If the proband represents a simplex case (i.e., a single occurrence in a family) and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Possible maternal germline mosaicism is suggested in a family described by Affected males with Affected males with Females with a Note: Molecular genetic testing may be able to identify the family member in whom a The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a primary PDCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a primary PDCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Intrafamilial clinical variability may be observed between sibs who inherit biallelic primary PDCD-causing pathogenic variants. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Once the primary PDCD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the mother may have somatic/germline mosaicism, or the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • A female proband may have • To date, all reported female probands with • Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a • The risk to sibs of a male proband of inheriting a • The risk to sibs of a female proband of inheriting a • If the mother of the proband has a • If the father of the proband has a • If the mother of the proband has a • If the father of the proband has a • The risk that a sib who inherits a • If the proband represents a simplex case (i.e., a single occurrence in a family) and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Possible maternal germline mosaicism is suggested in a family described by • If the mother of the proband has a • If the father of the proband has a • Affected males with • Affected males with • Females with a • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a primary PDCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a primary PDCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Intrafamilial clinical variability may be observed between sibs who inherit biallelic primary PDCD-causing pathogenic variants. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Mode of Inheritance Unlike many X-linked disorders, an equal frequency of clinically affected males and females has been observed in Primary PDCD caused by pathogenic variants in ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the mother may have somatic/germline mosaicism, or the affected male may have a Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. A female proband may have To date, all reported female probands with Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a The risk to sibs of a male proband of inheriting a The risk to sibs of a female proband of inheriting a If the mother of the proband has a If the father of the proband has a The risk that a sib who inherits a If the proband represents a simplex case (i.e., a single occurrence in a family) and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Possible maternal germline mosaicism is suggested in a family described by Affected males with Affected males with Females with a Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the mother may have somatic/germline mosaicism, or the affected male may have a • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • A female proband may have • To date, all reported female probands with • Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a • The risk to sibs of a male proband of inheriting a • The risk to sibs of a female proband of inheriting a • If the mother of the proband has a • If the father of the proband has a • If the mother of the proband has a • If the father of the proband has a • The risk that a sib who inherits a • If the proband represents a simplex case (i.e., a single occurrence in a family) and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Possible maternal germline mosaicism is suggested in a family described by • If the mother of the proband has a • If the father of the proband has a • Affected males with • Affected males with • Females with a ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a primary PDCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a primary PDCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Intrafamilial clinical variability may be observed between sibs who inherit biallelic primary PDCD-causing pathogenic variants. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a primary PDCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a primary PDCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Intrafamilial clinical variability may be observed between sibs who inherit biallelic primary PDCD-causing pathogenic variants. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Prenatal Testing and Preimplantation Genetic Testing Once the primary PDCD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • • • ## Chapter Notes All of the authors work together in the Rebecca Ganetzky, MD ( Elizabeth M McCormick, MS, LGCC ( Marni J Falk, MD ( This work was funded in part by the Mitochondrial Medicine Frontier Program at Children's Hospital of Philadelphia and the National Institutes of Health (R35-GM134863, U24-HD093483, K08-DK113250). The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsors or the National Institutes of Health. 17 June 2021 (sw) Review posted live 22 March 2021 (rg) Original submission • Rebecca Ganetzky, MD ( • Elizabeth M McCormick, MS, LGCC ( • Marni J Falk, MD ( • 17 June 2021 (sw) Review posted live • 22 March 2021 (rg) Original submission ## Author Notes All of the authors work together in the Rebecca Ganetzky, MD ( Elizabeth M McCormick, MS, LGCC ( Marni J Falk, MD ( • Rebecca Ganetzky, MD ( • Elizabeth M McCormick, MS, LGCC ( • Marni J Falk, MD ( ## Acknowledgments This work was funded in part by the Mitochondrial Medicine Frontier Program at Children's Hospital of Philadelphia and the National Institutes of Health (R35-GM134863, U24-HD093483, K08-DK113250). The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsors or the National Institutes of Health. ## Revision History 17 June 2021 (sw) Review posted live 22 March 2021 (rg) Original submission • 17 June 2021 (sw) Review posted live • 22 March 2021 (rg) Original submission ## References ## Literature Cited	[]	17/6/2021			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pds	pds	[ "AASADH Deficiency", "ALDH7A1 Deficiency", "Alpha Aminoadipic Semialdehyde (α-AASA) Dehydrogenase Deficiency", "Antiquitin (ATQ) Deficiency", "PDE-ALDH7A1", "AASADH Deficiency", "ALDH7A1 Deficiency", "Alpha Amino Adipic Semialdehyde (a-AASA) Dehydrogenase Deficiency", "Antiquitin (ATQ) Deficiency", "PDE-ALDH7A1", "Alpha-aminoadipic semialdehyde dehydrogenase", "ALDH7A1", "Pyridoxine-Dependent Epilepsy - ALDH7A1" ]	Pyridoxine-Dependent Epilepsy –	Sidney M Gospe	Summary Pyridoxine-dependent epilepsy – In classic PDE- In atypical PDE- The diagnosis of PDE- PDE-	## Diagnosis Pyridoxine-dependent epilepsy – Seizures in any child younger than age one year without an apparent brain malformation or acquired brain injury as the cause of the epilepsy Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history In neonates, a phenotype suggestive of hypoxic ischemic encephalopathy and with difficult-to-control seizures The occurrence of long-lasting focal or unilateral seizures, resistant to anti-seizure medications, often with partial preservation of consciousness In infants and children, seizures that are partially responsive to anti-seizure medications, in particular if associated with developmental delay and intellectual disability Signs of encephalopathy including irritability, restlessness, abnormal crying, and vomiting preceding and/or following the actual seizures A history of transient or unclear response of seizures to pyridoxine In infants and children, a history of seizures responsive to folinic acid In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. Elevated plasma and urinary levels of Note that α-AASA is a nonspecific biomarker, as it can also be elevated in individuals with Elevated concentrations of Note: Pipecolic acid concentrations may normalize after many years of therapy [ Analysis of cerebrospinal fluid Note: Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. The diagnosis of PDE- Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: Previously when deletion/duplication analysis was not widely available, a diagnosis of PDE- Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pyridoxine-Dependent Epilepsy – See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Deep intronic variants may be missed by sequence analysis that includes exons and flanking regions only. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Seizures in any child younger than age one year without an apparent brain malformation or acquired brain injury as the cause of the epilepsy • Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history • In neonates, a phenotype suggestive of hypoxic ischemic encephalopathy and with difficult-to-control seizures • The occurrence of long-lasting focal or unilateral seizures, resistant to anti-seizure medications, often with partial preservation of consciousness • In infants and children, seizures that are partially responsive to anti-seizure medications, in particular if associated with developmental delay and intellectual disability • Signs of encephalopathy including irritability, restlessness, abnormal crying, and vomiting preceding and/or following the actual seizures • A history of transient or unclear response of seizures to pyridoxine • In infants and children, a history of seizures responsive to folinic acid • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. • Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. • Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. • Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. • Elevated plasma and urinary levels of • Note that α-AASA is a nonspecific biomarker, as it can also be elevated in individuals with • Elevated concentrations of • Note: Pipecolic acid concentrations may normalize after many years of therapy [ • Analysis of cerebrospinal fluid • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Pyridoxine-dependent epilepsy – Seizures in any child younger than age one year without an apparent brain malformation or acquired brain injury as the cause of the epilepsy Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history In neonates, a phenotype suggestive of hypoxic ischemic encephalopathy and with difficult-to-control seizures The occurrence of long-lasting focal or unilateral seizures, resistant to anti-seizure medications, often with partial preservation of consciousness In infants and children, seizures that are partially responsive to anti-seizure medications, in particular if associated with developmental delay and intellectual disability Signs of encephalopathy including irritability, restlessness, abnormal crying, and vomiting preceding and/or following the actual seizures A history of transient or unclear response of seizures to pyridoxine In infants and children, a history of seizures responsive to folinic acid In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. Elevated plasma and urinary levels of Note that α-AASA is a nonspecific biomarker, as it can also be elevated in individuals with Elevated concentrations of Note: Pipecolic acid concentrations may normalize after many years of therapy [ Analysis of cerebrospinal fluid Note: Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. • Seizures in any child younger than age one year without an apparent brain malformation or acquired brain injury as the cause of the epilepsy • Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history • In neonates, a phenotype suggestive of hypoxic ischemic encephalopathy and with difficult-to-control seizures • The occurrence of long-lasting focal or unilateral seizures, resistant to anti-seizure medications, often with partial preservation of consciousness • In infants and children, seizures that are partially responsive to anti-seizure medications, in particular if associated with developmental delay and intellectual disability • Signs of encephalopathy including irritability, restlessness, abnormal crying, and vomiting preceding and/or following the actual seizures • A history of transient or unclear response of seizures to pyridoxine • In infants and children, a history of seizures responsive to folinic acid • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. • Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. • Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes. • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours. • Note: In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows the administration of 100 mg of pyridoxine, making close systemic monitoring essential. • Elevated plasma and urinary levels of • Note that α-AASA is a nonspecific biomarker, as it can also be elevated in individuals with • Elevated concentrations of • Note: Pipecolic acid concentrations may normalize after many years of therapy [ • Analysis of cerebrospinal fluid ## Establishing the Diagnosis The diagnosis of PDE- Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: Previously when deletion/duplication analysis was not widely available, a diagnosis of PDE- Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pyridoxine-Dependent Epilepsy – See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from Deep intronic variants may be missed by sequence analysis that includes exons and flanking regions only. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The one clinical feature characteristic of all individuals with pyridoxine-dependent epilepsy – Multiple types of clinical seizures have been reported in untreated infants and children. While dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial, generalized, and atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Clinical seizures may be associated with facial grimacing and abnormal eye movements [ Untreated affected neonates frequently have periods of encephalopathy (irritability, crying, fluctuating tone, poor feeding) that precede the onset of clinical seizures. Low Apgar scores, abnormal umbilical cord blood gases, and other abnormalities of blood chemistries may also be observed. For this reason, it is not uncommon for these newborns to be initially diagnosed with hypoxic-ischemic encephalopathy [ Similar periods of encephalopathy may be seen in older infants, particularly prior to recurrence of clinical seizures that occur in children treated with pyridoxine whose vitamin B Individuals in whom seizures are incompletely controlled with pyridoxine require concurrent treatment with one or more ASMs and have significant intellectual disability [ Some affected individuals with normal intellectual function have been reported [ The few formal psychometric assessments that have been performed have had inconsistent findings. Two early studies indicated that verbal skills were more impaired than nonverbal skills [ Late-onset seizures and other atypical features of PDE- Late-onset seizures (i.e., beginning after age 2 months), sometimes presenting after age one year and as late as adolescence Seizures that initially respond to ASM but then become intractable Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [ Universal thinning of the corpus callosum (greatest in the isthmus) [ Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [ No genotype-phenotype correlations have been identified. The common c.1279G>C; p.(Glu427Gln) pathogenic variant in exon 14 accounts for approximately 33% of pathogenic variants [ Pathogenic missense variants that result in residual enzyme activity may be associated with a more favorable developmental phenotype [ First described by As of 2019, 185 individuals with PDE- • Late-onset seizures (i.e., beginning after age 2 months), sometimes presenting after age one year and as late as adolescence • Seizures that initially respond to ASM but then become intractable • Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later • Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation • In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [ • Universal thinning of the corpus callosum (greatest in the isthmus) [ • Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [ ## Clinical Description The one clinical feature characteristic of all individuals with pyridoxine-dependent epilepsy – Multiple types of clinical seizures have been reported in untreated infants and children. While dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial, generalized, and atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Clinical seizures may be associated with facial grimacing and abnormal eye movements [ Untreated affected neonates frequently have periods of encephalopathy (irritability, crying, fluctuating tone, poor feeding) that precede the onset of clinical seizures. Low Apgar scores, abnormal umbilical cord blood gases, and other abnormalities of blood chemistries may also be observed. For this reason, it is not uncommon for these newborns to be initially diagnosed with hypoxic-ischemic encephalopathy [ Similar periods of encephalopathy may be seen in older infants, particularly prior to recurrence of clinical seizures that occur in children treated with pyridoxine whose vitamin B Individuals in whom seizures are incompletely controlled with pyridoxine require concurrent treatment with one or more ASMs and have significant intellectual disability [ Some affected individuals with normal intellectual function have been reported [ The few formal psychometric assessments that have been performed have had inconsistent findings. Two early studies indicated that verbal skills were more impaired than nonverbal skills [ Late-onset seizures and other atypical features of PDE- Late-onset seizures (i.e., beginning after age 2 months), sometimes presenting after age one year and as late as adolescence Seizures that initially respond to ASM but then become intractable Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [ Universal thinning of the corpus callosum (greatest in the isthmus) [ Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [ • Late-onset seizures (i.e., beginning after age 2 months), sometimes presenting after age one year and as late as adolescence • Seizures that initially respond to ASM but then become intractable • Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later • Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation • In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [ • Universal thinning of the corpus callosum (greatest in the isthmus) [ • Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [ ## Classic PDE- Multiple types of clinical seizures have been reported in untreated infants and children. While dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial, generalized, and atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Clinical seizures may be associated with facial grimacing and abnormal eye movements [ Untreated affected neonates frequently have periods of encephalopathy (irritability, crying, fluctuating tone, poor feeding) that precede the onset of clinical seizures. Low Apgar scores, abnormal umbilical cord blood gases, and other abnormalities of blood chemistries may also be observed. For this reason, it is not uncommon for these newborns to be initially diagnosed with hypoxic-ischemic encephalopathy [ Similar periods of encephalopathy may be seen in older infants, particularly prior to recurrence of clinical seizures that occur in children treated with pyridoxine whose vitamin B Individuals in whom seizures are incompletely controlled with pyridoxine require concurrent treatment with one or more ASMs and have significant intellectual disability [ Some affected individuals with normal intellectual function have been reported [ The few formal psychometric assessments that have been performed have had inconsistent findings. Two early studies indicated that verbal skills were more impaired than nonverbal skills [ ## Atypical PDE- Late-onset seizures and other atypical features of PDE- Late-onset seizures (i.e., beginning after age 2 months), sometimes presenting after age one year and as late as adolescence Seizures that initially respond to ASM but then become intractable Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [ • Late-onset seizures (i.e., beginning after age 2 months), sometimes presenting after age one year and as late as adolescence • Seizures that initially respond to ASM but then become intractable • Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later • Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation • In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [ ## Classic PDE- Universal thinning of the corpus callosum (greatest in the isthmus) [ Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [ • Universal thinning of the corpus callosum (greatest in the isthmus) [ • Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. The common c.1279G>C; p.(Glu427Gln) pathogenic variant in exon 14 accounts for approximately 33% of pathogenic variants [ Pathogenic missense variants that result in residual enzyme activity may be associated with a more favorable developmental phenotype [ ## Nomenclature ## Prevalence First described by As of 2019, 185 individuals with PDE- ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Pyridoxine-dependent epilepsy – Selected Disorders of Interest in the Differential Diagnosis of Pyridoxine-Dependent Epilepsy – α-AASA = alpha-aminoadipic semialdehyde; ALP = alkaline phosphatase; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ERT = enzyme replacement therapy; ID = intellectual disability; P5C = pyrroline-5-carboxylate; PLP = pyridoxal 5'-phosphate; PN = pyridoxine; sz = seizure Epilepsies that respond to treatment with vitamin B Autosomal recessive mode of inheritance Epilepsies that may respond to treatment with vitamin B Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner. Autosomal dominant mode of inheritance X-linked mode of inheritance Note: In the Far East, PLP has been used as an anticonvulsant when anti-seizure medications have failed, and to control seizures in children with infantile spasms and generalized and focal epilepsy in cohorts that had not undergone molecular genetic testing [ ## Other Considerations in the Differential Diagnosis of PDE- ## Management Clinical practice guidelines for pyridoxine-dependent epilepsy – To establish the extent of disease and needs in an individual diagnosed with PDE- Neurologic examination to evaluate cranial nerve function, muscle strength, tone (for hypotonia or rigidity), and symmetry, and to describe seizure semiology EEG including sleep and wake cycles As congenital brain developmental abnormalities may occur in PDE- Developmental assessment including motor, adaptive, cognitive, and speech-language evaluation Evaluation for early intervention programs / special education Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PDE- There is no cure for PDE- Newborns: 100 mg/day of pyridoxine (vitamin B Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) Because affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness (such as gastroenteritis or a febrile respiratory infection), the daily dose of pyridoxine may be doubled for several days until the acute illness resolves. Once seizures come under control with the addition of daily pyridoxine monotherapy in pharmacologic doses, all anti-seizure medication (ASM) can be withdrawn in the majority of individuals. The combination of pyridoxine and lysine-reduction therapies improves the developmental profile of individuals with PDE- The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended: Regular assessment by treating neurologist for: Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ Assessment for developmental progress and educational needs at each visit If lysine reduction therapies are used, regular follow up by a biochemical geneticist and/or medical dietician Avoid overuse of pyridoxine (see Targeted Therapies, Prophylactic treatment with pyridoxine until molecular genetic testing clarifies whether the newborn is affected Note: At least one newborn at risk for PDE- Clinical and EEG monitoring with initiation of treatment with pyridoxine at the first sign of seizures or encephalopathy Note: It would be unlikely for the proband's older sibs who have not experienced seizures to be pyridoxine dependent; however, testing to determine the genetic status of asymptomatic sibs should be considered, as late-onset seizures (developing in adolescence) have been reported. If an older sib has neurodevelopmental disabilities, biomarker screening for alpha-aminoadipic semialdehyde in urine or plasma and/or molecular genetic testing should be considered. See As recurrence risk for couples who have a child with PDE- Prenatal testing for the family-specific Search • Neurologic examination to evaluate cranial nerve function, muscle strength, tone (for hypotonia or rigidity), and symmetry, and to describe seizure semiology • EEG including sleep and wake cycles • As congenital brain developmental abnormalities may occur in PDE- • Developmental assessment including motor, adaptive, cognitive, and speech-language evaluation • Evaluation for early intervention programs / special education • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PDE- • Newborns: 100 mg/day of pyridoxine (vitamin B • Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) • Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Regular assessment by treating neurologist for: • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM • Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM • Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ • Assessment for developmental progress and educational needs at each visit • If lysine reduction therapies are used, regular follow up by a biochemical geneticist and/or medical dietician • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM • Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ • Prophylactic treatment with pyridoxine until molecular genetic testing clarifies whether the newborn is affected • Note: At least one newborn at risk for PDE- • Clinical and EEG monitoring with initiation of treatment with pyridoxine at the first sign of seizures or encephalopathy ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PDE- Neurologic examination to evaluate cranial nerve function, muscle strength, tone (for hypotonia or rigidity), and symmetry, and to describe seizure semiology EEG including sleep and wake cycles As congenital brain developmental abnormalities may occur in PDE- Developmental assessment including motor, adaptive, cognitive, and speech-language evaluation Evaluation for early intervention programs / special education Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PDE- • Neurologic examination to evaluate cranial nerve function, muscle strength, tone (for hypotonia or rigidity), and symmetry, and to describe seizure semiology • EEG including sleep and wake cycles • As congenital brain developmental abnormalities may occur in PDE- • Developmental assessment including motor, adaptive, cognitive, and speech-language evaluation • Evaluation for early intervention programs / special education • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PDE- ## Treatment of Manifestations There is no cure for PDE- Newborns: 100 mg/day of pyridoxine (vitamin B Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) Because affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness (such as gastroenteritis or a febrile respiratory infection), the daily dose of pyridoxine may be doubled for several days until the acute illness resolves. Once seizures come under control with the addition of daily pyridoxine monotherapy in pharmacologic doses, all anti-seizure medication (ASM) can be withdrawn in the majority of individuals. The combination of pyridoxine and lysine-reduction therapies improves the developmental profile of individuals with PDE- The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Newborns: 100 mg/day of pyridoxine (vitamin B • Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) • Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Targeted Therapies There is no cure for PDE- Newborns: 100 mg/day of pyridoxine (vitamin B Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) Because affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness (such as gastroenteritis or a febrile respiratory infection), the daily dose of pyridoxine may be doubled for several days until the acute illness resolves. Once seizures come under control with the addition of daily pyridoxine monotherapy in pharmacologic doses, all anti-seizure medication (ASM) can be withdrawn in the majority of individuals. The combination of pyridoxine and lysine-reduction therapies improves the developmental profile of individuals with PDE- • Newborns: 100 mg/day of pyridoxine (vitamin B • Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) • Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) ## There is no cure for PDE- Newborns: 100 mg/day of pyridoxine (vitamin B Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) Because affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness (such as gastroenteritis or a febrile respiratory infection), the daily dose of pyridoxine may be doubled for several days until the acute illness resolves. Once seizures come under control with the addition of daily pyridoxine monotherapy in pharmacologic doses, all anti-seizure medication (ASM) can be withdrawn in the majority of individuals. • Newborns: 100 mg/day of pyridoxine (vitamin B • Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day) • Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day) ## The combination of pyridoxine and lysine-reduction therapies improves the developmental profile of individuals with PDE- ## Supportive Care The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## ## Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended: Regular assessment by treating neurologist for: Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ Assessment for developmental progress and educational needs at each visit If lysine reduction therapies are used, regular follow up by a biochemical geneticist and/or medical dietician • Regular assessment by treating neurologist for: • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM • Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM • Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ • Assessment for developmental progress and educational needs at each visit • If lysine reduction therapies are used, regular follow up by a biochemical geneticist and/or medical dietician • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM • Development of clinical signs of a sensory neuropathy including regular assessments of joint-position sense, ankle jerks, gait, and station [ ## Agents/Circumstances to Avoid Avoid overuse of pyridoxine (see Targeted Therapies, ## Evaluation of Relatives at Risk Prophylactic treatment with pyridoxine until molecular genetic testing clarifies whether the newborn is affected Note: At least one newborn at risk for PDE- Clinical and EEG monitoring with initiation of treatment with pyridoxine at the first sign of seizures or encephalopathy Note: It would be unlikely for the proband's older sibs who have not experienced seizures to be pyridoxine dependent; however, testing to determine the genetic status of asymptomatic sibs should be considered, as late-onset seizures (developing in adolescence) have been reported. If an older sib has neurodevelopmental disabilities, biomarker screening for alpha-aminoadipic semialdehyde in urine or plasma and/or molecular genetic testing should be considered. See • Prophylactic treatment with pyridoxine until molecular genetic testing clarifies whether the newborn is affected • Note: At least one newborn at risk for PDE- • Clinical and EEG monitoring with initiation of treatment with pyridoxine at the first sign of seizures or encephalopathy ## Pregnancy Management As recurrence risk for couples who have a child with PDE- Prenatal testing for the family-specific ## Therapies Under Investigation Search ## Genetic Counseling Pyridoxine-dependent epilepsy – The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Note: Once a molecular diagnosis has been established in the proband, testing to determine the genetic status of asymptomatic sibs of the proband should be considered, as late-onset seizures developing during adolescence have been reported. For those who inherited both Unless an affected individual's reproductive partner also has PDE- Note: Adults diagnosed with PDE- Carrier testing for at-risk relatives requires prior identification of the See Management, As the recurrence risk for couples who have a child with PDE- The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Note: Once a molecular diagnosis has been established in the proband, testing to determine the genetic status of asymptomatic sibs of the proband should be considered, as late-onset seizures developing during adolescence have been reported. For those who inherited both • Unless an affected individual's reproductive partner also has PDE- • Note: Adults diagnosed with PDE- • As the recurrence risk for couples who have a child with PDE- • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Pyridoxine-dependent epilepsy – ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Note: Once a molecular diagnosis has been established in the proband, testing to determine the genetic status of asymptomatic sibs of the proband should be considered, as late-onset seizures developing during adolescence have been reported. For those who inherited both Unless an affected individual's reproductive partner also has PDE- Note: Adults diagnosed with PDE- • The parents of an affected child are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Note: Once a molecular diagnosis has been established in the proband, testing to determine the genetic status of asymptomatic sibs of the proband should be considered, as late-onset seizures developing during adolescence have been reported. For those who inherited both • Unless an affected individual's reproductive partner also has PDE- • Note: Adults diagnosed with PDE- ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, As the recurrence risk for couples who have a child with PDE- The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • As the recurrence risk for couples who have a child with PDE- • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada Canada PDE Consortium • • • • Canada • • • Canada • • • • • PDE Consortium • ## Molecular Genetics Pyridoxine-Dependent Epilepsy - ALDH7A1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pyridoxine-Dependent Epilepsy - ALDH7A1 ( Additional novel metabolites, 6-oxo-pipecolate (6-oxo-PIP) and two diastereomers of 2-oxopropylpiperidine-2-carobylic acid (2-OPP), have been detected [ Antiquitin localizes to radial glia, astrocytes, and ependymal cells but not to neurons. Deficiency of antiquitin in pyridoxine-dependent epilepsy – Notable Variants listed in the table have been provided by the author. Results in introduction of pseudoexon between exons 7 & 8 ## Molecular Pathogenesis Additional novel metabolites, 6-oxo-pipecolate (6-oxo-PIP) and two diastereomers of 2-oxopropylpiperidine-2-carobylic acid (2-OPP), have been detected [ Antiquitin localizes to radial glia, astrocytes, and ependymal cells but not to neurons. Deficiency of antiquitin in pyridoxine-dependent epilepsy – Notable Variants listed in the table have been provided by the author. Results in introduction of pseudoexon between exons 7 & 8 ## Chapter Notes For diagnosed patients, operated by the The author wishes to acknowledge research support from the Division of Neurology, Seattle Children's Hospital, Seattle and the Department of Neurology, University of Washington, Seattle, together with research collaborations with Drs Seth Friedman, Curtis Coughlin, Laura Tseng, and Clara van Karnebeek. 22 September 2022 (bp) Comprehensive update posted live 29 July 2021 (bp) Comprehensive update posted live 13 April 2017 (ma) Comprehensive update posted live 19 June 2014 (me) Comprehensive update posted live 7 June 2012 (sg) Revision: 26 April 2012 (sg) Revision: additions to molecular genetic testing table ( 1 March 2012 (me) Comprehensive update posted live 10 November 2009 (me) Comprehensive update posted live 24 July 2007 (cd) Revision: clinical testing available: analyte and sequence analysis; prenatal diagnosis 9 June 2006 (sg) Revision: mutations in 8 March 2006 (me) Comprehensive update posted live 18 December 2003 (me) Comprehensive update posted live 7 December 2001 (me) Review posted live 17 September 2001 (sg) Original submission • 22 September 2022 (bp) Comprehensive update posted live • 29 July 2021 (bp) Comprehensive update posted live • 13 April 2017 (ma) Comprehensive update posted live • 19 June 2014 (me) Comprehensive update posted live • 7 June 2012 (sg) Revision: • 26 April 2012 (sg) Revision: additions to molecular genetic testing table ( • 1 March 2012 (me) Comprehensive update posted live • 10 November 2009 (me) Comprehensive update posted live • 24 July 2007 (cd) Revision: clinical testing available: analyte and sequence analysis; prenatal diagnosis • 9 June 2006 (sg) Revision: mutations in • 8 March 2006 (me) Comprehensive update posted live • 18 December 2003 (me) Comprehensive update posted live • 7 December 2001 (me) Review posted live • 17 September 2001 (sg) Original submission ## Author Notes For diagnosed patients, operated by the ## Acknowledgments The author wishes to acknowledge research support from the Division of Neurology, Seattle Children's Hospital, Seattle and the Department of Neurology, University of Washington, Seattle, together with research collaborations with Drs Seth Friedman, Curtis Coughlin, Laura Tseng, and Clara van Karnebeek. ## Revision History 22 September 2022 (bp) Comprehensive update posted live 29 July 2021 (bp) Comprehensive update posted live 13 April 2017 (ma) Comprehensive update posted live 19 June 2014 (me) Comprehensive update posted live 7 June 2012 (sg) Revision: 26 April 2012 (sg) Revision: additions to molecular genetic testing table ( 1 March 2012 (me) Comprehensive update posted live 10 November 2009 (me) Comprehensive update posted live 24 July 2007 (cd) Revision: clinical testing available: analyte and sequence analysis; prenatal diagnosis 9 June 2006 (sg) Revision: mutations in 8 March 2006 (me) Comprehensive update posted live 18 December 2003 (me) Comprehensive update posted live 7 December 2001 (me) Review posted live 17 September 2001 (sg) Original submission • 22 September 2022 (bp) Comprehensive update posted live • 29 July 2021 (bp) Comprehensive update posted live • 13 April 2017 (ma) Comprehensive update posted live • 19 June 2014 (me) Comprehensive update posted live • 7 June 2012 (sg) Revision: • 26 April 2012 (sg) Revision: additions to molecular genetic testing table ( • 1 March 2012 (me) Comprehensive update posted live • 10 November 2009 (me) Comprehensive update posted live • 24 July 2007 (cd) Revision: clinical testing available: analyte and sequence analysis; prenatal diagnosis • 9 June 2006 (sg) Revision: mutations in • 8 March 2006 (me) Comprehensive update posted live • 18 December 2003 (me) Comprehensive update posted live • 7 December 2001 (me) Review posted live • 17 September 2001 (sg) Original submission ## Key Sections in this ## References ## Literature Cited Midsagittal magnetic resonance image of the brain of an adult male with PDE- Outline of the metabolism of L-lysine via the saccharopine and pipecolic acid pathways and biochemical pathophysiology of PDE- The two pathways converge where L-Δ Reprinted from	[]	7/12/2001	22/9/2022	7/6/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
peaf	peaf	[ "ADEAF", "Autosomal Dominant Lateral Temporal Lobe Epilepsy", "Autosomal Dominant Partial Epilepsy with Auditory Features", "ADEAF", "Autosomal Dominant Lateral Temporal Lobe Epilepsy", "Autosomal Dominant Partial Epilepsy with Auditory Features", "[F-actin]-monooxygenase MICAL1", "Leucine-rich glioma-inactivated protein 1", "Reelin", "LGI1", "MICAL1", "RELN", "Autosomal Dominant Epilepsy with Auditory Features" ]	Autosomal Dominant Epilepsy with Auditory Features	Roberto Michelucci, Elena Pasini, Emanuela Dazzo	Summary Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Age at onset is usually in adolescence or early adulthood (age 10-30 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy. The clinical diagnosis of ADEAF can be established in a proband with characteristic clinical features, normal brain imaging by MRI, and family history consistent with autosomal dominant inheritance. The molecular diagnosis is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in By definition, ADEAF is inherited in an autosomal dominant manner. Most individuals diagnosed with ADEAF have an affected parent; the proportion of individuals with ADEAF caused by a	## Diagnosis Consensus clinical diagnostic criteria for autosomal dominant epilepsy with auditory features (ADEAF) have been published by the International League Against Epilepsy (ILAE) [ ADEAF An aura immediately preceding a bilateral tonic-clonic seizure; A component of focal aware or focal impaired-awareness seizures; The only ictal symptom. Early development and neurologic examination are typically normal. The Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Consensus clinical diagnostic criteria for ADEAF have been published by the ILAE [ Focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia Normal brain imaging by MRI Generalized-onset seizures or other focal-onset seizures Moderate or severe intellectual disability Generalized epileptiform discharges Focal abnormalities on neurologic examination Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other epilepsy disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Epilepsy with Auditory Features Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several partial and total gene deletions involving A locus on 19q13.11-q13.31 likely to contain a gene associated with ADEAF was identified in a large Brazilian family [ • An aura immediately preceding a bilateral tonic-clonic seizure; • A component of focal aware or focal impaired-awareness seizures; • The only ictal symptom. • An aura immediately preceding a bilateral tonic-clonic seizure; • A component of focal aware or focal impaired-awareness seizures; • The only ictal symptom. • An aura immediately preceding a bilateral tonic-clonic seizure; • A component of focal aware or focal impaired-awareness seizures; • The only ictal symptom. • Focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia • Normal brain imaging by MRI • Generalized-onset seizures or other focal-onset seizures • Moderate or severe intellectual disability • Generalized epileptiform discharges • Focal abnormalities on neurologic examination ## Suggestive Findings ADEAF An aura immediately preceding a bilateral tonic-clonic seizure; A component of focal aware or focal impaired-awareness seizures; The only ictal symptom. Early development and neurologic examination are typically normal. • An aura immediately preceding a bilateral tonic-clonic seizure; • A component of focal aware or focal impaired-awareness seizures; • The only ictal symptom. • An aura immediately preceding a bilateral tonic-clonic seizure; • A component of focal aware or focal impaired-awareness seizures; • The only ictal symptom. • An aura immediately preceding a bilateral tonic-clonic seizure; • A component of focal aware or focal impaired-awareness seizures; • The only ictal symptom. ## Establishing the Diagnosis The Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Consensus clinical diagnostic criteria for ADEAF have been published by the ILAE [ Focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia Normal brain imaging by MRI Generalized-onset seizures or other focal-onset seizures Moderate or severe intellectual disability Generalized epileptiform discharges Focal abnormalities on neurologic examination Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other epilepsy disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Epilepsy with Auditory Features Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several partial and total gene deletions involving A locus on 19q13.11-q13.31 likely to contain a gene associated with ADEAF was identified in a large Brazilian family [ • Focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia • Normal brain imaging by MRI • Generalized-onset seizures or other focal-onset seizures • Moderate or severe intellectual disability • Generalized epileptiform discharges • Focal abnormalities on neurologic examination ## Clinical Diagnosis Consensus clinical diagnostic criteria for ADEAF have been published by the ILAE [ Focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia Normal brain imaging by MRI Generalized-onset seizures or other focal-onset seizures Moderate or severe intellectual disability Generalized epileptiform discharges Focal abnormalities on neurologic examination • Focal sensory auditory seizures and/or focal cognitive seizures with receptive aphasia • Normal brain imaging by MRI • Generalized-onset seizures or other focal-onset seizures • Moderate or severe intellectual disability • Generalized epileptiform discharges • Focal abnormalities on neurologic examination ## Molecular Diagnosis Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other epilepsy disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Epilepsy with Auditory Features Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several partial and total gene deletions involving A locus on 19q13.11-q13.31 likely to contain a gene associated with ADEAF was identified in a large Brazilian family [ ## For an introduction to multigene panels click ## When the phenotype is indistinguishable from many other epilepsy disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Epilepsy with Auditory Features Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Several partial and total gene deletions involving A locus on 19q13.11-q13.31 likely to contain a gene associated with ADEAF was identified in a large Brazilian family [ ## Clinical Characteristics Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by adolescence/adulthood onset of focal aware seizures with auditory symptoms and/or receptive aphasia in individuals with normal cognitive and neurologic development [ Autosomal Dominant Epilepsy with Auditory Features: Frequency of Select Features Focal to bilateral tonic-clonic seizures accompanied by focal aware or focal impaired-awareness seizures, w/auditory symptoms (~88%-92%) Reflex seizures (in response to sudden noises or a noisy environment) (~8%-13%) ADEAF is characterized by focal epilepsy not caused by a previous illness or injury, with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. Age at onset has ranged from 4 to 50 years in previously reported families [ Febrile seizures do not appear to occur with increased frequency in ADEAF. Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history. Since tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events or to raise a strong suspicion of the ictal nature of the auditory symptom if not associated with other clinical features. Note: Persons with epilepsy may report the inability to comprehend speech at the onset of seizures as a result of nonspecific confusion or alteration in consciousness; thus, care should be taken in obtaining the medical history to distinguish this confusion from specific symptoms of aphasia (i.e., an inability to understand language in the absence of alteration of consciousness). Behavioral problems (e.g., explosive violent behaviors, impulsiveness) and depression (with suicide attempts) have been reported in single pedigrees [ Migraine headaches segregating with occipitotemporal epilepsy resembling ADEAF has been described in one family [ In a series of 34 affected individuals from seven Spanish and Italian families, focal to bilateral tonic-clonic seizures occurred only once or twice per year. The frequency of focal aware or focal impaired-awareness seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses [ In a Norwegian family with prominent ictal aphasia, all individuals were seizure-free (from focal or bilateral tonic-clonic seizures) for two or more years, and focal aware seizures occurred infrequently in most individuals. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed [ In one other family with an In one family with ADEAF caused by a pathogenic In a large retrospective cohort study investigating a heterogeneous group of individuals with epilepsy with auditory features (EAF), prognosis seems to be more variable, ranging from mild to severe intractable epilepsy. However, in this cohort familial cases represented 32% of individuals, with a clear autosomal dominant inheritance pattern of ADEAF identified only in 12% [ Ictal EEGs have been reported in rare cases [ Findings from magnetoencephalography (MEG) with auditory stimuli showed significantly delayed peak auditory evoked field latency in individuals with A left lateral temporal lobe malformation was identified by high-resolution MRI in ten individuals in a Brazilian family with an Diffusion tensor imaging identified a region of increased fractional anisotropy in the left temporal lobe in eight individuals with ADEAF with an Using functional MRI with an auditory description decision task, individuals with epilepsy in families with an An interictal single-photon emission computed tomography scan in one person identified hypoperfusion in the left temporal lobe [ In another study, two individuals with ADEAF in the same family underwent stereoelectroencephalography (SEEG) investigation and subsequent SEEG-guided radiofrequency thermocoagulation and in one case surgical resection. Fast activities recorded with deep electrodes originated from the right superior temporal gyrus with rapid spreading to other network's nodes. Despite a normal cerebral MRI, an FDG-PET scan showed hypometabolism in the superior temporal gyrus. Genetic findings were incomplete [ Auditory symptoms were less frequent with Phenotypic features were similar in published familial cases with Estimates of penetrance in studies of families with ADEAF range from 54% to 85% [ In a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an All these estimates are likely to be inflated by ascertainment bias, as they are based on families selected for analysis because they comprised many affected individuals. The term "epilepsy with auditory features (EAF)" refers to all individuals with a diagnosis of EAF, encompassing individuals with a known family history of EAF ("familial EAF [FEAF]") and individuals who appear to represent simplex cases (i.e., the only family known to be affected with EAF). EAF has been proposed to replace the family history-dependent terms – "autosomal dominant lateral temporal lobe epilepsy (ADLTE)" and "autosomal dominant partial epilepsy with auditory features (ADPEAF)" – used previously to refer to the disorder [ "Autosomal dominant epilepsy with auditory features (ADEAF)" refers to individuals with EAF whose family history is consistent with autosomal dominant inheritance (e.g., affected family members in multiple generations) and/or individuals with EAF known to be caused by a heterozygous pathogenic variant. (Note: An individual with ADEAF may appear to represent a simplex case due to the possibility of reduced penetrance in asymptomatic, heterozygous family members.) The alternative term of ADLTE may be preferred, since some ictal symptoms of this condition (such as aphasia, vertiginous and complex visual auras, high propensity to generalize) indicate a clear localization over the lateral temporal cortex. The prevalence of ADEAF is unknown but likely very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy, and only a fraction of these have clinical features consistent with ADEAF. Further, isolated auditory symptoms, especially when simple, might not be adequately recognized as pertaining to a disease and especially epilepsy. Therefore, a precise estimate of the incidence of EAF is currently not available. Whereas genetic epilepsy syndromes account for a fraction of all epilepsy, findings from one study suggest that among mendelian forms of focal epilepsy, ADEAF may not be rare, as 9/48 (19%) of families with two or more individuals with idiopathic focal epilepsy met criteria for ADEAF (i.e., they comprised ≥2 individuals with ictal auditory symptoms) [ • Focal to bilateral tonic-clonic seizures accompanied by focal aware or focal impaired-awareness seizures, w/auditory symptoms (~88%-92%) • Reflex seizures (in response to sudden noises or a noisy environment) (~8%-13%) • Behavioral problems (e.g., explosive violent behaviors, impulsiveness) and depression (with suicide attempts) have been reported in single pedigrees [ • Migraine headaches segregating with occipitotemporal epilepsy resembling ADEAF has been described in one family [ • In a series of 34 affected individuals from seven Spanish and Italian families, focal to bilateral tonic-clonic seizures occurred only once or twice per year. The frequency of focal aware or focal impaired-awareness seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses [ • In a Norwegian family with prominent ictal aphasia, all individuals were seizure-free (from focal or bilateral tonic-clonic seizures) for two or more years, and focal aware seizures occurred infrequently in most individuals. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed [ • In one other family with an • In one family with ADEAF caused by a pathogenic • In a large retrospective cohort study investigating a heterogeneous group of individuals with epilepsy with auditory features (EAF), prognosis seems to be more variable, ranging from mild to severe intractable epilepsy. However, in this cohort familial cases represented 32% of individuals, with a clear autosomal dominant inheritance pattern of ADEAF identified only in 12% [ ## Clinical Description Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by adolescence/adulthood onset of focal aware seizures with auditory symptoms and/or receptive aphasia in individuals with normal cognitive and neurologic development [ Autosomal Dominant Epilepsy with Auditory Features: Frequency of Select Features Focal to bilateral tonic-clonic seizures accompanied by focal aware or focal impaired-awareness seizures, w/auditory symptoms (~88%-92%) Reflex seizures (in response to sudden noises or a noisy environment) (~8%-13%) ADEAF is characterized by focal epilepsy not caused by a previous illness or injury, with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. Age at onset has ranged from 4 to 50 years in previously reported families [ Febrile seizures do not appear to occur with increased frequency in ADEAF. Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history. Since tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events or to raise a strong suspicion of the ictal nature of the auditory symptom if not associated with other clinical features. Note: Persons with epilepsy may report the inability to comprehend speech at the onset of seizures as a result of nonspecific confusion or alteration in consciousness; thus, care should be taken in obtaining the medical history to distinguish this confusion from specific symptoms of aphasia (i.e., an inability to understand language in the absence of alteration of consciousness). Behavioral problems (e.g., explosive violent behaviors, impulsiveness) and depression (with suicide attempts) have been reported in single pedigrees [ Migraine headaches segregating with occipitotemporal epilepsy resembling ADEAF has been described in one family [ In a series of 34 affected individuals from seven Spanish and Italian families, focal to bilateral tonic-clonic seizures occurred only once or twice per year. The frequency of focal aware or focal impaired-awareness seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses [ In a Norwegian family with prominent ictal aphasia, all individuals were seizure-free (from focal or bilateral tonic-clonic seizures) for two or more years, and focal aware seizures occurred infrequently in most individuals. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed [ In one other family with an In one family with ADEAF caused by a pathogenic In a large retrospective cohort study investigating a heterogeneous group of individuals with epilepsy with auditory features (EAF), prognosis seems to be more variable, ranging from mild to severe intractable epilepsy. However, in this cohort familial cases represented 32% of individuals, with a clear autosomal dominant inheritance pattern of ADEAF identified only in 12% [ Ictal EEGs have been reported in rare cases [ Findings from magnetoencephalography (MEG) with auditory stimuli showed significantly delayed peak auditory evoked field latency in individuals with A left lateral temporal lobe malformation was identified by high-resolution MRI in ten individuals in a Brazilian family with an Diffusion tensor imaging identified a region of increased fractional anisotropy in the left temporal lobe in eight individuals with ADEAF with an Using functional MRI with an auditory description decision task, individuals with epilepsy in families with an An interictal single-photon emission computed tomography scan in one person identified hypoperfusion in the left temporal lobe [ In another study, two individuals with ADEAF in the same family underwent stereoelectroencephalography (SEEG) investigation and subsequent SEEG-guided radiofrequency thermocoagulation and in one case surgical resection. Fast activities recorded with deep electrodes originated from the right superior temporal gyrus with rapid spreading to other network's nodes. Despite a normal cerebral MRI, an FDG-PET scan showed hypometabolism in the superior temporal gyrus. Genetic findings were incomplete [ • Focal to bilateral tonic-clonic seizures accompanied by focal aware or focal impaired-awareness seizures, w/auditory symptoms (~88%-92%) • Reflex seizures (in response to sudden noises or a noisy environment) (~8%-13%) • Behavioral problems (e.g., explosive violent behaviors, impulsiveness) and depression (with suicide attempts) have been reported in single pedigrees [ • Migraine headaches segregating with occipitotemporal epilepsy resembling ADEAF has been described in one family [ • In a series of 34 affected individuals from seven Spanish and Italian families, focal to bilateral tonic-clonic seizures occurred only once or twice per year. The frequency of focal aware or focal impaired-awareness seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses [ • In a Norwegian family with prominent ictal aphasia, all individuals were seizure-free (from focal or bilateral tonic-clonic seizures) for two or more years, and focal aware seizures occurred infrequently in most individuals. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed [ • In one other family with an • In one family with ADEAF caused by a pathogenic • In a large retrospective cohort study investigating a heterogeneous group of individuals with epilepsy with auditory features (EAF), prognosis seems to be more variable, ranging from mild to severe intractable epilepsy. However, in this cohort familial cases represented 32% of individuals, with a clear autosomal dominant inheritance pattern of ADEAF identified only in 12% [ ## Genotype-Phenotype Correlations Auditory symptoms were less frequent with Phenotypic features were similar in published familial cases with ## Penetrance Estimates of penetrance in studies of families with ADEAF range from 54% to 85% [ In a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an All these estimates are likely to be inflated by ascertainment bias, as they are based on families selected for analysis because they comprised many affected individuals. ## Nomenclature The term "epilepsy with auditory features (EAF)" refers to all individuals with a diagnosis of EAF, encompassing individuals with a known family history of EAF ("familial EAF [FEAF]") and individuals who appear to represent simplex cases (i.e., the only family known to be affected with EAF). EAF has been proposed to replace the family history-dependent terms – "autosomal dominant lateral temporal lobe epilepsy (ADLTE)" and "autosomal dominant partial epilepsy with auditory features (ADPEAF)" – used previously to refer to the disorder [ "Autosomal dominant epilepsy with auditory features (ADEAF)" refers to individuals with EAF whose family history is consistent with autosomal dominant inheritance (e.g., affected family members in multiple generations) and/or individuals with EAF known to be caused by a heterozygous pathogenic variant. (Note: An individual with ADEAF may appear to represent a simplex case due to the possibility of reduced penetrance in asymptomatic, heterozygous family members.) The alternative term of ADLTE may be preferred, since some ictal symptoms of this condition (such as aphasia, vertiginous and complex visual auras, high propensity to generalize) indicate a clear localization over the lateral temporal cortex. ## Prevalence The prevalence of ADEAF is unknown but likely very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy, and only a fraction of these have clinical features consistent with ADEAF. Further, isolated auditory symptoms, especially when simple, might not be adequately recognized as pertaining to a disease and especially epilepsy. Therefore, a precise estimate of the incidence of EAF is currently not available. Whereas genetic epilepsy syndromes account for a fraction of all epilepsy, findings from one study suggest that among mendelian forms of focal epilepsy, ADEAF may not be rare, as 9/48 (19%) of families with two or more individuals with idiopathic focal epilepsy met criteria for ADEAF (i.e., they comprised ≥2 individuals with ictal auditory symptoms) [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Biallelic pathogenic variants in ## Differential Diagnosis Selected genes associated with focal epilepsy in the differential diagnosis of autosomal dominant epilepsy with auditory features (ADEAF) are listed in Selected Genes of Interest in the Differential Diagnosis of Autosomal Dominant Epilepsy with Auditory Features 19% (persons w/family history of SHE) 7% (persons w/negative family history) Interictal & ictal scalp EEG features may be normal. Prolonged video EEG recording is best diagnostic test to assess seizure occurrence. Characterized by clusters of nocturnal motor seizures, often stereotyped & brief (5 secs to 5 mins) Clinical neurologic exam normal & intellect usually preserved, but psychiatric comorbidity or cognitive deficits may occur. Manifestations may vary considerably w/in a family. Psychic symptoms (esp déjà vu) most common Autonomic or special sensory components in ~50% Auditory symptoms in <10% Febrile seizure frequency as in general population Benign clinical course, w/long remissions & good response to range of therapies (carbamazepine, phenytoin, or valproate) Epileptogenic zone (frontal, temporal, or occipital) differs among family members. Frontal lobe seizures most common. SHE = sleep-related hypermotor (hyperkinetic) epilepsy Pathogenic variants in • 19% (persons w/family history of SHE) • 7% (persons w/negative family history) • Interictal & ictal scalp EEG features may be normal. • Prolonged video EEG recording is best diagnostic test to assess seizure occurrence. • Characterized by clusters of nocturnal motor seizures, often stereotyped & brief (5 secs to 5 mins) • Clinical neurologic exam normal & intellect usually preserved, but psychiatric comorbidity or cognitive deficits may occur. • Manifestations may vary considerably w/in a family. • Psychic symptoms (esp déjà vu) most common • Autonomic or special sensory components in ~50% • Auditory symptoms in <10% • Febrile seizure frequency as in general population • Benign clinical course, w/long remissions & good response to range of therapies (carbamazepine, phenytoin, or valproate) • Epileptogenic zone (frontal, temporal, or occipital) differs among family members. • Frontal lobe seizures most common. ## Management No clinical practice guidelines for autosomal dominant epilepsy with auditory features (ADEAF) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with autosomal dominant epilepsy with auditory features (ADEAF), the evaluations summarized in Autosomal Dominant Epilepsy with Auditory Features: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education ADEAF = autosomal dominant epilepsy with auditory features; ASM = anti-seizure medication; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves care by specialists in relevant fields (see Autosomal Dominant Epilepsy with Auditory Features: Treatment of Manifestations Most persons are responsive to standard ASMs & in most cases monotherapy is effective for complete seizure control. Education of parents/caregivers ASM = anti-seizure medication Traditionally sodium channel blockers such as carbamazepine have been more frequently used with clear benefit. However, no clinical trials of different anti-seizure medications have been carried out, therefore definite therapeutic guidelines have not been published to date. Total remission might be lower than expected and treatment withdrawal might lead to relapses in some individuals. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Autosomal Dominant Epilepsy with Auditory Features: Recommended Surveillance It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and measures to minimize risk in the event of seizure onset (e.g., avoidance of unattended swimming). If the ADEAF-related pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, interview of relatives at risk may identify sensory symptoms (visual, olfactory, vertiginous, or cephalic) and/or motor, psychic, and autonomic symptoms possibly related to seizures. Note: Approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance. Seizures are treatable in most affected individuals. No interventions have been identified to prevent the development or occurrence of seizures in individuals with an ADEAF-related pathogenic. See In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Most persons are responsive to standard ASMs & in most cases monotherapy is effective for complete seizure control. • Education of parents/caregivers • If the ADEAF-related pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, interview of relatives at risk may identify sensory symptoms (visual, olfactory, vertiginous, or cephalic) and/or motor, psychic, and autonomic symptoms possibly related to seizures. • Approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance. • Seizures are treatable in most affected individuals. • No interventions have been identified to prevent the development or occurrence of seizures in individuals with an ADEAF-related pathogenic. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with autosomal dominant epilepsy with auditory features (ADEAF), the evaluations summarized in Autosomal Dominant Epilepsy with Auditory Features: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education ADEAF = autosomal dominant epilepsy with auditory features; ASM = anti-seizure medication; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves care by specialists in relevant fields (see Autosomal Dominant Epilepsy with Auditory Features: Treatment of Manifestations Most persons are responsive to standard ASMs & in most cases monotherapy is effective for complete seizure control. Education of parents/caregivers ASM = anti-seizure medication Traditionally sodium channel blockers such as carbamazepine have been more frequently used with clear benefit. However, no clinical trials of different anti-seizure medications have been carried out, therefore definite therapeutic guidelines have not been published to date. Total remission might be lower than expected and treatment withdrawal might lead to relapses in some individuals. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Most persons are responsive to standard ASMs & in most cases monotherapy is effective for complete seizure control. • Education of parents/caregivers ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Autosomal Dominant Epilepsy with Auditory Features: Recommended Surveillance ## Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and measures to minimize risk in the event of seizure onset (e.g., avoidance of unattended swimming). If the ADEAF-related pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, interview of relatives at risk may identify sensory symptoms (visual, olfactory, vertiginous, or cephalic) and/or motor, psychic, and autonomic symptoms possibly related to seizures. Note: Approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance. Seizures are treatable in most affected individuals. No interventions have been identified to prevent the development or occurrence of seizures in individuals with an ADEAF-related pathogenic. See • If the ADEAF-related pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, interview of relatives at risk may identify sensory symptoms (visual, olfactory, vertiginous, or cephalic) and/or motor, psychic, and autonomic symptoms possibly related to seizures. • Approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance. • Seizures are treatable in most affected individuals. • No interventions have been identified to prevent the development or occurrence of seizures in individuals with an ADEAF-related pathogenic. ## Pregnancy Management In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See ## Therapies Under Investigation Search ## Genetic Counseling By definition, autosomal dominant epilepsy with auditory features (ADEAF) is inherited in an autosomal dominant manner. Most individuals diagnosed with ADEAF have an affected parent. Some individuals diagnosed with ADEAF may have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a medical history to ascertain a history of seizures and – if a molecular diagnosis has been established in the proband – genetic testing for the pathogenic variant identified in the proband. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. The family history of some individuals diagnosed with ADEAF may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of seizures, late onset of the disease in the affected parent, or reduced penetrance (approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance). Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent has clinical characteristics consistent with ADEAF and/or has the pathogenic variant identified in the proband, the likelihood that each sib will inherit the pathogenic variant is 50%. The chance that a sib who inherits the pathogenic variant will manifest ADEAF ranges from 54% to 85%, depending on the assumed penetrance (see Note: In a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, sibs are presumed to be at increased risk for ADEAF because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. Predictive testing for at-risk relatives is possible if the ADEAF-related pathogenic variant has been identified in an affected family member. Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. See Management, Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the ADEAF-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with ADEAF have an affected parent. • Some individuals diagnosed with ADEAF may have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a medical history to ascertain a history of seizures and – if a molecular diagnosis has been established in the proband – genetic testing for the pathogenic variant identified in the proband. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The family history of some individuals diagnosed with ADEAF may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of seizures, late onset of the disease in the affected parent, or reduced penetrance (approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance). Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent has clinical characteristics consistent with ADEAF and/or has the pathogenic variant identified in the proband, the likelihood that each sib will inherit the pathogenic variant is 50%. The chance that a sib who inherits the pathogenic variant will manifest ADEAF ranges from 54% to 85%, depending on the assumed penetrance (see • Note: In a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, sibs are presumed to be at increased risk for ADEAF because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • Predictive testing for at-risk relatives is possible if the ADEAF-related pathogenic variant has been identified in an affected family member. • Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance By definition, autosomal dominant epilepsy with auditory features (ADEAF) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with ADEAF have an affected parent. Some individuals diagnosed with ADEAF may have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a medical history to ascertain a history of seizures and – if a molecular diagnosis has been established in the proband – genetic testing for the pathogenic variant identified in the proband. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. The family history of some individuals diagnosed with ADEAF may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of seizures, late onset of the disease in the affected parent, or reduced penetrance (approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance). Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent has clinical characteristics consistent with ADEAF and/or has the pathogenic variant identified in the proband, the likelihood that each sib will inherit the pathogenic variant is 50%. The chance that a sib who inherits the pathogenic variant will manifest ADEAF ranges from 54% to 85%, depending on the assumed penetrance (see Note: In a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, sibs are presumed to be at increased risk for ADEAF because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • Most individuals diagnosed with ADEAF have an affected parent. • Some individuals diagnosed with ADEAF may have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a medical history to ascertain a history of seizures and – if a molecular diagnosis has been established in the proband – genetic testing for the pathogenic variant identified in the proband. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The family history of some individuals diagnosed with ADEAF may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of seizures, late onset of the disease in the affected parent, or reduced penetrance (approximately one third of individuals with an ADEAF-related pathogenic variant will remain unaffected due to reduced penetrance). Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicismand will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent has clinical characteristics consistent with ADEAF and/or has the pathogenic variant identified in the proband, the likelihood that each sib will inherit the pathogenic variant is 50%. The chance that a sib who inherits the pathogenic variant will manifest ADEAF ranges from 54% to 85%, depending on the assumed penetrance (see • Note: In a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, sibs are presumed to be at increased risk for ADEAF because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible if the ADEAF-related pathogenic variant has been identified in an affected family member. Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. See Management, Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible if the ADEAF-related pathogenic variant has been identified in an affected family member. • Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the ADEAF-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada Canada • • • • Canada • • • • • Canada • • • ## Molecular Genetics Autosomal Dominant Epilepsy with Auditory Features: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Autosomal Dominant Epilepsy with Auditory Features ( Despite its clinical homogeneity, autosomal dominant epilepsy with auditory features (ADEAF) is genetically heterogeneous. To date, three causative genes have been identified, Most pathogenic variants of Most pathogenic variants reported in ## Molecular Pathogenesis Despite its clinical homogeneity, autosomal dominant epilepsy with auditory features (ADEAF) is genetically heterogeneous. To date, three causative genes have been identified, Most pathogenic variants of Most pathogenic variants reported in ## Chapter Notes Project Coordinator, Epilepsy Family Study of Columbia UniversityColumbia University Tel: 212-305-9188 Email: We are grateful for the research support of the Telethon Foundation, the Genetics Commission of the Italian League Against Epilepsy, and the Fondo di Beneficenza Intesa San Paolo. Emanuela Dazzo, PhD (2024-present)Roberto Michelucci, MD, PhD (2019-present)Carlo Nobile, PhD; CNR Institute of Neuroscience (2019-2024)Ruth Ottman, PhD; Columbia University (2007-2019)Elena Pasini, MD (2024-present) 9 May 2024 (gm) Comprehensive update posted live 10 January 2019 (bp) Comprehensive update posted live 27 August 2015 (me) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 13 July 2010 (me) Comprehensive update posted live 20 April 2007 (me) Review posted live 1 February 2007 (ro) Original submission • 9 May 2024 (gm) Comprehensive update posted live • 10 January 2019 (bp) Comprehensive update posted live • 27 August 2015 (me) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 13 July 2010 (me) Comprehensive update posted live • 20 April 2007 (me) Review posted live • 1 February 2007 (ro) Original submission ## Author Notes Project Coordinator, Epilepsy Family Study of Columbia UniversityColumbia University Tel: 212-305-9188 Email: ## Acknowledgements We are grateful for the research support of the Telethon Foundation, the Genetics Commission of the Italian League Against Epilepsy, and the Fondo di Beneficenza Intesa San Paolo. ## Author History Emanuela Dazzo, PhD (2024-present)Roberto Michelucci, MD, PhD (2019-present)Carlo Nobile, PhD; CNR Institute of Neuroscience (2019-2024)Ruth Ottman, PhD; Columbia University (2007-2019)Elena Pasini, MD (2024-present) ## Revision History 9 May 2024 (gm) Comprehensive update posted live 10 January 2019 (bp) Comprehensive update posted live 27 August 2015 (me) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 13 July 2010 (me) Comprehensive update posted live 20 April 2007 (me) Review posted live 1 February 2007 (ro) Original submission • 9 May 2024 (gm) Comprehensive update posted live • 10 January 2019 (bp) Comprehensive update posted live • 27 August 2015 (me) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 13 July 2010 (me) Comprehensive update posted live • 20 April 2007 (me) Review posted live • 1 February 2007 (ro) Original submission ## References ## Literature Cited	[]	20/4/2007	9/5/2024	26/9/2007	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pendred	pendred	[ "PDS/NSEVA", "PDS/DFNB4", "Nonsyndromic SLC26A4-Related Sensorineural Hearing Loss", "DFNB4", "NSEVA", "DFNB4/NSEVA", "Pendred Syndrome (PDS)", "Pendrin", "SLC26A4", "SLC26A4-Related Sensorineural Hearing Loss" ]		Richard JH Smith, Hela Azaiez, Amanda M Odell	Summary The diagnosis of	Nonsyndromic Pendred syndrome (PDS) NSEVA = nonsyndromic enlargement of the vestibular aqueduct For additional synonyms and outdated names, see • Nonsyndromic • Pendred syndrome (PDS) ## Diagnosis No consensus clinical diagnostic criteria for Onset varies (congenital, prelingual, postlingual). Newborn hearing screening can be normal. Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ Fluctuating or progressive SNHL can occur. An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ Euthyroid goiter is incompletely penetrant [ In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ The diagnosis of Note: The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Multigene panels and exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Intragenic deletions/duplications are rare; two probands, one homozygous for a deletion encompassing exons 13-21 of • • Onset varies (congenital, prelingual, postlingual). • Newborn hearing screening can be normal. • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ • Fluctuating or progressive SNHL can occur. • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ • Onset varies (congenital, prelingual, postlingual). • Newborn hearing screening can be normal. • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ • Fluctuating or progressive SNHL can occur. • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ • * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." • * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ • • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ • * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ • Euthyroid goiter is incompletely penetrant [ • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ • * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ • Euthyroid goiter is incompletely penetrant [ • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ • Onset varies (congenital, prelingual, postlingual). • Newborn hearing screening can be normal. • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ • Fluctuating or progressive SNHL can occur. • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ • * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ • * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ • Euthyroid goiter is incompletely penetrant [ • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Onset varies (congenital, prelingual, postlingual). Newborn hearing screening can be normal. Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ Fluctuating or progressive SNHL can occur. An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ Euthyroid goiter is incompletely penetrant [ In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ • • Onset varies (congenital, prelingual, postlingual). • Newborn hearing screening can be normal. • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ • Fluctuating or progressive SNHL can occur. • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ • Onset varies (congenital, prelingual, postlingual). • Newborn hearing screening can be normal. • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ • Fluctuating or progressive SNHL can occur. • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ • * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." • * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ • • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ • * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ • Euthyroid goiter is incompletely penetrant [ • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ • * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ • Euthyroid goiter is incompletely penetrant [ • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ • Onset varies (congenital, prelingual, postlingual). • Newborn hearing screening can be normal. • Average hearing thresholds are 80 dB (severe hearing loss) by age three years [ • Fluctuating or progressive SNHL can occur. • An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [ • * The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad." • Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting. • Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [ • Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [ • * (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [ • Euthyroid goiter is incompletely penetrant [ • In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [ ## Establishing the Diagnosis The diagnosis of Note: The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Multigene panels and exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Intragenic deletions/duplications are rare; two probands, one homozygous for a deletion encompassing exons 13-21 of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The considerable intrafamilial variability (i.e., variability in clinical presentation of a particular disorder among affected individuals within the same immediate or extended family) in temporal bone anomalies, hearing loss, and thyroid disease makes the distinction between nonsyndromic Hundreds of individuals have been identified with biallelic Although there are reports describing progressive hearing loss in association with head injury, infection, or balance disturbances and tinnitus [ Thyroid enlargement (goiter) occurs gradually and is typically not evident until the second decade, especially if iodine is not routinely included in the diet (in contrast to countries that have salt iodization programs). Thyroid size can be identified by ultrasonography; whereas thyroid function tests are not helpful in diagnosing goiter, they are important in No clinically relevant genotype-phenotype correlations have been identified in individuals with biallelic Nonsyndromic Pendred syndrome is also referred to as "autosomal recessive sensorineural hearing loss, enlarged vestibular aqueduct, and goiter." EVA is also referred to as EVA is the most common radiologic malformation of the inner ear associated with SNHL [ For studies of the ## Clinical Description The considerable intrafamilial variability (i.e., variability in clinical presentation of a particular disorder among affected individuals within the same immediate or extended family) in temporal bone anomalies, hearing loss, and thyroid disease makes the distinction between nonsyndromic Hundreds of individuals have been identified with biallelic Although there are reports describing progressive hearing loss in association with head injury, infection, or balance disturbances and tinnitus [ Thyroid enlargement (goiter) occurs gradually and is typically not evident until the second decade, especially if iodine is not routinely included in the diet (in contrast to countries that have salt iodization programs). Thyroid size can be identified by ultrasonography; whereas thyroid function tests are not helpful in diagnosing goiter, they are important in Although there are reports describing progressive hearing loss in association with head injury, infection, or balance disturbances and tinnitus [ ## Pendred Syndrome (PDS) Thyroid Involvement Thyroid enlargement (goiter) occurs gradually and is typically not evident until the second decade, especially if iodine is not routinely included in the diet (in contrast to countries that have salt iodization programs). Thyroid size can be identified by ultrasonography; whereas thyroid function tests are not helpful in diagnosing goiter, they are important in ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified in individuals with biallelic ## Nomenclature Nonsyndromic Pendred syndrome is also referred to as "autosomal recessive sensorineural hearing loss, enlarged vestibular aqueduct, and goiter." EVA is also referred to as ## Prevalence EVA is the most common radiologic malformation of the inner ear associated with SNHL [ For studies of the ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Although enlarged vestibular aqueduct (EVA) with or without cochlear hypoplasia are seen in virtually all individuals with Genetic Disorders with Temporal Bone Malformations in the Differential Diagnosis of SNHL Malformations of inner ear incl EVA SNHL Malformations of inner ear incl EVA & cochlear hypoplasia Abnormalities of semicircular canals Malformation of outer & middle ear Branchial fistulae & cysts Renal malformations Hearing loss (conductive) in ~40%-50% of persons Occasionally, malformations of inner ear incl dysplasia of vestibule Abnormalities of semicircular canals Malformations of outer & middle ear Facial abnormalities incl maxillary hypoplasia & micrognathia Ocular abnormalities incl eyelid coloboma AD = autosomal dominant; AR = autosomal recessive; EVA = enlarged vestibular aqueduct; MOI = mode of inheritance; SNHL = sensorineural hearing loss • Although enlarged vestibular aqueduct (EVA) with or without cochlear hypoplasia are seen in virtually all individuals with • SNHL • Malformations of inner ear incl EVA • SNHL • Malformations of inner ear incl EVA & cochlear hypoplasia • Abnormalities of semicircular canals • Malformation of outer & middle ear • Branchial fistulae & cysts • Renal malformations • Hearing loss (conductive) in ~40%-50% of persons • Occasionally, malformations of inner ear incl dysplasia of vestibule • Abnormalities of semicircular canals • Malformations of outer & middle ear • Facial abnormalities incl maxillary hypoplasia & micrognathia • Ocular abnormalities incl eyelid coloboma ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Assessment of auditory acuity (auditory brain stem response testing, pure tone audiometry) Assessment of vestibular function during early childhood (should be considered) Thyroid ultrasonography and thyroid function tests (T Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of Assessment of need for family support and resources including community or online See also There is no cure for For general information on management of hearing loss in children and adults, see Genetic Hearing Loss Overview, Hearing aids may be used in persons with mild-to-severe hearing loss. Cochlear implantation (CI), which provides good hearing habilitation in individuals with CI in individuals with To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. The primary focus should be routinely scheduled audiometric follow up that includes assessment of suitability for CI to avoid unnecessary and counterproductive delay if/when the hearing loss progresses and hearing aids are no longer adequate [ Repeat audiometric testing every three to six months until age three years and annually thereafter. Baseline ultrasonography should be performed to assess thyroid size after age ten years and repeated every five to ten years based on findings on palpation of thyroid size. (The odds of developing a goiter are 1.1 for each one-year increase in age. Thus, after age 20 years, the increase in odds of developing goiter is 6.7-fold [ While tests of thyroid function are usually normal in individuals with See Genetic Hearing Loss Overview, There are anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing, leading some providers to recommend avoiding activities like weightlifting and contact sports [ It is appropriate to determine the genetic status of at-risk sibs of a proband with Note: As individuals with nonsyndromic enlarged vestibular aqueduct can have normal hearing at birth only to develop progressive hearing loss during early childhood, a normal newborn hearing screening does not rule out the possibility that an at-risk sib has See Search • Assessment of auditory acuity (auditory brain stem response testing, pure tone audiometry) • Assessment of vestibular function during early childhood (should be considered) • Thyroid ultrasonography and thyroid function tests (T • Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of • Assessment of need for family support and resources including community or online • Hearing aids may be used in persons with mild-to-severe hearing loss. • Cochlear implantation (CI), which provides good hearing habilitation in individuals with • CI in individuals with • The primary focus should be routinely scheduled audiometric follow up that includes assessment of suitability for CI to avoid unnecessary and counterproductive delay if/when the hearing loss progresses and hearing aids are no longer adequate [ • Repeat audiometric testing every three to six months until age three years and annually thereafter. • Baseline ultrasonography should be performed to assess thyroid size after age ten years and repeated every five to ten years based on findings on palpation of thyroid size. (The odds of developing a goiter are 1.1 for each one-year increase in age. Thus, after age 20 years, the increase in odds of developing goiter is 6.7-fold [ • While tests of thyroid function are usually normal in individuals with ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Assessment of auditory acuity (auditory brain stem response testing, pure tone audiometry) Assessment of vestibular function during early childhood (should be considered) Thyroid ultrasonography and thyroid function tests (T Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of Assessment of need for family support and resources including community or online See also • Assessment of auditory acuity (auditory brain stem response testing, pure tone audiometry) • Assessment of vestibular function during early childhood (should be considered) • Thyroid ultrasonography and thyroid function tests (T • Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of • Assessment of need for family support and resources including community or online ## Treatment of Manifestations There is no cure for For general information on management of hearing loss in children and adults, see Genetic Hearing Loss Overview, Hearing aids may be used in persons with mild-to-severe hearing loss. Cochlear implantation (CI), which provides good hearing habilitation in individuals with CI in individuals with • Hearing aids may be used in persons with mild-to-severe hearing loss. • Cochlear implantation (CI), which provides good hearing habilitation in individuals with • CI in individuals with ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. The primary focus should be routinely scheduled audiometric follow up that includes assessment of suitability for CI to avoid unnecessary and counterproductive delay if/when the hearing loss progresses and hearing aids are no longer adequate [ Repeat audiometric testing every three to six months until age three years and annually thereafter. Baseline ultrasonography should be performed to assess thyroid size after age ten years and repeated every five to ten years based on findings on palpation of thyroid size. (The odds of developing a goiter are 1.1 for each one-year increase in age. Thus, after age 20 years, the increase in odds of developing goiter is 6.7-fold [ While tests of thyroid function are usually normal in individuals with • The primary focus should be routinely scheduled audiometric follow up that includes assessment of suitability for CI to avoid unnecessary and counterproductive delay if/when the hearing loss progresses and hearing aids are no longer adequate [ • Repeat audiometric testing every three to six months until age three years and annually thereafter. • Baseline ultrasonography should be performed to assess thyroid size after age ten years and repeated every five to ten years based on findings on palpation of thyroid size. (The odds of developing a goiter are 1.1 for each one-year increase in age. Thus, after age 20 years, the increase in odds of developing goiter is 6.7-fold [ • While tests of thyroid function are usually normal in individuals with ## Agents/Circumstances to Avoid See Genetic Hearing Loss Overview, There are anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing, leading some providers to recommend avoiding activities like weightlifting and contact sports [ ## Evaluation of Sibs at Risk It is appropriate to determine the genetic status of at-risk sibs of a proband with Note: As individuals with nonsyndromic enlarged vestibular aqueduct can have normal hearing at birth only to develop progressive hearing loss during early childhood, a normal newborn hearing screening does not rule out the possibility that an at-risk sib has See ## Therapies Under Investigation Search ## Genetic Counseling Note: Although digenic inheritance of hearing loss with enlarged vestibular aqueduct has been described involving pathogenic variants in The parents of a child with biallelic Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If an A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes do not develop If both parents are known to be heterozygous for an Considerable intrafamilial variability in hearing loss, temporal bone anomalies, and thyroid dysfunction may be observed among sibs with Heterozygotes do not develop See Management, The optimal time for clarification of genetic status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling to young adults with Once biallelic Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of a child with biallelic • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes do not develop • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Considerable intrafamilial variability in hearing loss, temporal bone anomalies, and thyroid dysfunction may be observed among sibs with • Heterozygotes do not develop • The optimal time for clarification of genetic status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling to young adults with ## Mode of Inheritance Note: Although digenic inheritance of hearing loss with enlarged vestibular aqueduct has been described involving pathogenic variants in ## Risk to Family Members (Proband with Biallelic The parents of a child with biallelic Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If an A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes do not develop If both parents are known to be heterozygous for an Considerable intrafamilial variability in hearing loss, temporal bone anomalies, and thyroid dysfunction may be observed among sibs with Heterozygotes do not develop • The parents of a child with biallelic • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes do not develop • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Considerable intrafamilial variability in hearing loss, temporal bone anomalies, and thyroid dysfunction may be observed among sibs with • Heterozygotes do not develop ## Related Genetic Counseling Issues See Management, The optimal time for clarification of genetic status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling to young adults with • The optimal time for clarification of genetic status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling to young adults with ## Prenatal Testing and Preimplantation Genetic Testing Once biallelic Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Health Resources & Services Administration • • • • • • • • Health Resources & Services Administration • ## Molecular Genetics SLC26A4-Related Sensorineural Hearing Loss: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SLC26A4-Related Sensorineural Hearing Loss ( In individuals of Chinese, Korean, and Japanese ancestry with enlarged vestibular aqueduct (EVA), 67%-90% have biallelic In individuals of northern European ancestry with EVA, about 25% have biallelic Although the CEVA haplotype is frequently reported on the opposite homologous chromosome in affected persons with one If molecular genetic testing reveals only one ## Molecular Pathogenesis In individuals of Chinese, Korean, and Japanese ancestry with enlarged vestibular aqueduct (EVA), 67%-90% have biallelic In individuals of northern European ancestry with EVA, about 25% have biallelic Although the CEVA haplotype is frequently reported on the opposite homologous chromosome in affected persons with one If molecular genetic testing reveals only one ## Chapter Notes Supported in part by grants DC02842 and DC012049 from the NIDCD (RJHS). Fatemeh Alasti, PhD; University of Iowa (2011-2017)Hela Azaiez, MS, PhD (2025-present)Lorraine A Everett, MD; National Institutes of Health (1998-2001)Eric D Green, MD, PhD; National Institutes of Health (1998-2001)Yoichiro Iwasa, MD, PhD; University of Iowa (2020-2025)Daryl A Scott, MD, PhD; University of Iowa (1998-2001)Amanda M Odell, MS, LGC (2020-present)Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)Richard JH Smith, MD (1998-present)Guy Van Camp, PhD; University of Antwerp (1998-2017)Peter Van Hauwe; University of Antwerp (1998-2001) 3 April 2025 (aa) Revision: 9 January 2025 (bp) Comprehensive update posted live 19 October 2017 (bp) Comprehensive update posted live 29 May 2014 (me) Comprehensive update posted live 22 December 2011 (me) Comprehensive update posted live 2 April 2009 (me) Comprehensive update posted live 31 August 2006 (me) Comprehensive update posted to live Web site 28 June 2004 (me) Comprehensive update posted to live Web site 1 May 2001 (me) Comprehensive update posted to live Web site 28 September 1998 (pb) Review posted to live Web site 4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe • 3 April 2025 (aa) Revision: • 9 January 2025 (bp) Comprehensive update posted live • 19 October 2017 (bp) Comprehensive update posted live • 29 May 2014 (me) Comprehensive update posted live • 22 December 2011 (me) Comprehensive update posted live • 2 April 2009 (me) Comprehensive update posted live • 31 August 2006 (me) Comprehensive update posted to live Web site • 28 June 2004 (me) Comprehensive update posted to live Web site • 1 May 2001 (me) Comprehensive update posted to live Web site • 28 September 1998 (pb) Review posted to live Web site • 4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe ## Author Notes ## Acknowledgments Supported in part by grants DC02842 and DC012049 from the NIDCD (RJHS). ## Author History Fatemeh Alasti, PhD; University of Iowa (2011-2017)Hela Azaiez, MS, PhD (2025-present)Lorraine A Everett, MD; National Institutes of Health (1998-2001)Eric D Green, MD, PhD; National Institutes of Health (1998-2001)Yoichiro Iwasa, MD, PhD; University of Iowa (2020-2025)Daryl A Scott, MD, PhD; University of Iowa (1998-2001)Amanda M Odell, MS, LGC (2020-present)Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)Richard JH Smith, MD (1998-present)Guy Van Camp, PhD; University of Antwerp (1998-2017)Peter Van Hauwe; University of Antwerp (1998-2001) ## Revision History 3 April 2025 (aa) Revision: 9 January 2025 (bp) Comprehensive update posted live 19 October 2017 (bp) Comprehensive update posted live 29 May 2014 (me) Comprehensive update posted live 22 December 2011 (me) Comprehensive update posted live 2 April 2009 (me) Comprehensive update posted live 31 August 2006 (me) Comprehensive update posted to live Web site 28 June 2004 (me) Comprehensive update posted to live Web site 1 May 2001 (me) Comprehensive update posted to live Web site 28 September 1998 (pb) Review posted to live Web site 4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe • 3 April 2025 (aa) Revision: • 9 January 2025 (bp) Comprehensive update posted live • 19 October 2017 (bp) Comprehensive update posted live • 29 May 2014 (me) Comprehensive update posted live • 22 December 2011 (me) Comprehensive update posted live • 2 April 2009 (me) Comprehensive update posted live • 31 August 2006 (me) Comprehensive update posted to live Web site • 28 June 2004 (me) Comprehensive update posted to live Web site • 1 May 2001 (me) Comprehensive update posted to live Web site • 28 September 1998 (pb) Review posted to live Web site • 4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe ## References ## Literature Cited Computed tomography in a proband with Pendred syndrome shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow). EVA is also present (black arrow). Inset shows a normal right cochlea and no enlargement of the vestibular aqueduct. In an unbiased screen of 2,434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic	[]	28/9/1998	9/1/2025	3/4/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
perrault	perrault	[ "ATP-dependent Clp protease proteolytic subunit, mitochondrial", "Geranylgeranyl pyrophosphate synthase", "GTPase Era, mitochondrial", "Histidine--tRNA ligase, mitochondrial", "Large ribosomal subunit protein mL49", "Leucine--tRNA ligase, mitochondrial", "Mitochondrial ribonuclease P catalytic subunit", "Peroxisomal ATPase PEX6", "Peroxisomal multifunctional enzyme type 2", "Required for meiotic nuclear division protein 1 homolog", "Small ribosomal subunit protein mS29", "Twinkle mtDNA helicase", "CLPP", "DAP3", "ERAL1", "GGPS1", "HARS2", "HSD17B4", "LARS2", "MRPL49", "PEX6", "PRORP", "RMND1", "TWNK", "Perrault Syndrome", "Overview" ]	Perrault Syndrome Overview	Tianyi Li, Rabia Faridi, William G Newman, Thomas B Friedman	Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform	## Clinical Characteristics of Perrault Syndrome Perrault syndrome, a rare multisystem disorder, has been reported in more than 170 individuals to date. Perrault syndrome was initially defined 70 years ago as bilateral sensorineural hearing loss (SNHL) and ovarian dysfunction in females with a normal 46,XX karyotype [ Type 1 Perrault syndrome can be considered the mild end of the phenotypic spectrum and type 2 Perrault syndrome can be considered the severe end of the spectrum. Audiograms typically initially show steeply sloping threshold elevations (>40 dB hearing loss [HL]) at 4-8 kHz that later extend to lower frequencies (0.5-2 kHz). Progression to profound SNHL (70-100 dB HL) can occur with absent otoacoustic emissions (OAEs), indicating outer hair cell dysfunction and abnormal auditory brain stem responses (ABRs) with absent waveforms / prolonged latency indicating cochlear or auditory nerve pathology. While MRI in most individuals shows structurally normal inner ears, up to 10% of individuals have cochlear nerve hypoplasia. Middle ear function is normal based either in young children on acoustic immittance testing (i.e., normal tympanograms [type A] with absent/elevated stapedial reflexes) or in older children on an audiogram that shows similar hearing thresholds for both bone and air conduction. Vestibular function in individuals with Perrault syndrome is largely unexplored. This distinct audiologic profile aids in differentiation from other causes of genetic hearing loss and underscores the need for early intervention such as cochlear implantation to improve acquisition of speech and language. Variability in age of onset and degree of hearing loss do not depend on the sex of the affected individual. ## Type 1 Perrault Syndrome Audiograms typically initially show steeply sloping threshold elevations (>40 dB hearing loss [HL]) at 4-8 kHz that later extend to lower frequencies (0.5-2 kHz). Progression to profound SNHL (70-100 dB HL) can occur with absent otoacoustic emissions (OAEs), indicating outer hair cell dysfunction and abnormal auditory brain stem responses (ABRs) with absent waveforms / prolonged latency indicating cochlear or auditory nerve pathology. While MRI in most individuals shows structurally normal inner ears, up to 10% of individuals have cochlear nerve hypoplasia. Middle ear function is normal based either in young children on acoustic immittance testing (i.e., normal tympanograms [type A] with absent/elevated stapedial reflexes) or in older children on an audiogram that shows similar hearing thresholds for both bone and air conduction. Vestibular function in individuals with Perrault syndrome is largely unexplored. This distinct audiologic profile aids in differentiation from other causes of genetic hearing loss and underscores the need for early intervention such as cochlear implantation to improve acquisition of speech and language. Variability in age of onset and degree of hearing loss do not depend on the sex of the affected individual. ## Type 2 Perrault Syndrome ## Genetic Causes of Perrault Syndrome Perrault syndrome, caused by biallelic pathogenic (or likely pathogenic) variants in at least 12 genes, is inherited in an autosomal recessive manner (see Note: There is significant interfamilial and intrafamilial variability in the 12 genes listed in Perrault Syndrome: Associated Genes Genes are listed in alphabetic order. Sensorineural hearing loss (SNHL). Congenital and usually severe to profound Ovarian dysfunction. Ovarian dysgenesis to premature ovarian insufficiency (POI) Fertility in males. Azoospermia in some males [ Type 2 findings. Learning difficulties, autism spectrum disorder, epilepsy, spastic-ataxic gait, dystonia SNHL. Congenital profound hearing loss Ovarian dysfunction. POI Fertility in males. Not reported Type 2 findings. Mild-to-severe intellectual disability, epilepsy, diffuse leukodystrophy SNHL. Congenital and profound; early-childhood onset and progressive with varying degrees of severity Ovarian dysfunction. Ovarian dysgenesis to POI Fertility in males. Not reported Type 2 findings. Not reported Founder variant. SNHL. Congenital hearing loss with slow progression Ovarian dysfunction. Absent ovaries to normal Fertility in males. Not reported Type 2 findings. Early-onset, progressive proximal or generalized muscular dystrophy SNHL. Can be congenital and profound; usually early-childhood onset and progressive with varying severity Ovarian dysfunction. Ovarian dysgenesis to normal Fertility in males. Not reported Type 2 findings. Rare; cerebellar ataxia reported SNHL. Congenital and profound; mild with a progressive course in childhood Ovarian dysfunction. Ovarian dysgenesis to POI Fertility in males. Not reported Type 2 findings. All reported individuals have neurologic findings including retinitis pigmentosa, spastic diplegic cerebral palsy, progressive sensory and motor peripheral neuropathy, cerebellar ataxia, and learning disability. SNHL. Can be congenital and profound; onset usually in early childhood and can be progressive with varying degrees of severity Low-frequency SNHL resulting in an upsloping audiogram has been associated with pathogenic variant Individuals with no hearing impairment have been reported [ Ovarian dysfunction. Ovarian dysgenesis to POI Fertility in males. Not reported, but undervirilization noted Type 2 findings. Seizures, progressive cognitive impairment, leukodystrophy SNHL. Childhood-onset bilateral profound hearing loss Ovarian dysfunction. Ovarian dysgenesis to POI Fertility in males. Not reported Type 2 findings. Retinal dystrophy, learning disability; cerebellar atrophy and leukodystrophy especially in the globus pallidus SNHL. Childhood onset; degree not reported Ovarian dysfunction. POI Fertility in males. Not reported Type 2 findings. Retinal dystrophy, peripheral neuropathy, leukodystrophy SNHL. Mild-to-severe hearing loss; not in all affected individuals Ovarian dysfunction. POI to normal Fertility in males. Not reported Type 2 findings. Learning disability, leukodystrophy SNHL. Moderate-to-severe hearing loss Ovarian dysfunction. POI Fertility in males. Not reported Type 2 findings. Learning disability, leukodystrophy SNHL. Moderate-to-severe hearing loss (includes auditory neuropathy) Ovarian dysfunction. Ovarian dysgenesis to POI Fertility in males. Not specifically reported, but evidence of reduced fertility in males [ Type 2 findings. All individuals reported to date have had associated neurologic findings, including ataxia and peripheral neuropathy [ • Sensorineural hearing loss (SNHL). Congenital and usually severe to profound • Ovarian dysfunction. Ovarian dysgenesis to premature ovarian insufficiency (POI) • Fertility in males. Azoospermia in some males [ • Type 2 findings. Learning difficulties, autism spectrum disorder, epilepsy, spastic-ataxic gait, dystonia • SNHL. Congenital profound hearing loss • Ovarian dysfunction. POI • Fertility in males. Not reported • Type 2 findings. Mild-to-severe intellectual disability, epilepsy, diffuse leukodystrophy • SNHL. Congenital and profound; early-childhood onset and progressive with varying degrees of severity • Ovarian dysfunction. Ovarian dysgenesis to POI • Fertility in males. Not reported • Type 2 findings. Not reported • Founder variant. • SNHL. Congenital hearing loss with slow progression • Ovarian dysfunction. Absent ovaries to normal • Fertility in males. Not reported • Type 2 findings. Early-onset, progressive proximal or generalized muscular dystrophy • SNHL. Can be congenital and profound; usually early-childhood onset and progressive with varying severity • Ovarian dysfunction. Ovarian dysgenesis to normal • Fertility in males. Not reported • Type 2 findings. Rare; cerebellar ataxia reported • SNHL. Congenital and profound; mild with a progressive course in childhood • Ovarian dysfunction. Ovarian dysgenesis to POI • Fertility in males. Not reported • Type 2 findings. All reported individuals have neurologic findings including retinitis pigmentosa, spastic diplegic cerebral palsy, progressive sensory and motor peripheral neuropathy, cerebellar ataxia, and learning disability. • SNHL. Can be congenital and profound; onset usually in early childhood and can be progressive with varying degrees of severity • Low-frequency SNHL resulting in an upsloping audiogram has been associated with pathogenic variant • Individuals with no hearing impairment have been reported [ • Low-frequency SNHL resulting in an upsloping audiogram has been associated with pathogenic variant • Individuals with no hearing impairment have been reported [ • Ovarian dysfunction. Ovarian dysgenesis to POI • Fertility in males. Not reported, but undervirilization noted • Type 2 findings. Seizures, progressive cognitive impairment, leukodystrophy • Low-frequency SNHL resulting in an upsloping audiogram has been associated with pathogenic variant • Individuals with no hearing impairment have been reported [ • SNHL. Childhood-onset bilateral profound hearing loss • Ovarian dysfunction. Ovarian dysgenesis to POI • Fertility in males. Not reported • Type 2 findings. Retinal dystrophy, learning disability; cerebellar atrophy and leukodystrophy especially in the globus pallidus • SNHL. Childhood onset; degree not reported • Ovarian dysfunction. POI • Fertility in males. Not reported • Type 2 findings. Retinal dystrophy, peripheral neuropathy, leukodystrophy • SNHL. Mild-to-severe hearing loss; not in all affected individuals • Ovarian dysfunction. POI to normal • Fertility in males. Not reported • Type 2 findings. Learning disability, leukodystrophy • SNHL. Moderate-to-severe hearing loss • Ovarian dysfunction. POI • Fertility in males. Not reported • Type 2 findings. Learning disability, leukodystrophy • SNHL. Moderate-to-severe hearing loss (includes auditory neuropathy) • Ovarian dysfunction. Ovarian dysgenesis to POI • Fertility in males. Not specifically reported, but evidence of reduced fertility in males [ • Type 2 findings. All individuals reported to date have had associated neurologic findings, including ataxia and peripheral neuropathy [ ## Differential Diagnosis of Perrault Syndrome For individuals with a clinical diagnosis of Perrault syndrome in whom a molecular diagnosis has not been established, other causes of sensorineural hearing loss (SNHL) and ovarian dysfunction need to be excluded before a clinical diagnosis of Perrault syndrome can made with confidence. Note: Perrault syndrome is associated with a distinct audiologic profile (see Genes Associated with Ovarian Dysfunction in the Differential Diagnosis of Perrault Syndrome AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; POI = primary ovarian insufficiency; XL = X-linked A ## Evaluation Strategies to Identify the Genetic Cause of Perrault Syndrome in a Proband The diagnosis of Perrault syndrome is molecularly confirmed by the presence of biallelic pathogenic (or likely pathogenic) variants in one of 12 genes: Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Genomic/Genetic Testing The diagnosis of Perrault syndrome is molecularly confirmed by the presence of biallelic pathogenic (or likely pathogenic) variants in one of 12 genes: Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management No clinical practice guidelines for Perrault syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with Perrault syndrome, the evaluations summarized in Perrault Syndrome: Recommended Evaluations Following Initial Diagnosis Determine if ataxia, peripheral neuropathy, &/or learning disability is present. Brain MRI to determine if evidence of white matter changes is present. Community or Social work involvement for parental support Home nursing referral FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance Males and females Females only Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for Perrault syndrome. No pharmacologic therapies are available. Although the pathogenic mechanism in most of the genetic causes of Perrault syndrome is mitochondrial dysfunction, therapies used in most known mitochondrial disorders aimed at improving metabolism (such as complex B vitamins, coenzyme Q Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Perrault Syndrome: Treatment of Manifestations Hearing aids Vibrotactile devices Cochlear implantation Assessment & treatment by multidisciplinary team incl audiologist, otolaryngologist, & speech therapist Provide for any special educational needs. Early intervention for young children w/profound hearing loss improves cognitive & language development (summarized in To ensure involvement of appropriate educational agencies To maximize quality of life for person w/hearing loss & their family In consultation w/pediatric endocrinologist If puberty is complete, administer cyclic estrogen & progesterone to mimic menstrual cycle & trigger withdrawal bleeding. Estrogen replacement therapy (if no contraindications) until age ≥50 yrs to ↓ risks of cardiovascular disease & osteoporosis For females w/ovarian dysgenesis: consider assisted reproduction through in vitro fertilization using donor eggs. For females at risk for POI: consider oocyte cryopreservation if ovarian function is sufficient to allow successful harvesting of oocytes. Consider use of donor eggs. Before considering pregnancy, assess uterine size (ideally 7-9 cm in length). For males with ↓ fertility, consider assisted reproduction through in vitro fertilization using donor sperm. ADL = activities of daily living; OT = occupational therapy; POI = primary ovarian insufficiency; PT = physical therapy Cochlear implantation can be considered in children age >12 months who have severe-to-profound hearing loss. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Perrault Syndrome: Recommended Surveillance Before puberty: clinical staging of puberty During induction of puberty: adjustment of estrogen dose Not required for individuals with profound hearing loss For individuals with hearing loss, avoid: Ototoxic medication such as aminoglycosides if alternatives are available; Exposure to loud noise, which may contribute to deterioration of hearing. It is appropriate to evaluate older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt diagnosis and early intervention for hearing loss and/or ovarian insufficiency. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variants in the family are not known, screening of sibs should include audiologic assessment in males and females and baseline measurements of serum luteinizing hormone and follicle-stimulating hormone in females. • Determine if ataxia, peripheral neuropathy, &/or learning disability is present. • Brain MRI to determine if evidence of white matter changes is present. • Community or • Social work involvement for parental support • Home nursing referral • Hearing aids • Vibrotactile devices • Cochlear implantation • Assessment & treatment by multidisciplinary team incl audiologist, otolaryngologist, & speech therapist • Provide for any special educational needs. • Early intervention for young children w/profound hearing loss improves cognitive & language development (summarized in • To ensure involvement of appropriate educational agencies • To maximize quality of life for person w/hearing loss & their family • In consultation w/pediatric endocrinologist • If puberty is complete, administer cyclic estrogen & progesterone to mimic menstrual cycle & trigger withdrawal bleeding. • Estrogen replacement therapy (if no contraindications) until age ≥50 yrs to ↓ risks of cardiovascular disease & osteoporosis • For females w/ovarian dysgenesis: consider assisted reproduction through in vitro fertilization using donor eggs. • For females at risk for POI: consider oocyte cryopreservation if ovarian function is sufficient to allow successful harvesting of oocytes. • Consider use of donor eggs. • Before considering pregnancy, assess uterine size (ideally 7-9 cm in length). • For males with ↓ fertility, consider assisted reproduction through in vitro fertilization using donor sperm. • Before puberty: clinical staging of puberty • During induction of puberty: adjustment of estrogen dose • Ototoxic medication such as aminoglycosides if alternatives are available; • Exposure to loud noise, which may contribute to deterioration of hearing. • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variants in the family are not known, screening of sibs should include audiologic assessment in males and females and baseline measurements of serum luteinizing hormone and follicle-stimulating hormone in females. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Perrault syndrome, the evaluations summarized in Perrault Syndrome: Recommended Evaluations Following Initial Diagnosis Determine if ataxia, peripheral neuropathy, &/or learning disability is present. Brain MRI to determine if evidence of white matter changes is present. Community or Social work involvement for parental support Home nursing referral FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance Males and females Females only Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Determine if ataxia, peripheral neuropathy, &/or learning disability is present. • Brain MRI to determine if evidence of white matter changes is present. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Perrault syndrome. No pharmacologic therapies are available. Although the pathogenic mechanism in most of the genetic causes of Perrault syndrome is mitochondrial dysfunction, therapies used in most known mitochondrial disorders aimed at improving metabolism (such as complex B vitamins, coenzyme Q Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Perrault Syndrome: Treatment of Manifestations Hearing aids Vibrotactile devices Cochlear implantation Assessment & treatment by multidisciplinary team incl audiologist, otolaryngologist, & speech therapist Provide for any special educational needs. Early intervention for young children w/profound hearing loss improves cognitive & language development (summarized in To ensure involvement of appropriate educational agencies To maximize quality of life for person w/hearing loss & their family In consultation w/pediatric endocrinologist If puberty is complete, administer cyclic estrogen & progesterone to mimic menstrual cycle & trigger withdrawal bleeding. Estrogen replacement therapy (if no contraindications) until age ≥50 yrs to ↓ risks of cardiovascular disease & osteoporosis For females w/ovarian dysgenesis: consider assisted reproduction through in vitro fertilization using donor eggs. For females at risk for POI: consider oocyte cryopreservation if ovarian function is sufficient to allow successful harvesting of oocytes. Consider use of donor eggs. Before considering pregnancy, assess uterine size (ideally 7-9 cm in length). For males with ↓ fertility, consider assisted reproduction through in vitro fertilization using donor sperm. ADL = activities of daily living; OT = occupational therapy; POI = primary ovarian insufficiency; PT = physical therapy Cochlear implantation can be considered in children age >12 months who have severe-to-profound hearing loss. • Hearing aids • Vibrotactile devices • Cochlear implantation • Assessment & treatment by multidisciplinary team incl audiologist, otolaryngologist, & speech therapist • Provide for any special educational needs. • Early intervention for young children w/profound hearing loss improves cognitive & language development (summarized in • To ensure involvement of appropriate educational agencies • To maximize quality of life for person w/hearing loss & their family • In consultation w/pediatric endocrinologist • If puberty is complete, administer cyclic estrogen & progesterone to mimic menstrual cycle & trigger withdrawal bleeding. • Estrogen replacement therapy (if no contraindications) until age ≥50 yrs to ↓ risks of cardiovascular disease & osteoporosis • For females w/ovarian dysgenesis: consider assisted reproduction through in vitro fertilization using donor eggs. • For females at risk for POI: consider oocyte cryopreservation if ovarian function is sufficient to allow successful harvesting of oocytes. • Consider use of donor eggs. • Before considering pregnancy, assess uterine size (ideally 7-9 cm in length). • For males with ↓ fertility, consider assisted reproduction through in vitro fertilization using donor sperm. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Perrault Syndrome: Recommended Surveillance Before puberty: clinical staging of puberty During induction of puberty: adjustment of estrogen dose Not required for individuals with profound hearing loss • Before puberty: clinical staging of puberty • During induction of puberty: adjustment of estrogen dose ## Agents/Circumstances to Avoid For individuals with hearing loss, avoid: Ototoxic medication such as aminoglycosides if alternatives are available; Exposure to loud noise, which may contribute to deterioration of hearing. • Ototoxic medication such as aminoglycosides if alternatives are available; • Exposure to loud noise, which may contribute to deterioration of hearing. ## Evaluation of Relatives at Risk It is appropriate to evaluate older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt diagnosis and early intervention for hearing loss and/or ovarian insufficiency. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. If the pathogenic variants in the family are not known, screening of sibs should include audiologic assessment in males and females and baseline measurements of serum luteinizing hormone and follicle-stimulating hormone in females. • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. • If the pathogenic variants in the family are not known, screening of sibs should include audiologic assessment in males and females and baseline measurements of serum luteinizing hormone and follicle-stimulating hormone in females. ## Genetic Counseling Perrault syndrome is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for a Perrault syndrome-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Perrault syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a PRLTS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Significant intrafamilial variability has been observed among affected sibs [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the Perrault syndrome-related pathogenic variants in the family. See Management, The increased risk for primary ovarian insufficiency and infertility in females with Perrault syndrome should be addressed when discussing family planning. Although the risk of Perrault syndrome-related male infertility is considered lower than in females, males at risk for decreased fertility may benefit from fertility counseling and discussion of assistive reproductive technology options when they reach reproductive age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. If the Perrault syndrome-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a Perrault syndrome-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Perrault syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a PRLTS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Significant intrafamilial variability has been observed among affected sibs [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The increased risk for primary ovarian insufficiency and infertility in females with Perrault syndrome should be addressed when discussing family planning. • Although the risk of Perrault syndrome-related male infertility is considered lower than in females, males at risk for decreased fertility may benefit from fertility counseling and discussion of assistive reproductive technology options when they reach reproductive age. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Perrault syndrome is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Perrault syndrome-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Perrault syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a PRLTS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Significant intrafamilial variability has been observed among affected sibs [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for a Perrault syndrome-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Perrault syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multi-exon deletion in the proband was not detected by sequence analysis and resulted in an artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a PRLTS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Significant intrafamilial variability has been observed among affected sibs [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the Perrault syndrome-related pathogenic variants in the family. ## Related Genetic Counseling Issues See Management, The increased risk for primary ovarian insufficiency and infertility in females with Perrault syndrome should be addressed when discussing family planning. Although the risk of Perrault syndrome-related male infertility is considered lower than in females, males at risk for decreased fertility may benefit from fertility counseling and discussion of assistive reproductive technology options when they reach reproductive age. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The increased risk for primary ovarian insufficiency and infertility in females with Perrault syndrome should be addressed when discussing family planning. • Although the risk of Perrault syndrome-related male infertility is considered lower than in females, males at risk for decreased fertility may benefit from fertility counseling and discussion of assistive reproductive technology options when they reach reproductive age. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing If the Perrault syndrome-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources InterNational Council on Infertility Information Dissemination • • • • • • InterNational Council on Infertility Information Dissemination • • • • • ## Chapter Notes William Newman ( Rabia Faridi ( Contact Rabia Faridi, William Newman, and Thomas Friedman to inquire about review of variants of uncertain significance in genes associated with Perrault syndrome. William Newman is supported by the Medical Research Council (MR/W019027/1), Action on Hearing Loss (S60_Newman), and NIHR Manchester Biomedical Research Centre (NIHR203308). Rabia Faridi and Thomas Friedman are supported by the Intramural Research Program of the NIDCD at the NIH (DC000039). Gerard S Conway, MD; University College London (2014-2025)Leigh AM Demain, PhD; University of Manchester (2018-2025)Rabia Faridi, PhD (2025-present)Thomas B Friedman, PhD (2014-present)Tianyi Li, MD, PhD (2025-present)William G Newman, MD, PhD (2014-present) 8 May 2025 (bp) Comprehensive update posted live; scope changed to overview 6 September 2018 (bp) Comprehensive update posted live 25 September 2014 (me) Review posted live 10 March 2014 (wn) Original submission • 8 May 2025 (bp) Comprehensive update posted live; scope changed to overview • 6 September 2018 (bp) Comprehensive update posted live • 25 September 2014 (me) Review posted live • 10 March 2014 (wn) Original submission ## Author Notes William Newman ( Rabia Faridi ( Contact Rabia Faridi, William Newman, and Thomas Friedman to inquire about review of variants of uncertain significance in genes associated with Perrault syndrome. ## Acknowledgments William Newman is supported by the Medical Research Council (MR/W019027/1), Action on Hearing Loss (S60_Newman), and NIHR Manchester Biomedical Research Centre (NIHR203308). Rabia Faridi and Thomas Friedman are supported by the Intramural Research Program of the NIDCD at the NIH (DC000039). ## Author History Gerard S Conway, MD; University College London (2014-2025)Leigh AM Demain, PhD; University of Manchester (2018-2025)Rabia Faridi, PhD (2025-present)Thomas B Friedman, PhD (2014-present)Tianyi Li, MD, PhD (2025-present)William G Newman, MD, PhD (2014-present) ## Revision History 8 May 2025 (bp) Comprehensive update posted live; scope changed to overview 6 September 2018 (bp) Comprehensive update posted live 25 September 2014 (me) Review posted live 10 March 2014 (wn) Original submission • 8 May 2025 (bp) Comprehensive update posted live; scope changed to overview • 6 September 2018 (bp) Comprehensive update posted live • 25 September 2014 (me) Review posted live • 10 March 2014 (wn) Original submission ## References ## Literature Cited	[]	25/9/2014	8/5/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
perry	perry	[ "Perry Syndrome", "Distal Hereditary Motor Neuronopathy Type 7B (dHMN7B)", "DCTN1-Related Frontotemporal Dementia", "DCTN1-Related Motor Neuron Disease / Amyotrophic Lateral Sclerosis", "DCTN1-Related Progressive Supranuclear Palsy", "Dynactin subunit 1", "DCTN1", "DCTN1-Related Neurodegeneration" ]		Jaroslaw Dulski, Takuya Konno, Zbigniew Wszolek	Summary The spectrum of Perry syndrome (the most common of the phenotypes associated with The diagnosis of	Perry syndrome Distal hereditary motor neuronopathy type 7B Frontotemporal dementia Motor neuron disease / amyotrophic lateral sclerosis Progressive supranuclear palsy For other genetic causes of these phenotypes, see The most common phenotype associated with heterozygous • Perry syndrome • Distal hereditary motor neuronopathy type 7B • Frontotemporal dementia • Motor neuron disease / amyotrophic lateral sclerosis • Progressive supranuclear palsy ## Diagnosis Parkinsonism Mood/personality/cognitive changes (depression, apathy, withdrawal, disinhibition, dementia) Weight loss Breathing disturbances (in particular central hypoventilation) Muscle atrophy Autonomic dysfunction Vocal fold paralysis Facial weakness Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. Electroneurography may reveal length-dependent predominantly motor neuropathy. Electromyography may show evidence of denervation. The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Therefore, individuals with the distinctive findings described in Note: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Since • Parkinsonism • Mood/personality/cognitive changes (depression, apathy, withdrawal, disinhibition, dementia) • Weight loss • Breathing disturbances (in particular central hypoventilation) • Muscle atrophy • Autonomic dysfunction • Vocal fold paralysis • Facial weakness • Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. • 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. • Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. • Electroneurography may reveal length-dependent predominantly motor neuropathy. • Electromyography may show evidence of denervation. ## Suggestive Findings Parkinsonism Mood/personality/cognitive changes (depression, apathy, withdrawal, disinhibition, dementia) Weight loss Breathing disturbances (in particular central hypoventilation) Muscle atrophy Autonomic dysfunction Vocal fold paralysis Facial weakness Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. Electroneurography may reveal length-dependent predominantly motor neuropathy. Electromyography may show evidence of denervation. • Parkinsonism • Mood/personality/cognitive changes (depression, apathy, withdrawal, disinhibition, dementia) • Weight loss • Breathing disturbances (in particular central hypoventilation) • Muscle atrophy • Autonomic dysfunction • Vocal fold paralysis • Facial weakness • Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. • 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. • Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. • Electroneurography may reveal length-dependent predominantly motor neuropathy. • Electromyography may show evidence of denervation. ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Therefore, individuals with the distinctive findings described in Note: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Since ## Option 1 Note: For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Since ## Clinical Characteristics The spectrum of The cardinal signs of Perry syndrome are parkinsonism, neuropsychiatric symptoms, hypoventilation, and weight loss [ Sleep difficulties occur in approximately 20% of individuals and probably reflect hypoventilation. Reported findings [ Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. Electroneurography may reveal length-dependent predominantly motor neuropathy. Electromyography may show evidence of denervation. The neuropathology of Histology showed severe neuronal loss and gliosis in the substantia nigra, and to a lesser degree in locus ceruleus, striatum, hypothalamus, periaqueductal gray matter, ventrolateral medulla, dorsal raphe nucleus, and brain stem reticular formation. Lewy bodies and neurofibrillary tangles were not present in most individuals. Immunohistochemistry showed abnormal deposition of transactive response DNA-binding protein 43 (TDP-43) in the form of neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, and axonal spheroids. If present, TDP-43 pathology was morphologically similar in Perry syndrome, FTD, motor neuron disease, and other disorders. However, its distribution was distinct in individuals with Perry syndrome, who had most lesions located in the extrapyramidal system [ In No clear genotype-phenotype correlations have been identified. While affected family members often share the same phenotype, intrafamilial variability has also been reported. For example, individuals from one Chinese family with the same Although precise estimates have not been calculated given the limited number of families reported, penetrance is age related and high, with all asymptomatic heterozygotes being younger than or within the range of age of onset. Since the discovery of • Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. • 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. • Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. • Electroneurography may reveal length-dependent predominantly motor neuropathy. • Electromyography may show evidence of denervation. ## Clinical Description The spectrum of The cardinal signs of Perry syndrome are parkinsonism, neuropsychiatric symptoms, hypoventilation, and weight loss [ Sleep difficulties occur in approximately 20% of individuals and probably reflect hypoventilation. Reported findings [ Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. Electroneurography may reveal length-dependent predominantly motor neuropathy. Electromyography may show evidence of denervation. The neuropathology of Histology showed severe neuronal loss and gliosis in the substantia nigra, and to a lesser degree in locus ceruleus, striatum, hypothalamus, periaqueductal gray matter, ventrolateral medulla, dorsal raphe nucleus, and brain stem reticular formation. Lewy bodies and neurofibrillary tangles were not present in most individuals. Immunohistochemistry showed abnormal deposition of transactive response DNA-binding protein 43 (TDP-43) in the form of neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, and axonal spheroids. If present, TDP-43 pathology was morphologically similar in Perry syndrome, FTD, motor neuron disease, and other disorders. However, its distribution was distinct in individuals with Perry syndrome, who had most lesions located in the extrapyramidal system [ In • Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. • 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. • Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. • Electroneurography may reveal length-dependent predominantly motor neuropathy. • Electromyography may show evidence of denervation. ## Perry Syndrome The cardinal signs of Perry syndrome are parkinsonism, neuropsychiatric symptoms, hypoventilation, and weight loss [ Sleep difficulties occur in approximately 20% of individuals and probably reflect hypoventilation. ## Other Phenotypes ## Neuroimaging and Other Studies Reported findings [ Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. Electroneurography may reveal length-dependent predominantly motor neuropathy. Electromyography may show evidence of denervation. • Brain CT and MRI may reveal atrophy of the frontal and temporal lobes or the midbrain. • 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET may demonstrate cortical and subcortical disruption of serotonergic neurotransmission. • Transcranial sonography may show hyperechogenicity in the substantia nigra comparable to that observed in Parkinson disease. • Electroneurography may reveal length-dependent predominantly motor neuropathy. • Electromyography may show evidence of denervation. ## Neuropathology The neuropathology of Histology showed severe neuronal loss and gliosis in the substantia nigra, and to a lesser degree in locus ceruleus, striatum, hypothalamus, periaqueductal gray matter, ventrolateral medulla, dorsal raphe nucleus, and brain stem reticular formation. Lewy bodies and neurofibrillary tangles were not present in most individuals. Immunohistochemistry showed abnormal deposition of transactive response DNA-binding protein 43 (TDP-43) in the form of neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, and axonal spheroids. If present, TDP-43 pathology was morphologically similar in Perry syndrome, FTD, motor neuron disease, and other disorders. However, its distribution was distinct in individuals with Perry syndrome, who had most lesions located in the extrapyramidal system [ In ## Genotype-Phenotype Correlations No clear genotype-phenotype correlations have been identified. While affected family members often share the same phenotype, intrafamilial variability has also been reported. For example, individuals from one Chinese family with the same ## Penetrance Although precise estimates have not been calculated given the limited number of families reported, penetrance is age related and high, with all asymptomatic heterozygotes being younger than or within the range of age of onset. ## Prevalence Since the discovery of ## Genetically Related (Allelic) Disorders To date, no phenotypes other than those discussed in this ## Differential Diagnosis Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; bv = behavioral variant; FTD = frontotemporal dementia; MOI = mode of inheritance; PD = Parkinson disease; PSP = progressive supranuclear palsy An individual of Japanese ancestry who showed symptoms reminiscent of Perry syndrome had an Note: Only a few individuals with distal hereditary motor neuronopathy type 7B (dHMN7B) have been reported to date. ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Sleep study Eval by pulmonologist or sleep disorders consultant for ventilation support if required Psychiatric eval Neuropsychological exam if indicated Community or Social work involvement; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Evaluate weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes annually or more frequently as needed. Use of central respiratory depressants (e.g., benzodiazepines, alcohol, narcotics) should be minimized. See Search • Sleep study • Eval by pulmonologist or sleep disorders consultant for ventilation support if required • Psychiatric eval • Neuropsychological exam if indicated • Community or • Social work involvement; • Home nursing referral. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Sleep study Eval by pulmonologist or sleep disorders consultant for ventilation support if required Psychiatric eval Neuropsychological exam if indicated Community or Social work involvement; Home nursing referral. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Sleep study • Eval by pulmonologist or sleep disorders consultant for ventilation support if required • Psychiatric eval • Neuropsychological exam if indicated • Community or • Social work involvement; • Home nursing referral. ## Treatment of Manifestations ## Surveillance Evaluate weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes annually or more frequently as needed. ## Agents/Circumstances to Avoid Use of central respiratory depressants (e.g., benzodiazepines, alcohol, narcotics) should be minimized. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with Less commonly, individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with If a parent of the proband is affected and/or is known to have the If the If the parents have not been tested for the Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors • Most individuals diagnosed with • Less commonly, individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the • If the • If the parents have not been tested for the • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Most individuals diagnosed with Less commonly, individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with If a parent of the proband is affected and/or is known to have the If the If the parents have not been tested for the • Most individuals diagnosed with • Less commonly, individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors ## Resources • • • • • • • • ## Molecular Genetics DCTN1-Related Neurodegeneration: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DCTN1-Related Neurodegeneration ( Under physiologic conditions, dynactin subunit 1 interacts with TDP-43 and regulates its localization and aggregation. Dysfunction of dynactin subunit 1 may disrupt this process and underlie abnormal TDP-43 aggregation [ The link between Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Under physiologic conditions, dynactin subunit 1 interacts with TDP-43 and regulates its localization and aggregation. Dysfunction of dynactin subunit 1 may disrupt this process and underlie abnormal TDP-43 aggregation [ The link between Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Jaroslaw Dulski, MD, PhD is a specialist in neurology and an assistant professor at the Medical University of Gdansk and St Adalbert Hospital in Gdansk, Poland. His primary interests are neurogenetics and movement disorders. Dr Dulski has been involved in the clinical management of Perry syndrome since 2016. Takuya Konno, MD, PhD is an assistant professor in the Department of Neurology, Brain Research Institute, Niigata University in Niigata, Japan. He has been involved in the clinical management of neurodegenerative and movement disorders. He has special interest in genetic disorders including Zbigniew K Wszolek, MD, is a professor of neurology at the Mayo Clinic College of Medicine and Science, and the Haworth Family Professor in Neurodegenerative Diseases. Dr Wszolek has been researching Perry syndrome for 18 years. He has substantially contributed to the understanding of the clinical, pathologic, and genetic aspects of Perry syndrome, and he is a co-discoverer of the causative Jaroslaw Dulski MD, PhDDivision of Neurological and Psychiatric NursingFaculty of Health Sciences, Medical University of GdanskDębinki 7 Str, 80-211, Gdansk, Poland;Neurology DepartmentSt Adalbert Hospital, Gdansk, PolandPhone: +48 58 7684563E-mail: [email protected] Takuya Konno, MD, PhDDepartment of NeurologyBrain Research Institute, Niigata UniversityNiigata, JapanPhone: +81-25-227-0666E-mail: [email protected] Zbigniew K Wszolek, MDConsultant, Department of NeurologyHaworth Family Professor in Neurodegenerative DiseasesProfessor of NeurologyMayo Clinic Florida4500 San Pablo RoadJacksonville, FL 32224, USAPhone: 904-953-7229FAX: 904-953-0757Pager: 904-953-8173E-mail: [email protected] We are grateful to the patients and their families for their collaboration. Dr Dulski received honoraria for lectures and training courses from VM Media Ltd, Radosław Lipiński 90 Consulting, Ipsen. Dr Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from The Sol Goldman Charitable Trust, and the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206 and BHV3241-301), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.001) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. He is a co-editor-in-chief of the Neurologia I Neurochirurgia Polska (Polish Journal of Neurology and Neurosurgery). The work on this manuscript has been supported by the the Haworth Family Professorship in Neurodegenerative Diseases fund and The Albertson Parkinson's Research Foundation. Jaroslaw Dulski, MD, PhD (2021-presentTakuya Konno, MD (2016-present)Christian Wider, MD; Centre Hospitalier Universitaire Vaudois, Lausanne (2010-2016)Zbigniew Wszolek, MD (2010-present) 5 August 2021 (sw) Comprehensive update posted live 29 September 2016 (sw) Comprehensive update posted live 9 May 2013 (me) Comprehensive update posted live 30 September 2010 (me) Review posted live 3 May 2010 (cw) Original submission • 5 August 2021 (sw) Comprehensive update posted live • 29 September 2016 (sw) Comprehensive update posted live • 9 May 2013 (me) Comprehensive update posted live • 30 September 2010 (me) Review posted live • 3 May 2010 (cw) Original submission ## Author Notes Jaroslaw Dulski, MD, PhD is a specialist in neurology and an assistant professor at the Medical University of Gdansk and St Adalbert Hospital in Gdansk, Poland. His primary interests are neurogenetics and movement disorders. Dr Dulski has been involved in the clinical management of Perry syndrome since 2016. Takuya Konno, MD, PhD is an assistant professor in the Department of Neurology, Brain Research Institute, Niigata University in Niigata, Japan. He has been involved in the clinical management of neurodegenerative and movement disorders. He has special interest in genetic disorders including Zbigniew K Wszolek, MD, is a professor of neurology at the Mayo Clinic College of Medicine and Science, and the Haworth Family Professor in Neurodegenerative Diseases. Dr Wszolek has been researching Perry syndrome for 18 years. He has substantially contributed to the understanding of the clinical, pathologic, and genetic aspects of Perry syndrome, and he is a co-discoverer of the causative Jaroslaw Dulski MD, PhDDivision of Neurological and Psychiatric NursingFaculty of Health Sciences, Medical University of GdanskDębinki 7 Str, 80-211, Gdansk, Poland;Neurology DepartmentSt Adalbert Hospital, Gdansk, PolandPhone: +48 58 7684563E-mail: [email protected] Takuya Konno, MD, PhDDepartment of NeurologyBrain Research Institute, Niigata UniversityNiigata, JapanPhone: +81-25-227-0666E-mail: [email protected] Zbigniew K Wszolek, MDConsultant, Department of NeurologyHaworth Family Professor in Neurodegenerative DiseasesProfessor of NeurologyMayo Clinic Florida4500 San Pablo RoadJacksonville, FL 32224, USAPhone: 904-953-7229FAX: 904-953-0757Pager: 904-953-8173E-mail: [email protected] ## Contact Information Jaroslaw Dulski MD, PhDDivision of Neurological and Psychiatric NursingFaculty of Health Sciences, Medical University of GdanskDębinki 7 Str, 80-211, Gdansk, Poland;Neurology DepartmentSt Adalbert Hospital, Gdansk, PolandPhone: +48 58 7684563E-mail: [email protected] Takuya Konno, MD, PhDDepartment of NeurologyBrain Research Institute, Niigata UniversityNiigata, JapanPhone: +81-25-227-0666E-mail: [email protected] Zbigniew K Wszolek, MDConsultant, Department of NeurologyHaworth Family Professor in Neurodegenerative DiseasesProfessor of NeurologyMayo Clinic Florida4500 San Pablo RoadJacksonville, FL 32224, USAPhone: 904-953-7229FAX: 904-953-0757Pager: 904-953-8173E-mail: [email protected] ## Acknowledgments We are grateful to the patients and their families for their collaboration. Dr Dulski received honoraria for lectures and training courses from VM Media Ltd, Radosław Lipiński 90 Consulting, Ipsen. Dr Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from The Sol Goldman Charitable Trust, and the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206 and BHV3241-301), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.001) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. He is a co-editor-in-chief of the Neurologia I Neurochirurgia Polska (Polish Journal of Neurology and Neurosurgery). The work on this manuscript has been supported by the the Haworth Family Professorship in Neurodegenerative Diseases fund and The Albertson Parkinson's Research Foundation. ## Author History Jaroslaw Dulski, MD, PhD (2021-presentTakuya Konno, MD (2016-present)Christian Wider, MD; Centre Hospitalier Universitaire Vaudois, Lausanne (2010-2016)Zbigniew Wszolek, MD (2010-present) ## Revision History 5 August 2021 (sw) Comprehensive update posted live 29 September 2016 (sw) Comprehensive update posted live 9 May 2013 (me) Comprehensive update posted live 30 September 2010 (me) Review posted live 3 May 2010 (cw) Original submission • 5 August 2021 (sw) Comprehensive update posted live • 29 September 2016 (sw) Comprehensive update posted live • 9 May 2013 (me) Comprehensive update posted live • 30 September 2010 (me) Review posted live • 3 May 2010 (cw) Original submission ## References ## Literature Cited	[ "R Barreto, M Lopes, JM Roriz, M Magalhães. 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Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure.. Mov Disord. 2010;25:767-70", "M Omoto, S Suzuki, T Ikeuchi, T Ishihara, T Kobayashi, Y Tsuboi, J Ogasawara, M Koga, M Kawai, T Iwaki, T Kanda. Autosomal dominant tauopathy with parkinsonism and central hypoventilation.. Neurology 2012;78:762-4", "O Piguet, F. Kumfor. Frontotemporal dementias: main syndromes and underlying brain changes.. Curr Opin Neurol. 2020;33:215-21", "I Puls, C Jonnakuty, BH LaMonte, EL Holzbaur, M Tokito, E Mann, MK Floeter, K Bidus, D Drayna, SJ Oh, RH Brown, CL Ludlow, KH Fischbeck. Mutant dynactin in motor neuron disease.. Nat Genet 2003;33:455-6", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "E Saka, MA Topcuoglu, AU Demir, B Elibol. Transcranial sonography in Perry syndrome.. Parkinsonism Relat Disord 2010;16:68-70", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "WT Tian, LH Liu, HY Zhou, C Zhang, FX Zhan, ZY Zhu, SD Chen, XH Luan, L Cao. New phenotype of DCTN1-related spectrum: early-onset dHMN plus congenital foot deformity.. Ann Clin Transl Neurol. 2020;7:200-9", "Y Tsuboi, T Mishima, S. Fujioka. Perry disease: concept of a new disease and clinical diagnostic criteria.. J Mov Disord. 2021;14:1-9", "J Zhang, H Wang, W Liu, J Wang, J Zhang, X Chang, S Huang, X Pang, J Guo, Q Wang, W. Zhang. A novel Q93H missense mutation in DCTN1 caused distal hereditary motor neuropathy type 7B and Perry syndrome from a Chinese family.. Neurol Sci. 2021;42:3695-705" ]	30/9/2010	5/8/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
peters-plus	peters-plus	[ "Peters-Plus Syndrome", "Beta-1,3-glucosyltransferase", "B3GLCT", "Peters Plus Syndrome" ]	Peters Plus Syndrome	Saskia AJ Lesnik Oberstein, Claudia AL Ruivenkamp, Raoul C Hennekam	Summary Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay / intellectual disability. The most common anterior chamber defect is Peters' anomaly, consisting of central corneal clouding, thinning of the posterior cornea, and iridocorneal adhesions. Cataracts and glaucoma are common. Developmental delay is observed in about 80% of children; intellectual disability can range from mild to severe. The diagnosis of Peters plus syndrome is a clinical diagnosis that can be confirmed by identification of biallelic Peters plus syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one	## Diagnosis Peters plus syndrome Short limbs with broad distal extremities Characteristic facial features including an exaggerated Cupid's bow of the upper lip, short palpebral fissures, and ear anomalies Cleft lip/palate Variable developmental delay / intellectual disability The diagnosis of Peters plus syndrome For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Peters Plus Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results click Nine of 26 affected individuals tested, as identified by the Laboratory of Diagnostic Genome Analysis, Leiden, The Netherlands. Note: This is a clinically heterogeneous group. Twenty of 20 affected individuals tested, as identified by Most affected individuals tested to date are homozygous for a splice site pathogenic variant in intron 8 ( Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Short limbs with broad distal extremities • Characteristic facial features including an exaggerated Cupid's bow of the upper lip, short palpebral fissures, and ear anomalies • Cleft lip/palate • Variable developmental delay / intellectual disability • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Peters plus syndrome Short limbs with broad distal extremities Characteristic facial features including an exaggerated Cupid's bow of the upper lip, short palpebral fissures, and ear anomalies Cleft lip/palate Variable developmental delay / intellectual disability • Short limbs with broad distal extremities • Characteristic facial features including an exaggerated Cupid's bow of the upper lip, short palpebral fissures, and ear anomalies • Cleft lip/palate • Variable developmental delay / intellectual disability ## Establishing the Diagnosis The diagnosis of Peters plus syndrome For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Peters Plus Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results click Nine of 26 affected individuals tested, as identified by the Laboratory of Diagnostic Genome Analysis, Leiden, The Netherlands. Note: This is a clinically heterogeneous group. Twenty of 20 affected individuals tested, as identified by Most affected individuals tested to date are homozygous for a splice site pathogenic variant in intron 8 ( Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, variable developmental delay / intellectual disability, typical facial features, and cleft lip/palate. Unless otherwise stated, the following description of clinical findings is based on the reports of Cataracts and glaucoma can subsequently develop later in life. Other, often unspecified anterior chamber defects have been reported, such as mild mesenchymal dysgenesis [ Growth hormone deficiency with good response to growth hormone replacement therapy has been reported in some children [ Adult height range is 128-151 cm in females and 141-155 cm in males. A behavioral phenotype has not been well delineated thus far. Cleft lip is present in 45% of individuals and cleft palate in 33%. Ear anomalies, including preauricular pits, are seen in more than one third of affected individuals. A broad neck occurs in approximately 75% of individuals. Congenital heart defects (≤33% of individuals), including atrial septal defect, ventricular septal defect, subvalvular aortic stenosis, pulmonary stenosis, and bicuspid pulmonary valve Genitourinary anomalies (10%-19%) including hydronephrosis, renal and ureteral duplication, renal underdevelopment with oligomeganephroma, multicystic dysplastic kidney [ Structural brain malformations include hypoplasia or agenesis of the corpus callosum, hydrocephalus [ Congenital hypothyroidism; reported in two children with features suggestive of Peters plus syndrome and subsequently described in another affected individual [ Conductive hearing loss; variably present in association with cleft palate but not otherwise a major feature Polyhydramnios occurred in 18.6% of pregnancies of affected children. No genotype-phenotype correlation has yet been demonstrated. Alternate terms for Peters plus syndrome have included Krause-Kivlin syndrome and Krause-van Schooneveld-Kivlin syndrome. Alternate spellings of Peters plus syndrome include: Peters-plus syndrome, Peters'-plus syndrome, Peters' plus syndrome. The prevalence of Peters plus syndrome is unknown. About 100 affected individuals of diverse ethnic background have been reported in the literature. • Congenital heart defects (≤33% of individuals), including atrial septal defect, ventricular septal defect, subvalvular aortic stenosis, pulmonary stenosis, and bicuspid pulmonary valve • Genitourinary anomalies (10%-19%) including hydronephrosis, renal and ureteral duplication, renal underdevelopment with oligomeganephroma, multicystic dysplastic kidney [ • Structural brain malformations include hypoplasia or agenesis of the corpus callosum, hydrocephalus [ • Congenital hypothyroidism; reported in two children with features suggestive of Peters plus syndrome and subsequently described in another affected individual [ • Conductive hearing loss; variably present in association with cleft palate but not otherwise a major feature ## Clinical Description Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, variable developmental delay / intellectual disability, typical facial features, and cleft lip/palate. Unless otherwise stated, the following description of clinical findings is based on the reports of Cataracts and glaucoma can subsequently develop later in life. Other, often unspecified anterior chamber defects have been reported, such as mild mesenchymal dysgenesis [ Growth hormone deficiency with good response to growth hormone replacement therapy has been reported in some children [ Adult height range is 128-151 cm in females and 141-155 cm in males. A behavioral phenotype has not been well delineated thus far. Cleft lip is present in 45% of individuals and cleft palate in 33%. Ear anomalies, including preauricular pits, are seen in more than one third of affected individuals. A broad neck occurs in approximately 75% of individuals. Congenital heart defects (≤33% of individuals), including atrial septal defect, ventricular septal defect, subvalvular aortic stenosis, pulmonary stenosis, and bicuspid pulmonary valve Genitourinary anomalies (10%-19%) including hydronephrosis, renal and ureteral duplication, renal underdevelopment with oligomeganephroma, multicystic dysplastic kidney [ Structural brain malformations include hypoplasia or agenesis of the corpus callosum, hydrocephalus [ Congenital hypothyroidism; reported in two children with features suggestive of Peters plus syndrome and subsequently described in another affected individual [ Conductive hearing loss; variably present in association with cleft palate but not otherwise a major feature Polyhydramnios occurred in 18.6% of pregnancies of affected children. • Congenital heart defects (≤33% of individuals), including atrial septal defect, ventricular septal defect, subvalvular aortic stenosis, pulmonary stenosis, and bicuspid pulmonary valve • Genitourinary anomalies (10%-19%) including hydronephrosis, renal and ureteral duplication, renal underdevelopment with oligomeganephroma, multicystic dysplastic kidney [ • Structural brain malformations include hypoplasia or agenesis of the corpus callosum, hydrocephalus [ • Congenital hypothyroidism; reported in two children with features suggestive of Peters plus syndrome and subsequently described in another affected individual [ • Conductive hearing loss; variably present in association with cleft palate but not otherwise a major feature ## Genotype-Phenotype Correlations No genotype-phenotype correlation has yet been demonstrated. ## Nomenclature Alternate terms for Peters plus syndrome have included Krause-Kivlin syndrome and Krause-van Schooneveld-Kivlin syndrome. Alternate spellings of Peters plus syndrome include: Peters-plus syndrome, Peters'-plus syndrome, Peters' plus syndrome. ## Prevalence The prevalence of Peters plus syndrome is unknown. About 100 affected individuals of diverse ethnic background have been reported in the literature. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of Peters plus syndrome comprises other conditions with short stature and limb shortening, including the following: Isolated Peters' anomaly (OMIM Fetal alcohol syndrome (FAS). FAS can also be associated with similar facial features and anterior chamber eye anomalies, including Peters' anomaly. Rieger syndrome (OMIM Walker-Warburg syndrome Chromosome imbalances such as a 6p25 microdeletion [ Associated with variants in mendelian acting genes such as The differential diagnosis of Peters plus syndrome also includes other disorders associated with Peters anomaly and intellectual impairment such as agenesis of corpus callosum, cardiac, ocular, and genital syndrome (OMIM • Isolated Peters' anomaly (OMIM • • • • • Fetal alcohol syndrome (FAS). FAS can also be associated with similar facial features and anterior chamber eye anomalies, including Peters' anomaly. • Rieger syndrome (OMIM • Walker-Warburg syndrome • Chromosome imbalances such as a 6p25 microdeletion [ • Associated with variants in mendelian acting genes such as ## Management To establish the extent of disease and needs in an individual diagnosed with Peters plus syndrome, the following evaluations are recommended if they have not already been completed: Complete ophthalmologic assessment including ocular ultrasonography for characterization of the eye anomaly and an assessment for associated ocular defects Growth hormone stimulation testing to address the possibility of a treatable cause of growth delay in those affected individuals in whom increased height would improve quality of life For neonates or infants, referral to an infant development program for appropriate developmental assessment Echocardiography for congenital heart malformations Abdominal ultrasound examination for renal anomalies Cranial imaging with head ultrasound examination or CT scan/MRI for hydrocephalus and/or structural brain abnormalities if neurologic symptoms are present Thyroid function testing in all infants who have not undergone newborn screening for congenital hypothyroidism Hearing assessment in a child with cleft palate or speech delay Consultation with a clinical geneticist and/or genetic counselor Management of amblyopia by a pediatric ophthalmologist is recommended for optimal visual outcome. Congenital glaucoma in association with Peters' anomaly is more difficult to treat than primary infantile glaucoma. Surgery and medical management result in adequate intraocular pressure in only 32%, and associated ophthalmologic issues such as amblyopia or postoperative complications contribute to poor visual results in long-term outcome studies [ The following are appropriate: Assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia Regular developmental assessments Agents that increase risk of glaucoma (e.g., corticosteroids) are to be avoided. See Search • Complete ophthalmologic assessment including ocular ultrasonography for characterization of the eye anomaly and an assessment for associated ocular defects • Growth hormone stimulation testing to address the possibility of a treatable cause of growth delay in those affected individuals in whom increased height would improve quality of life • For neonates or infants, referral to an infant development program for appropriate developmental assessment • Echocardiography for congenital heart malformations • Abdominal ultrasound examination for renal anomalies • Cranial imaging with head ultrasound examination or CT scan/MRI for hydrocephalus and/or structural brain abnormalities if neurologic symptoms are present • Thyroid function testing in all infants who have not undergone newborn screening for congenital hypothyroidism • Hearing assessment in a child with cleft palate or speech delay • Consultation with a clinical geneticist and/or genetic counselor • Assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia • Regular developmental assessments ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Peters plus syndrome, the following evaluations are recommended if they have not already been completed: Complete ophthalmologic assessment including ocular ultrasonography for characterization of the eye anomaly and an assessment for associated ocular defects Growth hormone stimulation testing to address the possibility of a treatable cause of growth delay in those affected individuals in whom increased height would improve quality of life For neonates or infants, referral to an infant development program for appropriate developmental assessment Echocardiography for congenital heart malformations Abdominal ultrasound examination for renal anomalies Cranial imaging with head ultrasound examination or CT scan/MRI for hydrocephalus and/or structural brain abnormalities if neurologic symptoms are present Thyroid function testing in all infants who have not undergone newborn screening for congenital hypothyroidism Hearing assessment in a child with cleft palate or speech delay Consultation with a clinical geneticist and/or genetic counselor • Complete ophthalmologic assessment including ocular ultrasonography for characterization of the eye anomaly and an assessment for associated ocular defects • Growth hormone stimulation testing to address the possibility of a treatable cause of growth delay in those affected individuals in whom increased height would improve quality of life • For neonates or infants, referral to an infant development program for appropriate developmental assessment • Echocardiography for congenital heart malformations • Abdominal ultrasound examination for renal anomalies • Cranial imaging with head ultrasound examination or CT scan/MRI for hydrocephalus and/or structural brain abnormalities if neurologic symptoms are present • Thyroid function testing in all infants who have not undergone newborn screening for congenital hypothyroidism • Hearing assessment in a child with cleft palate or speech delay • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Management of amblyopia by a pediatric ophthalmologist is recommended for optimal visual outcome. Congenital glaucoma in association with Peters' anomaly is more difficult to treat than primary infantile glaucoma. Surgery and medical management result in adequate intraocular pressure in only 32%, and associated ophthalmologic issues such as amblyopia or postoperative complications contribute to poor visual results in long-term outcome studies [ ## Surveillance The following are appropriate: Assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia Regular developmental assessments • Assessment by a pediatric ophthalmologist every three months or as indicated to monitor for glaucoma and amblyopia • Regular developmental assessments ## Agents/Circumstances to Avoid Agents that increase risk of glaucoma (e.g., corticosteroids) are to be avoided. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Peters plus syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. There is an increased chance for miscarriages and second- and third-trimester fetal loss of affected fetuses. Therefore, at birth the risk to a sib of a proband of being affected is less than 25%. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • There is an increased chance for miscarriages and second- and third-trimester fetal loss of affected fetuses. Therefore, at birth the risk to a sib of a proband of being affected is less than 25%. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Peters plus syndrome is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. There is an increased chance for miscarriages and second- and third-trimester fetal loss of affected fetuses. Therefore, at birth the risk to a sib of a proband of being affected is less than 25%. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • There is an increased chance for miscarriages and second- and third-trimester fetal loss of affected fetuses. Therefore, at birth the risk to a sib of a proband of being affected is less than 25%. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources • • • • • • • • • • ## Molecular Genetics Peters Plus Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Peters Plus Syndrome ( Variants listed in the table have been provided by the authors. ## Chapter Notes Gudrun Aubertin, MD, MSc; Children's & Women's Health Centre of British Columbia (2007-2014)Raoul C Hennekam, MD, PhD (2014-present)Marjolein Kriek, MD, PhD; Leiden University Medical Center (2011-2014)Saskia AJ Lesnik Oberstein, MD, PhD (2007-present)Claudia AL Ruivenkamp, PhD (2017-present)Martine van Belzen, PhD; Leiden University Medical Center (2014-2017)Marjan M Weiss, MD, PhD; Leiden University Medical Center (2007-2011) 30 January 2025 (aa) Revision: agenesis of corpus callosum, cardiac, ocular, and genital syndrome added to 24 August 2017 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 8 October 2007 (me) Review posted live 24 July 2007 (ga) Original submission • 30 January 2025 (aa) Revision: agenesis of corpus callosum, cardiac, ocular, and genital syndrome added to • 24 August 2017 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 8 October 2007 (me) Review posted live • 24 July 2007 (ga) Original submission ## Author History Gudrun Aubertin, MD, MSc; Children's & Women's Health Centre of British Columbia (2007-2014)Raoul C Hennekam, MD, PhD (2014-present)Marjolein Kriek, MD, PhD; Leiden University Medical Center (2011-2014)Saskia AJ Lesnik Oberstein, MD, PhD (2007-present)Claudia AL Ruivenkamp, PhD (2017-present)Martine van Belzen, PhD; Leiden University Medical Center (2014-2017)Marjan M Weiss, MD, PhD; Leiden University Medical Center (2007-2011) ## Revision History 30 January 2025 (aa) Revision: agenesis of corpus callosum, cardiac, ocular, and genital syndrome added to 24 August 2017 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 8 October 2007 (me) Review posted live 24 July 2007 (ga) Original submission • 30 January 2025 (aa) Revision: agenesis of corpus callosum, cardiac, ocular, and genital syndrome added to • 24 August 2017 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 8 October 2007 (me) Review posted live • 24 July 2007 (ga) Original submission ## References ## Literature Cited	[]	8/10/2007	24/8/2017	30/1/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pf	pf	[ "H/ACA ribonucleoprotein complex non-core subunit NAF1", "H/ACA ribonucleoprotein complex subunit DKC1", "Not applicable", "Phospholipid-transporting ATPase ABCA3", "Poly(A)-specific ribonuclease PARN", "Pulmonary surfactant-associated protein A1", "Pulmonary surfactant-associated protein A2", "Regulator of telomere elongation helicase 1", "Surfactant protein C", "Telomerase reverse transcriptase", "TERF1-interacting nuclear factor 2", "Zinc finger CCHC domain-containing protein 8", "ABCA3", "DKC1", "NAF1", "PARN", "RTEL1", "SFTPA1", "SFTPA2", "SFTPC", "TERC", "TERT", "TINF2", "ZCCHC8", "Pulmonary Fibrosis Predisposition", "Overview" ]	Pulmonary Fibrosis Predisposition Overview	Christine Kim Garcia, Janet L Talbert	Summary The purpose of this overview is to: Briefly describe the Review genetic Review the Provide an Review Inform	## Clinical Characteristics of Pulmonary Fibrosis Individuals with pulmonary fibrosis typically present with shortness of breath with exertion and a dry cough. Disease onset during adulthood is most common, but onset can range over multiple decades. Most individuals with pulmonary fibrosis have had a history of smoking or fibrogenic environmental exposures [ Dry rales are identified on pulmonary auscultation. Hypoxemia with exertion is usually one of the earliest signs. With disease progression, hypoxemia occurs at rest. Symptoms worsen over time as lung scarring progresses. Later findings include finger clubbing, signs of pulmonary hypertension, and sequelae of right heart failure. Degradation of pulmonary function occurs over time, with progressive decline of forced vital capacity and diffusion capacity. Most individuals die of respiratory causes. Transplant-free survival appears to be lower for individuals with The distribution and extent of specific radiographic features of pulmonary fibrosis can vary, but generally pulmonary fibrosis is characterized by reticulations, traction bronchiectasis, and honeycombing. Individual interstitial lung diseases are associated with different radiographic patterns and features. Radiographic patterns of lung involvement in individuals with certain pathogenic variants may be atypical (see ## Clinical Features of Pulmonary Fibrosis Individuals with pulmonary fibrosis typically present with shortness of breath with exertion and a dry cough. Disease onset during adulthood is most common, but onset can range over multiple decades. Most individuals with pulmonary fibrosis have had a history of smoking or fibrogenic environmental exposures [ Dry rales are identified on pulmonary auscultation. Hypoxemia with exertion is usually one of the earliest signs. With disease progression, hypoxemia occurs at rest. Symptoms worsen over time as lung scarring progresses. Later findings include finger clubbing, signs of pulmonary hypertension, and sequelae of right heart failure. Degradation of pulmonary function occurs over time, with progressive decline of forced vital capacity and diffusion capacity. Most individuals die of respiratory causes. Transplant-free survival appears to be lower for individuals with ## Radiographic Features of Pulmonary Fibrosis The distribution and extent of specific radiographic features of pulmonary fibrosis can vary, but generally pulmonary fibrosis is characterized by reticulations, traction bronchiectasis, and honeycombing. Individual interstitial lung diseases are associated with different radiographic patterns and features. Radiographic patterns of lung involvement in individuals with certain pathogenic variants may be atypical (see ## Genetic Causes of Pulmonary Fibrosis The presence of a genetic cause of predisposition to pulmonary fibrosis can be suggested by family history or by clinical features of a known genetic cause of pulmonary fibrosis (see Idiopathic pulmonary fibrosis (~50% of individuals with FPF) [ Chronic hypersensitivity pneumonitis (~10% of individuals with FPF) [ Progressive pulmonary fibrosis [ Idiopathic interstitial pneumonia (IIP) (e.g., unclassifiable IIP, nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, among others) [ Connective tissue disease-associated ILD, including rheumatoid arthritis ILD and scleroderma ILD [ Drug-induced ILD [ Pulmonary fibrosis and adenocarcinoma of the lung Combined pulmonary fibrosis and emphysema [ Median survival for those with Cigarette smoking and exposures to inhaled agents are frequently reported by individuals with an identified genetic predisposition to pulmonary fibrosis, suggesting that the combination of genetic predisposition and environmental exposures are particularly injurious [ See Predisposition to Pulmonary Fibrosis: Genes and Distinguishing Clinical Features AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PF = pulmonary fibrosis Genes are listed alphabetically. Persons w/predisposition to PF associated with a gene involved in telomere maintenance may have additional features within the spectrum of telomere biology disorders (of which classic Heterozygous females can be variably affected [ Loss-of-function variants in OMIM OMIM OMIM OMIM Individuals with germline pathogenic variants in genes associated with short telomere syndrome, especially those older than age 60 years, may acquire somatic OMIM Pathogenic variants in the surfactant metabolism genes ( OMIM OMIM Syndromes in which Pulmonary Fibrosis is a Common Feature: Genes and Distinguishing Clinical Features AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PF = pulmonary fibrosis; XL = X-linked To date, convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes. • Idiopathic pulmonary fibrosis (~50% of individuals with FPF) [ • Chronic hypersensitivity pneumonitis (~10% of individuals with FPF) [ • Progressive pulmonary fibrosis [ • Idiopathic interstitial pneumonia (IIP) (e.g., unclassifiable IIP, nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, among others) [ • Connective tissue disease-associated ILD, including rheumatoid arthritis ILD and scleroderma ILD [ • Drug-induced ILD [ • Pulmonary fibrosis and adenocarcinoma of the lung • Combined pulmonary fibrosis and emphysema [ ## Suggestive Features of a Genetic Cause of Pulmonary Fibrosis The presence of a genetic cause of predisposition to pulmonary fibrosis can be suggested by family history or by clinical features of a known genetic cause of pulmonary fibrosis (see Idiopathic pulmonary fibrosis (~50% of individuals with FPF) [ Chronic hypersensitivity pneumonitis (~10% of individuals with FPF) [ Progressive pulmonary fibrosis [ Idiopathic interstitial pneumonia (IIP) (e.g., unclassifiable IIP, nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, among others) [ Connective tissue disease-associated ILD, including rheumatoid arthritis ILD and scleroderma ILD [ Drug-induced ILD [ Pulmonary fibrosis and adenocarcinoma of the lung Combined pulmonary fibrosis and emphysema [ • Idiopathic pulmonary fibrosis (~50% of individuals with FPF) [ • Chronic hypersensitivity pneumonitis (~10% of individuals with FPF) [ • Progressive pulmonary fibrosis [ • Idiopathic interstitial pneumonia (IIP) (e.g., unclassifiable IIP, nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, among others) [ • Connective tissue disease-associated ILD, including rheumatoid arthritis ILD and scleroderma ILD [ • Drug-induced ILD [ • Pulmonary fibrosis and adenocarcinoma of the lung • Combined pulmonary fibrosis and emphysema [ ## Prognosis for Those with a Predisposition to Pulmonary Fibrosis Median survival for those with ## Influence of Environmental Exposures Cigarette smoking and exposures to inhaled agents are frequently reported by individuals with an identified genetic predisposition to pulmonary fibrosis, suggesting that the combination of genetic predisposition and environmental exposures are particularly injurious [ ## Pulmonary Fibrosis – Associated Genes and Syndromes See Predisposition to Pulmonary Fibrosis: Genes and Distinguishing Clinical Features AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PF = pulmonary fibrosis Genes are listed alphabetically. Persons w/predisposition to PF associated with a gene involved in telomere maintenance may have additional features within the spectrum of telomere biology disorders (of which classic Heterozygous females can be variably affected [ Loss-of-function variants in OMIM OMIM OMIM OMIM Individuals with germline pathogenic variants in genes associated with short telomere syndrome, especially those older than age 60 years, may acquire somatic OMIM Pathogenic variants in the surfactant metabolism genes ( OMIM OMIM Syndromes in which Pulmonary Fibrosis is a Common Feature: Genes and Distinguishing Clinical Features AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PF = pulmonary fibrosis; XL = X-linked To date, convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes. ## Differential Diagnosis of Pulmonary Fibrosis Fibrogenic environmental exposures, including smoking, radiation, asbestosis, inhaled metal and fine inorganic particulates, coal, bird antigens and droppings, certain organic dusts Inflammation, such as arising from respiratory infections Associated with other medical conditions (sarcoidosis, rheumatoid arthritis, scleroderma, dermatomyositis, connective tissue disorders, immunodeficiency, and others) Medications, especially chemotherapy and antiarrhythmia medications Other Inherited Disorders that Exhibit Diffuse Parenchymal Lung Disease as a Clinical Feature AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; ILD = interstitial lung disease; MOI = mode of inheritance; PF = pulmonary fibrosis • Fibrogenic environmental exposures, including smoking, radiation, asbestosis, inhaled metal and fine inorganic particulates, coal, bird antigens and droppings, certain organic dusts • Inflammation, such as arising from respiratory infections • Associated with other medical conditions (sarcoidosis, rheumatoid arthritis, scleroderma, dermatomyositis, connective tissue disorders, immunodeficiency, and others) • Medications, especially chemotherapy and antiarrhythmia medications ## Evaluation Strategies to Identify the Genetic Cause of Pulmonary Fibrosis in a Proband Establishing a specific genetic cause of pulmonary fibrosis: Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, family history, pulmonary function testing, imaging, lung biopsy, and molecular genetic testing. Note: (1) Telomere length measurement should be offered to individuals with pulmonary fibrosis and extrapulmonary manifestations of a short telomere syndrome (e.g., dyskeratosis congenita; see If the age-adjusted neutrophil or lymphocyte telomere length is <10th percentile, molecular genetic testing of genes associated with a short telomere syndrome should be considered (see If the age-adjusted neutrophil or lymphocyte telomere length is >10th percentile, panels that include surfactant metabolism genes ( Note: Shortened telomeres can be inherited independently of the associated pathogenic variant and result in a clinical phenocopy of the short telomere syndrome in offspring who do not inherit the associated pathogenic variant [ Panels that include genes associated with a short telomere syndrome (e.g., dyskeratosis congenita; see Panels should include Additional gene panels should be considered if there is overlap with clinical features associated with related disorders (see For an introduction to multigene panels click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, family history, pulmonary function testing, imaging, lung biopsy, and molecular genetic testing. • If the age-adjusted neutrophil or lymphocyte telomere length is <10th percentile, molecular genetic testing of genes associated with a short telomere syndrome should be considered (see • If the age-adjusted neutrophil or lymphocyte telomere length is >10th percentile, panels that include surfactant metabolism genes ( • Note: Shortened telomeres can be inherited independently of the associated pathogenic variant and result in a clinical phenocopy of the short telomere syndrome in offspring who do not inherit the associated pathogenic variant [ • Panels that include genes associated with a short telomere syndrome (e.g., dyskeratosis congenita; see • Panels should include • Additional gene panels should be considered if there is overlap with clinical features associated with related disorders (see ## Management of Pulmonary Fibrosis To establish the extent of disease and needs in an individual diagnosed with a predisposition to pulmonary fibrosis, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Predisposition to Pulmonary Fibrosis Clinical history & exam for comorbidities Chest radiograph HRCT scan of chest Pulmonary function studies Eval by pulmonologist, preferably one w/experience in PF FPF = familial pulmonary fibrosis; GERD = gastroesophageal reflux disease; HRCT = high-resolution computed tomography; MOI = mode of inheritance; PF = pulmonary fibrosis Most often associated with pathogenic variants in Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Clinical management of pulmonary fibrosis due to a genetic cause is similar to that for individuals with other causes of fibrotic interstitial lung disease and depends on the subtype of interstitial lung disease. It is recommended that individuals be evaluated by a pulmonologist, preferably one with experience in treating familial pulmonary fibrosis. Treatment of Manifestations in Individuals with Predisposition to Pulmonary Fibrosis In persons w/primarily lung limitations & few manifestations of other organ failure Often an option because most persons w/hereditary PF are age <70 yrs Adjustment of immunosuppressive medication may be required to avoid drug toxicities in those w/hematologic abnormalities. Subclinical bone marrow abnormalities may affect immunosuppression at time of lung transplantation. Cytomegalovirus-related morbidity after lung transplantation has been reported. GERD = gastroesophageal reflux disease; PF = pulmonary fibrosis Treatment with antifibrotic medications (e.g., nintedanib, pirfenidone), was associated with an improved trajectory in lung function (i.e., less forced vital capacity decline) in individuals with short telomere-related pathogenic variants. A European study did not find a difference between the two medications in terms of efficacy [ Recommended Surveillance for Individuals with Predisposition to Pulmonary Fibrosis PFTs: spirometry (incl FVC), plethysmography, & DLCO High-resolution chest CT Oxygen saturation by pulse oximetry at rest & w/exertion (exercise-related hypoxemia precedes development of hypoxemia at rest) 6-MWT distance & oxygen saturation measurements 6-MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; PFT = pulmonary function test It is appropriate to evaluate apparently asymptomatic older and younger first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from avoidance of environmental risks and initiation of antifibrotic medications to slow down the rate of progression of disease in those with early findings of lung fibrosis. Evaluations can include the following: Molecular genetic testing if a molecular diagnosis has been established in the proband If a molecular diagnosis has not been established in the proband but there is a family history of pulmonary fibrosis, the following evaluations are recommended: Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. Every effort should be made to remove and avoid environmental exposures linked to the development of pulmonary fibrosis. Deleterious environmental exposures include but are not limited to: smoking, metal fumes/dust, wood dust, stone and sand particulates, certain agricultural, farming and livestock exposures, bird feather and droppings, aerosolized molds, as well as certain medications including chemotherapeutics, antiarrhythmia agents, and nitrofurantoin. Many therapies are under investigation for the treatment of pulmonary fibrosis. Search • Clinical history & exam for comorbidities • Chest radiograph • HRCT scan of chest • Pulmonary function studies • Eval by pulmonologist, preferably one w/experience in PF • In persons w/primarily lung limitations & few manifestations of other organ failure • Often an option because most persons w/hereditary PF are age <70 yrs • Adjustment of immunosuppressive medication may be required to avoid drug toxicities in those w/hematologic abnormalities. • Subclinical bone marrow abnormalities may affect immunosuppression at time of lung transplantation. • Cytomegalovirus-related morbidity after lung transplantation has been reported. • PFTs: spirometry (incl FVC), plethysmography, & DLCO • High-resolution chest CT • Oxygen saturation by pulse oximetry at rest & w/exertion (exercise-related hypoxemia precedes development of hypoxemia at rest) • 6-MWT distance & oxygen saturation measurements • Molecular genetic testing if a molecular diagnosis has been established in the proband • If a molecular diagnosis has not been established in the proband but there is a family history of pulmonary fibrosis, the following evaluations are recommended: • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a predisposition to pulmonary fibrosis, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Predisposition to Pulmonary Fibrosis Clinical history & exam for comorbidities Chest radiograph HRCT scan of chest Pulmonary function studies Eval by pulmonologist, preferably one w/experience in PF FPF = familial pulmonary fibrosis; GERD = gastroesophageal reflux disease; HRCT = high-resolution computed tomography; MOI = mode of inheritance; PF = pulmonary fibrosis Most often associated with pathogenic variants in Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Clinical history & exam for comorbidities • Chest radiograph • HRCT scan of chest • Pulmonary function studies • Eval by pulmonologist, preferably one w/experience in PF ## Treatment Clinical management of pulmonary fibrosis due to a genetic cause is similar to that for individuals with other causes of fibrotic interstitial lung disease and depends on the subtype of interstitial lung disease. It is recommended that individuals be evaluated by a pulmonologist, preferably one with experience in treating familial pulmonary fibrosis. Treatment of Manifestations in Individuals with Predisposition to Pulmonary Fibrosis In persons w/primarily lung limitations & few manifestations of other organ failure Often an option because most persons w/hereditary PF are age <70 yrs Adjustment of immunosuppressive medication may be required to avoid drug toxicities in those w/hematologic abnormalities. Subclinical bone marrow abnormalities may affect immunosuppression at time of lung transplantation. Cytomegalovirus-related morbidity after lung transplantation has been reported. GERD = gastroesophageal reflux disease; PF = pulmonary fibrosis Treatment with antifibrotic medications (e.g., nintedanib, pirfenidone), was associated with an improved trajectory in lung function (i.e., less forced vital capacity decline) in individuals with short telomere-related pathogenic variants. A European study did not find a difference between the two medications in terms of efficacy [ • In persons w/primarily lung limitations & few manifestations of other organ failure • Often an option because most persons w/hereditary PF are age <70 yrs • Adjustment of immunosuppressive medication may be required to avoid drug toxicities in those w/hematologic abnormalities. • Subclinical bone marrow abnormalities may affect immunosuppression at time of lung transplantation. • Cytomegalovirus-related morbidity after lung transplantation has been reported. ## Surveillance Recommended Surveillance for Individuals with Predisposition to Pulmonary Fibrosis PFTs: spirometry (incl FVC), plethysmography, & DLCO High-resolution chest CT Oxygen saturation by pulse oximetry at rest & w/exertion (exercise-related hypoxemia precedes development of hypoxemia at rest) 6-MWT distance & oxygen saturation measurements 6-MWT = six-minute walk test; DLCO = diffusion capacity of the lung for carbon monoxide; FVC = forced vital capacity; PFT = pulmonary function test • PFTs: spirometry (incl FVC), plethysmography, & DLCO • High-resolution chest CT • Oxygen saturation by pulse oximetry at rest & w/exertion (exercise-related hypoxemia precedes development of hypoxemia at rest) • 6-MWT distance & oxygen saturation measurements ## Agents/Circumstances to Avoid ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from avoidance of environmental risks and initiation of antifibrotic medications to slow down the rate of progression of disease in those with early findings of lung fibrosis. Evaluations can include the following: Molecular genetic testing if a molecular diagnosis has been established in the proband If a molecular diagnosis has not been established in the proband but there is a family history of pulmonary fibrosis, the following evaluations are recommended: Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. Every effort should be made to remove and avoid environmental exposures linked to the development of pulmonary fibrosis. Deleterious environmental exposures include but are not limited to: smoking, metal fumes/dust, wood dust, stone and sand particulates, certain agricultural, farming and livestock exposures, bird feather and droppings, aerosolized molds, as well as certain medications including chemotherapeutics, antiarrhythmia agents, and nitrofurantoin. • Molecular genetic testing if a molecular diagnosis has been established in the proband • If a molecular diagnosis has not been established in the proband but there is a family history of pulmonary fibrosis, the following evaluations are recommended: • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. • Baseline high-resolution chest CT and PFTs for all individuals at age 40 years or ten years before the earliest diagnosis in affected family members • If any abnormality is discovered in a first-degree relative, it is recommended that testing be repeated to determine the durability and progression of findings. Although the frequency of testing has not been established, it is the author's clinical practice to repeat pulmonary function tests (PFTs), oxygen desaturation studies, or six-minute walk testing (6-MWT) every three to 12 months. Frequency of testing depends on symptoms and trend. Repeat PFTs, oxygen desaturation studies, and 6-MWT incur less radiation exposure than repeat chest CTs (see • Telomere length testing can be considered, especially if there is a personal or family history to suggest a short telomere syndrome. ## Therapies under Investigation Many therapies are under investigation for the treatment of pulmonary fibrosis. Search ## Genetic Counseling Almost all germline pathogenic variants known to be associated with predisposition to pulmonary fibrosis (see Genetic counseling for pulmonary fibrosis associated with a pathogenic variant(s) in a gene involved in telomere maintenance (see Note: Individuals with germline pathogenic variants in genes associated with short telomere syndrome, especially those older than age 60 years, may acquire somatic Some individuals diagnosed with predisposition to pulmonary fibrosis inherited a pathogenic variant from an affected parent. Because some genetic causes of pulmonary fibrosis can be associated with anticipation, an affected parent may have a later age of onset than the proband. Alternatively, a proband with predisposition to pulmonary fibrosis may have a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for both parents to ascertain their genetic status and to allow reliable recurrence risk counseling. (Note: Because individuals with predisposition to pulmonary fibrosis are often diagnosed late in the adult years, parental genetic testing is not feasible in many families.) If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with predisposition to pulmonary fibrosis may appear to be negative because of failure to recognize the disorder in affected family members (due to lack of appropriate radiographic imaging) and/or reduced, age-related penetrance (i.e., late onset of the disease in the affected parent or early death of the parent before onset of symptoms). Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (including radiographic imaging) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected or is known to have a pulmonary fibrosis-related pathogenic variant, the risk to the sibs of inheriting the pulmonary fibrosis-related pathogenic variant is 50%. Because predisposition to pulmonary fibrosis is associated with reduced penetrance and intrafamilial clinical variability, the age of onset and clinical manifestations in a sib who inherits a familial pathogenic variant cannot be predicted. In families segregating a pathogenic variant in a gene associated with telomere maintenance (see If the proband has a known pulmonary fibrosis pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for one One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. See Management of Pulmonary Fibrosis, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the pulmonary fibrosis-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by the family history or prenatal molecular genetic testing. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Some individuals diagnosed with predisposition to pulmonary fibrosis inherited a pathogenic variant from an affected parent. Because some genetic causes of pulmonary fibrosis can be associated with anticipation, an affected parent may have a later age of onset than the proband. • Alternatively, a proband with predisposition to pulmonary fibrosis may have a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for both parents to ascertain their genetic status and to allow reliable recurrence risk counseling. (Note: Because individuals with predisposition to pulmonary fibrosis are often diagnosed late in the adult years, parental genetic testing is not feasible in many families.) • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with predisposition to pulmonary fibrosis may appear to be negative because of failure to recognize the disorder in affected family members (due to lack of appropriate radiographic imaging) and/or reduced, age-related penetrance (i.e., late onset of the disease in the affected parent or early death of the parent before onset of symptoms). Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (including radiographic imaging) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected or is known to have a pulmonary fibrosis-related pathogenic variant, the risk to the sibs of inheriting the pulmonary fibrosis-related pathogenic variant is 50%. Because predisposition to pulmonary fibrosis is associated with reduced penetrance and intrafamilial clinical variability, the age of onset and clinical manifestations in a sib who inherits a familial pathogenic variant cannot be predicted. • In families segregating a pathogenic variant in a gene associated with telomere maintenance (see • If the proband has a known pulmonary fibrosis pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for one • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Almost all germline pathogenic variants known to be associated with predisposition to pulmonary fibrosis (see Genetic counseling for pulmonary fibrosis associated with a pathogenic variant(s) in a gene involved in telomere maintenance (see Note: Individuals with germline pathogenic variants in genes associated with short telomere syndrome, especially those older than age 60 years, may acquire somatic ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with predisposition to pulmonary fibrosis inherited a pathogenic variant from an affected parent. Because some genetic causes of pulmonary fibrosis can be associated with anticipation, an affected parent may have a later age of onset than the proband. Alternatively, a proband with predisposition to pulmonary fibrosis may have a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for both parents to ascertain their genetic status and to allow reliable recurrence risk counseling. (Note: Because individuals with predisposition to pulmonary fibrosis are often diagnosed late in the adult years, parental genetic testing is not feasible in many families.) If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with predisposition to pulmonary fibrosis may appear to be negative because of failure to recognize the disorder in affected family members (due to lack of appropriate radiographic imaging) and/or reduced, age-related penetrance (i.e., late onset of the disease in the affected parent or early death of the parent before onset of symptoms). Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (including radiographic imaging) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected or is known to have a pulmonary fibrosis-related pathogenic variant, the risk to the sibs of inheriting the pulmonary fibrosis-related pathogenic variant is 50%. Because predisposition to pulmonary fibrosis is associated with reduced penetrance and intrafamilial clinical variability, the age of onset and clinical manifestations in a sib who inherits a familial pathogenic variant cannot be predicted. In families segregating a pathogenic variant in a gene associated with telomere maintenance (see If the proband has a known pulmonary fibrosis pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • Some individuals diagnosed with predisposition to pulmonary fibrosis inherited a pathogenic variant from an affected parent. Because some genetic causes of pulmonary fibrosis can be associated with anticipation, an affected parent may have a later age of onset than the proband. • Alternatively, a proband with predisposition to pulmonary fibrosis may have a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for both parents to ascertain their genetic status and to allow reliable recurrence risk counseling. (Note: Because individuals with predisposition to pulmonary fibrosis are often diagnosed late in the adult years, parental genetic testing is not feasible in many families.) • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with predisposition to pulmonary fibrosis may appear to be negative because of failure to recognize the disorder in affected family members (due to lack of appropriate radiographic imaging) and/or reduced, age-related penetrance (i.e., late onset of the disease in the affected parent or early death of the parent before onset of symptoms). Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation (including radiographic imaging) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected or is known to have a pulmonary fibrosis-related pathogenic variant, the risk to the sibs of inheriting the pulmonary fibrosis-related pathogenic variant is 50%. Because predisposition to pulmonary fibrosis is associated with reduced penetrance and intrafamilial clinical variability, the age of onset and clinical manifestations in a sib who inherits a familial pathogenic variant cannot be predicted. • In families segregating a pathogenic variant in a gene associated with telomere maintenance (see • If the proband has a known pulmonary fibrosis pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for one One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for one • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Related Genetic Counseling Issues See Management of Pulmonary Fibrosis, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the pulmonary fibrosis-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by the family history or prenatal molecular genetic testing. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources 55 West Wacker Drive Suite 1150 Chicago IL 60601 230 East Ohio Street Suite 500 Chicago IL 60611 • • 55 West Wacker Drive • Suite 1150 • Chicago IL 60601 • • • • • • • • • 230 East Ohio Street • Suite 500 • Chicago IL 60611 • ## Chapter Notes Dr Garcia is the Frode-Jensen Professor of Medicine at Columbia University Irving Medical Center, as well as the Chief of the Division of Pulmonary, Allergy, and Critical Care Medicine, and the Acting Director of the Interstitial Lung Disease Program. She obtained her MD and PhD degrees, as well as completed residency in Internal Medicine and fellowship in Pulmonary and Critical Care Medicine, at the University of Texas Southwestern Medical Center in Dallas. Her laboratory has discovered rare pathogenic variants in several genes ( Janet Talbert earned her Master of Science (MS) in Biophysics and Genetics at the University of Colorado Medical Campus. She became a Diplomate of the American Board of Genetic Counselors (ABGC) in 2009. She is a member of the National Society of Genetic Counselors (NSGC) and the American Board of Genetic Counselors (ABGC). She worked in the Interstitial Lung Disease Program at National Jewish Health from 2003 to 2020 in roles that included oversight of a national familial pulmonary fibrosis genetic study that lead to discovery of several SNPs associated with IPF/FPF, providing genetic counseling services for the institution at large and to patients and families with FPF, genetic services manager (molecular laboratory report writing, provider-to-provider genetic services, and genetic test development) and a genetic advisor to the institution. She was the director of the Familial Pulmonary Fibrosis Genetic Counseling telephone line at National Jewish Health from 2008 to 2020. She serves on the Medical Advisory Board of the Pulmonary Fibrosis Foundation (PFF) and is part of an education outreach Ambassador Program for the PFF. From 2014 to 2015 she worked as faculty at the University of Colorado in the Hereditary Cancer clinic and from 2015 to 2020 at InformedDNA as a Senior Genetic Counselor performing genetic counseling via telehealth to patients nationwide with personal or family histories of cancer, inherited retinal disease, neurologic disorders, and FPF. As of 2021 she is an Associate Faculty member in Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University and Vanderbilt University Medical Center. Christine Kim Garcia, MD, PhD (2021-present)David Schwartz, MD; National Jewish Health (2005-2021)Janet Talbert, MS, CGC (2010-present)Anastasia Wise, PhD; National Jewish Health (2005-2010) 12 May 2022 (aa) Revision: edited information on 11 February 2021 (sw) Comprehensive update posted live; scope changed to overview 19 March 2015 (me) Comprehensive update posted live 19 October 2010 (me) Comprehensive update posted live 11 June 2007 (me) Comprehensive update posted live 21 January 2005 (me) Review posted live 8 April 2004 (ds) Original submission • 12 May 2022 (aa) Revision: edited information on • 11 February 2021 (sw) Comprehensive update posted live; scope changed to overview • 19 March 2015 (me) Comprehensive update posted live • 19 October 2010 (me) Comprehensive update posted live • 11 June 2007 (me) Comprehensive update posted live • 21 January 2005 (me) Review posted live • 8 April 2004 (ds) Original submission ## Author Notes Dr Garcia is the Frode-Jensen Professor of Medicine at Columbia University Irving Medical Center, as well as the Chief of the Division of Pulmonary, Allergy, and Critical Care Medicine, and the Acting Director of the Interstitial Lung Disease Program. She obtained her MD and PhD degrees, as well as completed residency in Internal Medicine and fellowship in Pulmonary and Critical Care Medicine, at the University of Texas Southwestern Medical Center in Dallas. Her laboratory has discovered rare pathogenic variants in several genes ( Janet Talbert earned her Master of Science (MS) in Biophysics and Genetics at the University of Colorado Medical Campus. She became a Diplomate of the American Board of Genetic Counselors (ABGC) in 2009. She is a member of the National Society of Genetic Counselors (NSGC) and the American Board of Genetic Counselors (ABGC). She worked in the Interstitial Lung Disease Program at National Jewish Health from 2003 to 2020 in roles that included oversight of a national familial pulmonary fibrosis genetic study that lead to discovery of several SNPs associated with IPF/FPF, providing genetic counseling services for the institution at large and to patients and families with FPF, genetic services manager (molecular laboratory report writing, provider-to-provider genetic services, and genetic test development) and a genetic advisor to the institution. She was the director of the Familial Pulmonary Fibrosis Genetic Counseling telephone line at National Jewish Health from 2008 to 2020. She serves on the Medical Advisory Board of the Pulmonary Fibrosis Foundation (PFF) and is part of an education outreach Ambassador Program for the PFF. From 2014 to 2015 she worked as faculty at the University of Colorado in the Hereditary Cancer clinic and from 2015 to 2020 at InformedDNA as a Senior Genetic Counselor performing genetic counseling via telehealth to patients nationwide with personal or family histories of cancer, inherited retinal disease, neurologic disorders, and FPF. As of 2021 she is an Associate Faculty member in Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University and Vanderbilt University Medical Center. ## Author History Christine Kim Garcia, MD, PhD (2021-present)David Schwartz, MD; National Jewish Health (2005-2021)Janet Talbert, MS, CGC (2010-present)Anastasia Wise, PhD; National Jewish Health (2005-2010) ## Revision History 12 May 2022 (aa) Revision: edited information on 11 February 2021 (sw) Comprehensive update posted live; scope changed to overview 19 March 2015 (me) Comprehensive update posted live 19 October 2010 (me) Comprehensive update posted live 11 June 2007 (me) Comprehensive update posted live 21 January 2005 (me) Review posted live 8 April 2004 (ds) Original submission • 12 May 2022 (aa) Revision: edited information on • 11 February 2021 (sw) Comprehensive update posted live; scope changed to overview • 19 March 2015 (me) Comprehensive update posted live • 19 October 2010 (me) Comprehensive update posted live • 11 June 2007 (me) Comprehensive update posted live • 21 January 2005 (me) Review posted live • 8 April 2004 (ds) Original submission ## References ## Literature Cited	[]	21/1/2005	11/2/2021	12/5/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pfcp	pfcp	[ "ECYT1", "Familial Erythrocytosis Type 1", "Primary Familial and Congenital Polycythemia", "Familial Erythrocytosis Type 1", "ECYT1", "Primary Familial and Congenital Polycythemia", "Erythropoietin receptor", "EPOR", "Primary Familial and Congenital Polycythemia" ]	Primary Familial and Congenital Erythrocytosis	Josef Prchal	Summary Primary familial and congenital erythrocytosis (PFCE), originally described as primary familial and congenital polycythemia, is characterized by isolated erythrocytosis in an individual with a normal to slightly enlarged spleen and absence of disorders causing secondary erythrocytosis. Clinical manifestations relate to the erythrocytosis and include rubor, and may or may not include hyperviscosity syndrome (headache, dizziness, altered mentation, visual disturbances, tinnitus, paresthesia, fatigue, lassitude, and weakness) and arterial and/or venous thromboembolic events. Although the majority of individuals with PFCE have absence of or only mild manifestations of hyperviscosity syndrome such as headache or dizziness, some affected individuals have severe and even fatal complications including arterial hypertension, coronary artery disease, myocardial infarction, intracerebral hemorrhage, and deep vein thrombosis (DVT). Phlebotomy-induced iron deficiency results in lassitude, impaired intellect, and impaired athletic performance, especially in children. Iron deficiency may also increase the risk of thromboses. Leukocyte count and differential are normal and platelet count tends to be low normal or slightly low due to hemodilution from increased red blood cells and increased whole blood volume. The clinical diagnosis of PFCE can be established in a proband with isolated absolute erythrocytosis, normal serum P PFCE is inherited in an autosomal dominant manner. Many individuals diagnosed with PFCE have an affected parent; a significant proportion of individuals (likely exceeding 10%) have the disorder as the result of a	## Diagnosis Consensus clinical diagnostic criteria for primary familial and congenital erythrocytosis (PFCE) – originally described as primary familial and congenital polycythemia – have been published [ PFCE Absence of marked splenomegaly Absence of cardiac, pulmonary, and kidney disease causing secondary erythrocytosis Rubor Complete blood count that shows isolated absolute erythrocytosis: Normal or mildly decreased platelet counts and normal white cell counts Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ Note: Absolute erythrocytosis is distinct from relative erythrocytosis, caused by severe reduction in plasma volume (e.g., due to diuretics or severe diarrhea). Normal hemoglobin oxygen affinity measured as P Erythropoietin (EPO) serum level that is below normal range (based on laboratory-specific reference values), which excludes secondary erythrocytosis associated with an increased serum EPO level (See Assay of colony-forming unit (CFU) of erythroid progenitors grown in vitro that are hypersensitive to extrinsic EPO [ The clinical diagnosis of PFCE The molecular diagnosis of PFCE Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Familial and Congenital Erythrocytosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Because • Absence of marked splenomegaly • Absence of cardiac, pulmonary, and kidney disease causing secondary erythrocytosis • Rubor • Complete blood count that shows isolated absolute erythrocytosis: • Normal or mildly decreased platelet counts and normal white cell counts • Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. • Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ • Note: Absolute erythrocytosis is distinct from relative erythrocytosis, caused by severe reduction in plasma volume (e.g., due to diuretics or severe diarrhea). • Normal or mildly decreased platelet counts and normal white cell counts • Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. • Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ • Normal hemoglobin oxygen affinity measured as P • Erythropoietin (EPO) serum level that is below normal range (based on laboratory-specific reference values), which excludes secondary erythrocytosis associated with an increased serum EPO level (See • Assay of colony-forming unit (CFU) of erythroid progenitors grown in vitro that are hypersensitive to extrinsic EPO [ • Normal or mildly decreased platelet counts and normal white cell counts • Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. • Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ • For an introduction to multigene panels click ## Suggestive Findings PFCE Absence of marked splenomegaly Absence of cardiac, pulmonary, and kidney disease causing secondary erythrocytosis Rubor Complete blood count that shows isolated absolute erythrocytosis: Normal or mildly decreased platelet counts and normal white cell counts Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ Note: Absolute erythrocytosis is distinct from relative erythrocytosis, caused by severe reduction in plasma volume (e.g., due to diuretics or severe diarrhea). Normal hemoglobin oxygen affinity measured as P Erythropoietin (EPO) serum level that is below normal range (based on laboratory-specific reference values), which excludes secondary erythrocytosis associated with an increased serum EPO level (See Assay of colony-forming unit (CFU) of erythroid progenitors grown in vitro that are hypersensitive to extrinsic EPO [ • Absence of marked splenomegaly • Absence of cardiac, pulmonary, and kidney disease causing secondary erythrocytosis • Rubor • Complete blood count that shows isolated absolute erythrocytosis: • Normal or mildly decreased platelet counts and normal white cell counts • Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. • Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ • Note: Absolute erythrocytosis is distinct from relative erythrocytosis, caused by severe reduction in plasma volume (e.g., due to diuretics or severe diarrhea). • Normal or mildly decreased platelet counts and normal white cell counts • Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. • Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ • Normal hemoglobin oxygen affinity measured as P • Erythropoietin (EPO) serum level that is below normal range (based on laboratory-specific reference values), which excludes secondary erythrocytosis associated with an increased serum EPO level (See • Assay of colony-forming unit (CFU) of erythroid progenitors grown in vitro that are hypersensitive to extrinsic EPO [ • Normal or mildly decreased platelet counts and normal white cell counts • Elevated hemoglobin and hematocrit above the normal reference range (adjusted to age and sex) on at least two occasions. • Note: Hemoglobin and hematocrit can be normal in menstruating females with PFCE [ ## Establishing the Diagnosis The clinical diagnosis of PFCE The molecular diagnosis of PFCE Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Familial and Congenital Erythrocytosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Because • For an introduction to multigene panels click ## Clinical Diagnosis The clinical diagnosis of PFCE ## Molecular diagnosis The molecular diagnosis of PFCE Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Familial and Congenital Erythrocytosis See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Because • For an introduction to multigene panels click ## Clinical Characteristics Primary familial and congenital erythrocytosis (PFCE) – originally described as primary familial and congenital polycythemia – is characterized by isolated erythrocytosis. The clinical manifestations of PFCE include symptoms caused by increased blood viscosity leading to hypoperfusion and local hypoxia and arterial and venous thromboembolic events. To date, PFCE caused by inherited pathogenic variants in No clinically relevant genotype-phenotype correlations have been identified. Penetrance is reduced, but data are insufficient to determine penetrance for PFCE is a rare disorder; the prevalence is not known. To date, PFCE caused by inherited heterozygous pathogenic variants in ## Clinical Description Primary familial and congenital erythrocytosis (PFCE) – originally described as primary familial and congenital polycythemia – is characterized by isolated erythrocytosis. The clinical manifestations of PFCE include symptoms caused by increased blood viscosity leading to hypoperfusion and local hypoxia and arterial and venous thromboembolic events. To date, PFCE caused by inherited pathogenic variants in ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified. ## Penetrance Penetrance is reduced, but data are insufficient to determine penetrance for ## Prevalence PFCE is a rare disorder; the prevalence is not known. To date, PFCE caused by inherited heterozygous pathogenic variants in ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Causes of erythrocytosis to be considered in the differential diagnosis of primary familial and congenital erythrocytosis (PFCE) include acquired primary erythrocytosis and secondary erythrocytosis. Primary erythrocytosis/polycythemia refers to erythrocytosis caused by intrinsic abnormalities of erythroid progenitors that renders them hypersensitive to erythropoietin (EPO) stimulation or EPO independent and associated with decreased EPO. In Events extrinsic to the erythroid compartment (e.g., cardiac or pulmonary insufficiency) that induce hypoxia and increase the production of EPO, resulting in erythrocytosis; Other circulating erythropoiesis-stimulating agents such as cobalt, insulin-like growth factor 1, manganese toxicities, and self-administration of EPO; Genetic disorders such as those listed in For diagnostic algorithms see Genetic Disorders Associated with Secondary Erythrocytosis AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance High oxygen affinity of hemoglobin causes tissue hypoxia. • Primary erythrocytosis/polycythemia refers to erythrocytosis caused by intrinsic abnormalities of erythroid progenitors that renders them hypersensitive to erythropoietin (EPO) stimulation or EPO independent and associated with decreased EPO. In • Events extrinsic to the erythroid compartment (e.g., cardiac or pulmonary insufficiency) that induce hypoxia and increase the production of EPO, resulting in erythrocytosis; • Other circulating erythropoiesis-stimulating agents such as cobalt, insulin-like growth factor 1, manganese toxicities, and self-administration of EPO; • Genetic disorders such as those listed in • Events extrinsic to the erythroid compartment (e.g., cardiac or pulmonary insufficiency) that induce hypoxia and increase the production of EPO, resulting in erythrocytosis; • Other circulating erythropoiesis-stimulating agents such as cobalt, insulin-like growth factor 1, manganese toxicities, and self-administration of EPO; • Genetic disorders such as those listed in • Events extrinsic to the erythroid compartment (e.g., cardiac or pulmonary insufficiency) that induce hypoxia and increase the production of EPO, resulting in erythrocytosis; • Other circulating erythropoiesis-stimulating agents such as cobalt, insulin-like growth factor 1, manganese toxicities, and self-administration of EPO; • Genetic disorders such as those listed in ## Management No clinical practice guidelines for primary familial and congenital erythrocytosis (PFCE) – originally described as primary familial and congenital polycythemia – have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with PFCE, the evaluations summarized in Primary Familial and Congenital Erythrocytosis: Recommended Evaluations Following Initial Diagnosis Headache Dizziness Altered mentation Visual disturbances Tinnitus Paresthesia Low performance Fatigue, lassitude Muscle weakness Eval w/cardiologist Blood pressure measurement Echocardiography MOI = mode of inheritance; PFCE = primary familial and congenital erythrocytosis Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Primary Familial and Congenital Erythrocytosis: Treatment of Manifestations Maintain good hydration. Use DVT precautions in higher-risk situations (e.g., long-distance airline flights). In some persons, anti-hypertensive treatment & phlebotomies are initiated to ↓ symptoms. This should be done only in extreme situations. While low-dose aspirin can be considered for prevention of thromboembolic events, no evidence of efficacy exists. 1 person (a male age 40 yrs) died from myocardial infarction despite regularly performed phlebotomies. Standard treatment for acute thromboembolic event Evaluate for other thrombophilic risk factors. Consider aspirin therapy. Consider life-long anti-coagulation (e.g., heparin, warfarin) when other severe additional risk factors are present or thromboembolic events have recurred. DVT = deep venous thrombosis; PFCE = primary familial and congenital erythrocytosis To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Primary Familial and Congenital Erythrocytosis: Recommended Surveillance Headache Dizziness Altered mentation Visual disturbances Tinnitus Paresthesia Low performance Fatigue, lassitude Muscle weakness Cardiology assessment Blood pressure measurement Echocardiography Plasma lipid panel Hgb A1c In those w/↑ blood pressure, perform 24-hour blood pressure assessment. Avoid the following: Dehydration Any activity that would potentially increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking) Additional cardiovascular risks if possible (e.g., hypertension, hyperlipidemia, diabetes, and obesity) Erythropoesis-stimulating agents It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those with PFCE who would benefit from education regarding treatment for clinical manifestations and Molecular genetic testing if the If the pathogenic variant in the family is not known, blood count and, if hemoglobin and hematocrit are increased, serum erythropoietin concentration. See Although the only survey of pregnancy in women with congenital erythrocytosis did not include any women with an Note: Hematocrit often decreases during pregnancy because of expansion of plasma volume. Search • Headache • Dizziness • Altered mentation • Visual disturbances • Tinnitus • Paresthesia • Low performance • Fatigue, lassitude • Muscle weakness • Eval w/cardiologist • Blood pressure measurement • Echocardiography • Maintain good hydration. • Use DVT precautions in higher-risk situations (e.g., long-distance airline flights). • In some persons, anti-hypertensive treatment & phlebotomies are initiated to ↓ symptoms. This should be done only in extreme situations. • While low-dose aspirin can be considered for prevention of thromboembolic events, no evidence of efficacy exists. 1 person (a male age 40 yrs) died from myocardial infarction despite regularly performed phlebotomies. • Standard treatment for acute thromboembolic event • Evaluate for other thrombophilic risk factors. • Consider aspirin therapy. • Consider life-long anti-coagulation (e.g., heparin, warfarin) when other severe additional risk factors are present or thromboembolic events have recurred. • Headache • Dizziness • Altered mentation • Visual disturbances • Tinnitus • Paresthesia • Low performance • Fatigue, lassitude • Muscle weakness • Cardiology assessment • Blood pressure measurement • Echocardiography • Plasma lipid panel • Hgb A1c • In those w/↑ blood pressure, perform 24-hour blood pressure assessment. • Dehydration • Any activity that would potentially increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking) • Additional cardiovascular risks if possible (e.g., hypertension, hyperlipidemia, diabetes, and obesity) • Erythropoesis-stimulating agents • Molecular genetic testing if the • If the pathogenic variant in the family is not known, blood count and, if hemoglobin and hematocrit are increased, serum erythropoietin concentration. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PFCE, the evaluations summarized in Primary Familial and Congenital Erythrocytosis: Recommended Evaluations Following Initial Diagnosis Headache Dizziness Altered mentation Visual disturbances Tinnitus Paresthesia Low performance Fatigue, lassitude Muscle weakness Eval w/cardiologist Blood pressure measurement Echocardiography MOI = mode of inheritance; PFCE = primary familial and congenital erythrocytosis Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Headache • Dizziness • Altered mentation • Visual disturbances • Tinnitus • Paresthesia • Low performance • Fatigue, lassitude • Muscle weakness • Eval w/cardiologist • Blood pressure measurement • Echocardiography ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Primary Familial and Congenital Erythrocytosis: Treatment of Manifestations Maintain good hydration. Use DVT precautions in higher-risk situations (e.g., long-distance airline flights). In some persons, anti-hypertensive treatment & phlebotomies are initiated to ↓ symptoms. This should be done only in extreme situations. While low-dose aspirin can be considered for prevention of thromboembolic events, no evidence of efficacy exists. 1 person (a male age 40 yrs) died from myocardial infarction despite regularly performed phlebotomies. Standard treatment for acute thromboembolic event Evaluate for other thrombophilic risk factors. Consider aspirin therapy. Consider life-long anti-coagulation (e.g., heparin, warfarin) when other severe additional risk factors are present or thromboembolic events have recurred. DVT = deep venous thrombosis; PFCE = primary familial and congenital erythrocytosis • Maintain good hydration. • Use DVT precautions in higher-risk situations (e.g., long-distance airline flights). • In some persons, anti-hypertensive treatment & phlebotomies are initiated to ↓ symptoms. This should be done only in extreme situations. • While low-dose aspirin can be considered for prevention of thromboembolic events, no evidence of efficacy exists. 1 person (a male age 40 yrs) died from myocardial infarction despite regularly performed phlebotomies. • Standard treatment for acute thromboembolic event • Evaluate for other thrombophilic risk factors. • Consider aspirin therapy. • Consider life-long anti-coagulation (e.g., heparin, warfarin) when other severe additional risk factors are present or thromboembolic events have recurred. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Primary Familial and Congenital Erythrocytosis: Recommended Surveillance Headache Dizziness Altered mentation Visual disturbances Tinnitus Paresthesia Low performance Fatigue, lassitude Muscle weakness Cardiology assessment Blood pressure measurement Echocardiography Plasma lipid panel Hgb A1c In those w/↑ blood pressure, perform 24-hour blood pressure assessment. • Headache • Dizziness • Altered mentation • Visual disturbances • Tinnitus • Paresthesia • Low performance • Fatigue, lassitude • Muscle weakness • Cardiology assessment • Blood pressure measurement • Echocardiography • Plasma lipid panel • Hgb A1c • In those w/↑ blood pressure, perform 24-hour blood pressure assessment. ## Agents/Circumstances to Avoid Avoid the following: Dehydration Any activity that would potentially increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking) Additional cardiovascular risks if possible (e.g., hypertension, hyperlipidemia, diabetes, and obesity) Erythropoesis-stimulating agents • Dehydration • Any activity that would potentially increase blood viscosity (e.g., living or prolonged stay at high altitudes, scuba diving, and smoking) • Additional cardiovascular risks if possible (e.g., hypertension, hyperlipidemia, diabetes, and obesity) • Erythropoesis-stimulating agents ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those with PFCE who would benefit from education regarding treatment for clinical manifestations and Molecular genetic testing if the If the pathogenic variant in the family is not known, blood count and, if hemoglobin and hematocrit are increased, serum erythropoietin concentration. See • Molecular genetic testing if the • If the pathogenic variant in the family is not known, blood count and, if hemoglobin and hematocrit are increased, serum erythropoietin concentration. ## Pregnancy Management Although the only survey of pregnancy in women with congenital erythrocytosis did not include any women with an Note: Hematocrit often decreases during pregnancy because of expansion of plasma volume. ## Therapies Under Investigation Search ## Genetic Counseling Primary familial and congenital erythrocytosis (PFCE) – originally described as primary familial and congenital polycythemia – is inherited in an autosomal dominant manner. Many individuals diagnosed with PFCE have an affected parent. A significant proportion of individuals diagnosed with PFCE (likely exceeding 10%) have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a complete blood count for determination of hemoglobin and – if a molecular diagnosis has been established in the proband – genetic testing for the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have an If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the PFCE-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, because of the clinical variability observed in PFCE even within the same family, molecular genetic test results cannot predict clinical findings or age at diagnosis. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Many individuals diagnosed with PFCE have an affected parent. • A significant proportion of individuals diagnosed with PFCE (likely exceeding 10%) have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a complete blood count for determination of hemoglobin and – if a molecular diagnosis has been established in the proband – genetic testing for the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have an • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Primary familial and congenital erythrocytosis (PFCE) – originally described as primary familial and congenital polycythemia – is inherited in an autosomal dominant manner. ## Risk to Family Members Many individuals diagnosed with PFCE have an affected parent. A significant proportion of individuals diagnosed with PFCE (likely exceeding 10%) have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a complete blood count for determination of hemoglobin and – if a molecular diagnosis has been established in the proband – genetic testing for the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have an If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism. • Many individuals diagnosed with PFCE have an affected parent. • A significant proportion of individuals diagnosed with PFCE (likely exceeding 10%) have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include a complete blood count for determination of hemoglobin and – if a molecular diagnosis has been established in the proband – genetic testing for the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have an • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the PFCE-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, because of the clinical variability observed in PFCE even within the same family, molecular genetic test results cannot predict clinical findings or age at diagnosis. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics Primary Familial and Congenital Erythrocytosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Primary Familial and Congenital Erythrocytosis ( Following phosphorylation of EPOR, a number of other signal transduction proteins also become phosphorylated, and initiation of the signal transduction pathways occurs. One such signal transducer and activator of transcription, the protein STAT5, binds to phosphorylated tyrosine present on the cytoplasmic tail of EPOR and itself becomes phosphorylated at the level of tyrosine residues [ Control of intensity and duration of EPO-EPOR signaling is necessary to tightly regulate erythropoiesis. A ubiquitin/proteasome system plays the major role in the control of EPOR signaling. After EPO binding, EPOR is ubiquitinated and the intracellular part is degraded by the proteasome, preventing further signal transduction. The remaining part of the receptor and associated EPO are internalized and degraded by the lysosomes [ Pathogenic variants in the cytoplasmic portion of EPOR identified in persons with primary familial and congenital erythrocytosis (PFCE) result in truncated EPORs lacking the cytoplasmic COOH-terminal of the receptor, which contains a negative regulatory domain and is essential in SHP-1 phosphatase binding (a negative regulator of EPOR signaling). Most A new mechanism of augmented erythropoiesis and EPO signaling was elucidated in a study of Subsequent erythrocytosis and increased tissue oxygen delivery is detected by hypoxia-sensing mechanisms, leading to low levels of EPO. The lack of downregulation of EPOR after ligand binding results in prolonged and increased proliferation rates due to the prolonged activation of JAK2-STAT5 signaling and other signaling cascades and is responsible for the EPO hypersensitivity of erythroid progenitors observed in vitro in persons with PFCE [ Iron-restricted anemias exhibit resistance to EPO, characterized by selective impairment of proliferation and differentiation while maintaining cell viability. Iron deficiency decreases the surface expression of EPOR on progenitor cells; however, survival signaling through Akt remains intact, enabling cells to survive despite reduced proliferative capacity [ Using epidermal growth factor receptor-EPOR chimeras, Variants listed in the table have been provided by the author. ## Molecular Pathogenesis Following phosphorylation of EPOR, a number of other signal transduction proteins also become phosphorylated, and initiation of the signal transduction pathways occurs. One such signal transducer and activator of transcription, the protein STAT5, binds to phosphorylated tyrosine present on the cytoplasmic tail of EPOR and itself becomes phosphorylated at the level of tyrosine residues [ Control of intensity and duration of EPO-EPOR signaling is necessary to tightly regulate erythropoiesis. A ubiquitin/proteasome system plays the major role in the control of EPOR signaling. After EPO binding, EPOR is ubiquitinated and the intracellular part is degraded by the proteasome, preventing further signal transduction. The remaining part of the receptor and associated EPO are internalized and degraded by the lysosomes [ Pathogenic variants in the cytoplasmic portion of EPOR identified in persons with primary familial and congenital erythrocytosis (PFCE) result in truncated EPORs lacking the cytoplasmic COOH-terminal of the receptor, which contains a negative regulatory domain and is essential in SHP-1 phosphatase binding (a negative regulator of EPOR signaling). Most A new mechanism of augmented erythropoiesis and EPO signaling was elucidated in a study of Subsequent erythrocytosis and increased tissue oxygen delivery is detected by hypoxia-sensing mechanisms, leading to low levels of EPO. The lack of downregulation of EPOR after ligand binding results in prolonged and increased proliferation rates due to the prolonged activation of JAK2-STAT5 signaling and other signaling cascades and is responsible for the EPO hypersensitivity of erythroid progenitors observed in vitro in persons with PFCE [ Iron-restricted anemias exhibit resistance to EPO, characterized by selective impairment of proliferation and differentiation while maintaining cell viability. Iron deficiency decreases the surface expression of EPOR on progenitor cells; however, survival signaling through Akt remains intact, enabling cells to survive despite reduced proliferative capacity [ Using epidermal growth factor receptor-EPOR chimeras, Variants listed in the table have been provided by the author. ## Chapter Notes Celeste Bento, PhD; Centro Hospitalar e Universitário de Coimbra (2016-2025)Holger Cario, MD; University Medical Center Ulm (2016-2025)Mary Frances McMullin, MD; Queens University (2016-2025)Melanie Percy, PhD; Belfast City Hospital (2016-2025)Josef Prchal, MD (2025-present) 23 January 2025 (sw) Comprehensive update posted live 10 November 2016 (bp) Review posted live 21 October 2015 (ch) Original submission • 23 January 2025 (sw) Comprehensive update posted live • 10 November 2016 (bp) Review posted live • 21 October 2015 (ch) Original submission ## Author History Celeste Bento, PhD; Centro Hospitalar e Universitário de Coimbra (2016-2025)Holger Cario, MD; University Medical Center Ulm (2016-2025)Mary Frances McMullin, MD; Queens University (2016-2025)Melanie Percy, PhD; Belfast City Hospital (2016-2025)Josef Prchal, MD (2025-present) ## Revision History 23 January 2025 (sw) Comprehensive update posted live 10 November 2016 (bp) Review posted live 21 October 2015 (ch) Original submission • 23 January 2025 (sw) Comprehensive update posted live • 10 November 2016 (bp) Review posted live • 21 October 2015 (ch) Original submission ## References ## Literature Cited	[]	10/11/2016	23/1/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pfic	pfic	[ "FIC1 Deficiency", "FIC1 Deficiency", "Severe ATP8B1 Deficiency (Progressive Familial Intrahepatic Cholestasis Type 1 [PFIC1])", "Mild-to-Moderate ATP8B1 Deficiency (Benign Recurrent Intrahepatic Cholestasis 1 [BRIC1])", "Phospholipid-transporting ATPase IC", "ATP8B1", "ATP8B1 Deficiency" ]	ATP8B1 Deficiency	Laura N Bull, Raffaella Morotti, James E Squires	Summary The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. The diagnosis of ATP8B1 deficiency is established in a proband with suggestive clinical and laboratory findings and biallelic pathogenic variants in ATP8B1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Severe ATP8B1 deficiency (progressive familial intrahepatic cholestasis type 1 [PFIC1]) Mild-to-moderate ATP8B1 deficiency (benign recurrent intrahepatic cholestasis 1 [BRIC1]) For synonyms and outdated names see • Severe ATP8B1 deficiency (progressive familial intrahepatic cholestasis type 1 [PFIC1]) • Mild-to-moderate ATP8B1 deficiency (benign recurrent intrahepatic cholestasis 1 [BRIC1]) ## Diagnosis No consensus clinical diagnostic criteria for ATP8B1 deficiency have been published. ATP8B1 deficiency While mild-to-moderate and severe phenotype classifications have been proposed, ATP8B1 deficiency occurs along a continuous spectrum of severity. Jaundice Clinically significant diarrhea Failure to thrive Hemorrhage (due to the coagulopathy of vitamin K deficiency) Hepatosplenomegaly Pruritus Discolored and/or pale stools The first episode of cholestasis in infancy may herald disease anywhere along the phenotypic continuum, including subsequent cirrhosis and end-stage liver disease or liver disease that appears likely to evolve to end stage if untreated. Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only. Age at onset of the first episode of cholestasis, the length of episodes, and the duration of disease-free intervals between episodes vary greatly. "Benign" generally refers to lack of progressive liver disease; however, this may be a misnomer as quality of life and other health-related manifestations may be affected. Also, some individuals who initially experience episodic manifestations may eventually develop progressive liver disease. Cholestasis as manifest by conjugated or direct hyperbilirubinemia and/or hypercholanemia in the setting of normal to low gamma-glutamyltranspeptidase (γ-GT) for age suggests ATP8B1 deficiency. Note: Conjugated bilirubin levels may not be an accurate marker of cholestasis. Serum γ-GT activity is low to normal despite conjugated hyperbilirubinemia and/or severe pruritus. Note: Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called "low-γ-GT cholestasis." Serum concentration of cholesterol is usually not elevated (an unusual finding in cholestasis). Serum concentration of total bile acids is elevated, often markedly so [ Serum Studies Consistent with ATP8B1 Deficiency HDL = high density lipoprotein; LDL = low density lipoprotein; γ-GT = gamma-glutamyltranspeptidase; nl = normal Usually elevated in cholestatic liver disease. May be elevated at onset or at resolution of an episode of cholestasis. Detailed study of one individual with mild ATP8B1 deficiency demonstrated low HDL and other lipid abnormalities during a bout of cholestasis [ Liver biopsy in the acute diagnosis and management of an infant with cholestasis helps to distinguish between biliary obstruction (including biliary atresia) and other possible diagnoses such as genetic disorders resulting in cholestasis. Family history is consistent with The diagnosis of ATP8B1 deficiency Note: Identification of biallelic Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ATP8B1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Jaundice • Clinically significant diarrhea • Failure to thrive • Hemorrhage (due to the coagulopathy of vitamin K deficiency) • Hepatosplenomegaly • Pruritus • Discolored and/or pale stools • Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only. • Age at onset of the first episode of cholestasis, the length of episodes, and the duration of disease-free intervals between episodes vary greatly. • "Benign" generally refers to lack of progressive liver disease; however, this may be a misnomer as quality of life and other health-related manifestations may be affected. Also, some individuals who initially experience episodic manifestations may eventually develop progressive liver disease. • Serum γ-GT activity is low to normal despite conjugated hyperbilirubinemia and/or severe pruritus. • Note: Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called "low-γ-GT cholestasis." • Serum concentration of cholesterol is usually not elevated (an unusual finding in cholestasis). • Serum concentration of total bile acids is elevated, often markedly so [ ## Suggestive Findings ATP8B1 deficiency While mild-to-moderate and severe phenotype classifications have been proposed, ATP8B1 deficiency occurs along a continuous spectrum of severity. Jaundice Clinically significant diarrhea Failure to thrive Hemorrhage (due to the coagulopathy of vitamin K deficiency) Hepatosplenomegaly Pruritus Discolored and/or pale stools The first episode of cholestasis in infancy may herald disease anywhere along the phenotypic continuum, including subsequent cirrhosis and end-stage liver disease or liver disease that appears likely to evolve to end stage if untreated. Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only. Age at onset of the first episode of cholestasis, the length of episodes, and the duration of disease-free intervals between episodes vary greatly. "Benign" generally refers to lack of progressive liver disease; however, this may be a misnomer as quality of life and other health-related manifestations may be affected. Also, some individuals who initially experience episodic manifestations may eventually develop progressive liver disease. Cholestasis as manifest by conjugated or direct hyperbilirubinemia and/or hypercholanemia in the setting of normal to low gamma-glutamyltranspeptidase (γ-GT) for age suggests ATP8B1 deficiency. Note: Conjugated bilirubin levels may not be an accurate marker of cholestasis. Serum γ-GT activity is low to normal despite conjugated hyperbilirubinemia and/or severe pruritus. Note: Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called "low-γ-GT cholestasis." Serum concentration of cholesterol is usually not elevated (an unusual finding in cholestasis). Serum concentration of total bile acids is elevated, often markedly so [ Serum Studies Consistent with ATP8B1 Deficiency HDL = high density lipoprotein; LDL = low density lipoprotein; γ-GT = gamma-glutamyltranspeptidase; nl = normal Usually elevated in cholestatic liver disease. May be elevated at onset or at resolution of an episode of cholestasis. Detailed study of one individual with mild ATP8B1 deficiency demonstrated low HDL and other lipid abnormalities during a bout of cholestasis [ Liver biopsy in the acute diagnosis and management of an infant with cholestasis helps to distinguish between biliary obstruction (including biliary atresia) and other possible diagnoses such as genetic disorders resulting in cholestasis. Family history is consistent with • Jaundice • Clinically significant diarrhea • Failure to thrive • Hemorrhage (due to the coagulopathy of vitamin K deficiency) • Hepatosplenomegaly • Pruritus • Discolored and/or pale stools • Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only. • Age at onset of the first episode of cholestasis, the length of episodes, and the duration of disease-free intervals between episodes vary greatly. • "Benign" generally refers to lack of progressive liver disease; however, this may be a misnomer as quality of life and other health-related manifestations may be affected. Also, some individuals who initially experience episodic manifestations may eventually develop progressive liver disease. • Serum γ-GT activity is low to normal despite conjugated hyperbilirubinemia and/or severe pruritus. • Note: Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called "low-γ-GT cholestasis." • Serum concentration of cholesterol is usually not elevated (an unusual finding in cholestasis). • Serum concentration of total bile acids is elevated, often markedly so [ ## Clinical Findings Jaundice Clinically significant diarrhea Failure to thrive Hemorrhage (due to the coagulopathy of vitamin K deficiency) Hepatosplenomegaly Pruritus Discolored and/or pale stools The first episode of cholestasis in infancy may herald disease anywhere along the phenotypic continuum, including subsequent cirrhosis and end-stage liver disease or liver disease that appears likely to evolve to end stage if untreated. Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only. Age at onset of the first episode of cholestasis, the length of episodes, and the duration of disease-free intervals between episodes vary greatly. "Benign" generally refers to lack of progressive liver disease; however, this may be a misnomer as quality of life and other health-related manifestations may be affected. Also, some individuals who initially experience episodic manifestations may eventually develop progressive liver disease. • Jaundice • Clinically significant diarrhea • Failure to thrive • Hemorrhage (due to the coagulopathy of vitamin K deficiency) • Hepatosplenomegaly • Pruritus • Discolored and/or pale stools • Episodes of cholestasis typically involve jaundice and pruritus; however, milder episodes may include pruritus only. • Age at onset of the first episode of cholestasis, the length of episodes, and the duration of disease-free intervals between episodes vary greatly. • "Benign" generally refers to lack of progressive liver disease; however, this may be a misnomer as quality of life and other health-related manifestations may be affected. Also, some individuals who initially experience episodic manifestations may eventually develop progressive liver disease. ## Preliminary Laboratory Findings Cholestasis as manifest by conjugated or direct hyperbilirubinemia and/or hypercholanemia in the setting of normal to low gamma-glutamyltranspeptidase (γ-GT) for age suggests ATP8B1 deficiency. Note: Conjugated bilirubin levels may not be an accurate marker of cholestasis. Serum γ-GT activity is low to normal despite conjugated hyperbilirubinemia and/or severe pruritus. Note: Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called "low-γ-GT cholestasis." Serum concentration of cholesterol is usually not elevated (an unusual finding in cholestasis). Serum concentration of total bile acids is elevated, often markedly so [ Serum Studies Consistent with ATP8B1 Deficiency HDL = high density lipoprotein; LDL = low density lipoprotein; γ-GT = gamma-glutamyltranspeptidase; nl = normal Usually elevated in cholestatic liver disease. May be elevated at onset or at resolution of an episode of cholestasis. Detailed study of one individual with mild ATP8B1 deficiency demonstrated low HDL and other lipid abnormalities during a bout of cholestasis [ • Serum γ-GT activity is low to normal despite conjugated hyperbilirubinemia and/or severe pruritus. • Note: Because γ-GT activity is elevated in most types of cholestasis, forms of cholestasis in which γ-GT is not elevated are called "low-γ-GT cholestasis." • Serum concentration of cholesterol is usually not elevated (an unusual finding in cholestasis). • Serum concentration of total bile acids is elevated, often markedly so [ ## Liver Biopsy Liver biopsy in the acute diagnosis and management of an infant with cholestasis helps to distinguish between biliary obstruction (including biliary atresia) and other possible diagnoses such as genetic disorders resulting in cholestasis. ## Family History Family history is consistent with ## Establishing the Diagnosis The diagnosis of ATP8B1 deficiency Note: Identification of biallelic Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ATP8B1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ATP8B1 Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and death. Mild-to-moderate ATP8B1 deficiency was initially thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis; however, some persons with clinically diagnosed mild disease have hepatic fibrosis on biopsy. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis) [ Family members with the same Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. While onset in the first year of life with progression to cirrhosis by the end of the first decade of life is typical in severe ATP8B1 deficiency, both interfamilial and intrafamilial variability have been noted among affected individuals with the same pathogenic variants [ In truly mild disease, chronic liver damage does not develop; however, in some individuals in whom ATP8B1 deficiency initially appears mild, clinical monitoring over time or detection of fibrosis on liver biopsy may indicate disease of moderate severity [ See ATP8B1 Deficiency: Comparison of Phenotypes by Select Features Post-transplantation steatohepatitis may also occur, and may evolve into cirrhosis [ Resistance to parathyroid hormone [ Kidney stones or acute renal failure [ Delayed puberty [ Epistaxis in the absence of a coagulopathy or thrombocytopenia Nail dystrophy [ Obligate heterozygotes for an Disease severity generally correlates with variant type: Pathogenic variants likely to severely impair ATP8B1 structure and/or function (e.g., nonsense and frameshift variants and large deletions) are more often found in individuals with severe disease. Missense variants, which may have a lesser effect on ATP8B1 structure/function, are found more commonly in individuals with mild disease [ The The In this review, the term "ATP8B1 deficiency" is used to encompass the full phenotypic spectrum ranging from severe ATP8B1 deficiency to intermediate to mild ATP8B1 deficiency. Phenotype-based nomenclature: progressive familial intrahepatic cholestasis (PFIC) Phenotype and locus-based nomenclature: progressive familial intrahepatic cholestasis type 1 (PFIC1) or severe familial intrahepatic cholestasis 1 (FIC1) deficiency Ethnicity-based nomenclature: Byler disease (refers to severe ATP8B1 deficiency in individuals of Amish ancestry [ Collectively, the estimated prevalence for all progressive familial intrahepatic cholestasis (PFIC) disorders accompanied by high serum gamma-glutamyltranspeptidase (γ-GT) levels and, in individuals with biallelic First described as Byler disease in children of Amish descent [ Carrier frequencies for ATP8B1 deficiency are unknown, except in the Greenland Inuit in whom the carrier frequency of the pathogenic variant • Resistance to parathyroid hormone [ • Kidney stones or acute renal failure [ • Delayed puberty [ • Epistaxis in the absence of a coagulopathy or thrombocytopenia • Nail dystrophy [ • Pathogenic variants likely to severely impair ATP8B1 structure and/or function (e.g., nonsense and frameshift variants and large deletions) are more often found in individuals with severe disease. • Missense variants, which may have a lesser effect on ATP8B1 structure/function, are found more commonly in individuals with mild disease [ • The • The • Phenotype-based nomenclature: progressive familial intrahepatic cholestasis (PFIC) • Phenotype and locus-based nomenclature: progressive familial intrahepatic cholestasis type 1 (PFIC1) or severe familial intrahepatic cholestasis 1 (FIC1) deficiency • Ethnicity-based nomenclature: Byler disease (refers to severe ATP8B1 deficiency in individuals of Amish ancestry [ ## Clinical Description ATP8B1 deficiency encompasses a phenotypic spectrum ranging from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and death. Mild-to-moderate ATP8B1 deficiency was initially thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis; however, some persons with clinically diagnosed mild disease have hepatic fibrosis on biopsy. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis) [ Family members with the same Secondary manifestations such as coagulopathy (due to vitamin K deficiency), malabsorption, and poor weight gain may present earlier than age three months. While onset in the first year of life with progression to cirrhosis by the end of the first decade of life is typical in severe ATP8B1 deficiency, both interfamilial and intrafamilial variability have been noted among affected individuals with the same pathogenic variants [ In truly mild disease, chronic liver damage does not develop; however, in some individuals in whom ATP8B1 deficiency initially appears mild, clinical monitoring over time or detection of fibrosis on liver biopsy may indicate disease of moderate severity [ See ATP8B1 Deficiency: Comparison of Phenotypes by Select Features Post-transplantation steatohepatitis may also occur, and may evolve into cirrhosis [ Resistance to parathyroid hormone [ Kidney stones or acute renal failure [ Delayed puberty [ Epistaxis in the absence of a coagulopathy or thrombocytopenia Nail dystrophy [ Obligate heterozygotes for an • Resistance to parathyroid hormone [ • Kidney stones or acute renal failure [ • Delayed puberty [ • Epistaxis in the absence of a coagulopathy or thrombocytopenia • Nail dystrophy [ ## Manifesting Heterozygotes Obligate heterozygotes for an ## Genotype-Phenotype Correlations Disease severity generally correlates with variant type: Pathogenic variants likely to severely impair ATP8B1 structure and/or function (e.g., nonsense and frameshift variants and large deletions) are more often found in individuals with severe disease. Missense variants, which may have a lesser effect on ATP8B1 structure/function, are found more commonly in individuals with mild disease [ The The • Pathogenic variants likely to severely impair ATP8B1 structure and/or function (e.g., nonsense and frameshift variants and large deletions) are more often found in individuals with severe disease. • Missense variants, which may have a lesser effect on ATP8B1 structure/function, are found more commonly in individuals with mild disease [ • The • The ## Nomenclature In this review, the term "ATP8B1 deficiency" is used to encompass the full phenotypic spectrum ranging from severe ATP8B1 deficiency to intermediate to mild ATP8B1 deficiency. Phenotype-based nomenclature: progressive familial intrahepatic cholestasis (PFIC) Phenotype and locus-based nomenclature: progressive familial intrahepatic cholestasis type 1 (PFIC1) or severe familial intrahepatic cholestasis 1 (FIC1) deficiency Ethnicity-based nomenclature: Byler disease (refers to severe ATP8B1 deficiency in individuals of Amish ancestry [ • Phenotype-based nomenclature: progressive familial intrahepatic cholestasis (PFIC) • Phenotype and locus-based nomenclature: progressive familial intrahepatic cholestasis type 1 (PFIC1) or severe familial intrahepatic cholestasis 1 (FIC1) deficiency • Ethnicity-based nomenclature: Byler disease (refers to severe ATP8B1 deficiency in individuals of Amish ancestry [ ## Prevalence Collectively, the estimated prevalence for all progressive familial intrahepatic cholestasis (PFIC) disorders accompanied by high serum gamma-glutamyltranspeptidase (γ-GT) levels and, in individuals with biallelic First described as Byler disease in children of Amish descent [ Carrier frequencies for ATP8B1 deficiency are unknown, except in the Greenland Inuit in whom the carrier frequency of the pathogenic variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Autosomal Recessive Pediatric Cholestatic Liver Disorders with Low or Normal Serum γ-GT Levels in the Differential Diagnosis of ATP8B1 Deficiency Bland canalicular cholestasis Coarsely granular canalicular bile Cholesterol concentrations usually not ↑ Often marked ↑ of total bile acids Modest ↑ of transaminases Primary manifestations are limited to the liver. Hepatobiliary malignancy (HCC & cholangiocarcinoma) in childhood High incidence of gallstones Giant cell transformation & necrosis of hepatocytes Bile pigment accumulation in hepatocytes & in lumina of bile canaliculi Ultrastructural study of canalicular bile does not identify coarse granularity. Expression of ectoenzymes (e.g., γ-GT) along canalicular walls ABCB11 expression is often deficient. Transaminase activity values are higher in ABCB11 deficiency (than in ATP8B1 deficiency). Albumin, bile acid, & AFP concentrations tend to be higher in severe ABCB11 deficiency. Giant cell change Hepatocellular & canalicular cholestasis Poor expression of γ-GT along bile canaliculi Intralobular cholestasis Ductular reaction Giant cell transformation Intralobular cholestasis Giant cell transformation Fibrotic changes Ductular reaction Ultrastructural changes may incl elongated hepatocyte-hepatocyte tight junctions Adapted from AFP = alphafetoprotein; HCC = hepatocellular carcinoma; PFIC = progressive familial intrahepatic cholestasis; γ-GT = gamma-glutamyltranspeptidase Extrahepatic disease manifestations are less common in ABCB11 deficiency than in ATP8B1 deficiency. For example, while gallstone disease is more common in children with severe ABCB11 deficiency than in those with severe ATP8B1 deficiency, children with ATP8B1 deficiency appear more likely to manifest hearing loss, pancreatic disease, diarrhea, rickets, and poor growth [ Malignancy is not a reported feature of ATP8B1 deficiency. ABCB11 is usually well expressed along bile canaliculi in ATP8B1 deficiency. • Bland canalicular cholestasis • Coarsely granular canalicular bile • Cholesterol concentrations usually not ↑ • Often marked ↑ of total bile acids • Modest ↑ of transaminases • Primary manifestations are limited to the liver. • Hepatobiliary malignancy (HCC & cholangiocarcinoma) in childhood • High incidence of gallstones • Giant cell transformation & necrosis of hepatocytes • Bile pigment accumulation in hepatocytes & in lumina of bile canaliculi • Ultrastructural study of canalicular bile does not identify coarse granularity. • Expression of ectoenzymes (e.g., γ-GT) along canalicular walls • ABCB11 expression is often deficient. • Transaminase activity values are higher in ABCB11 deficiency (than in ATP8B1 deficiency). • Albumin, bile acid, & AFP concentrations tend to be higher in severe ABCB11 deficiency. • Giant cell change • Hepatocellular & canalicular cholestasis • Poor expression of γ-GT along bile canaliculi • Intralobular cholestasis • Ductular reaction • Giant cell transformation • Intralobular cholestasis • Giant cell transformation • Fibrotic changes • Ductular reaction • Ultrastructural changes may incl elongated hepatocyte-hepatocyte tight junctions ## Management Clinical practice guidelines for ATP8B1 deficiency have not been published. To establish the extent of disease and needs in an individual diagnosed with ATP8B1 deficiency, all possible manifestations of this disorder (if not addressed as part of the evaluation that led to the diagnosis) should be included in the initial evaluation. See Recommended Evaluations Following Initial Diagnosis in Individuals with ATP8B1 Deficiency Standard biochemical assays of hepatocellular function & hepatobiliary injury Liver imaging Liver biopsy if indicated by imaging studies &/or biochemical assays Assess for portal hypertension. Consider use of clinical tools to quantify itch. Consider serum bile acid quantification. Specific focus on diarrhea Review of growth parameters Consider measurements of mid-arm circumference. Use of Need for social work involvement for parental support. MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with ATP8B1 Deficiency Can incl partial/total external diversion, partial/total internal diversion, or ileal exclusion Primary surgical therapy; can ↓ pruritus & slow or reverse progression to hepatic fibrosis Consider LTX if cirrhosis is present. In some LTX constitutes definitive therapy; in others secretory diarrhea in absence of steatorrhea continues or worsens after LTX Consideration of diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis Relatively ineffective & do not alter progression to end-stage liver disease. Future efforts focusing on real-world experience w/recently FDA-approved IBAT inhibitors are needed. Bile acid chelators Clonidine has palliated diarrhea after LTX in some persons. Consider diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis. May prevent &/or treat growth failure Nasogastric tube feeding has been helpful in some. May not be responsive to LTX Preparations of vitamin E (e.g., tocopheryl polyethylene glycol-1000 succinate) are useful in severe cholestasis. Vitamin K administration in newborn period (1st 28 days of life) is essential. Supportive care for acute pancreatitis episodes Replacement therapy for insufficiency if documented IBAT = ileal bile acid transporter; LTX = liver transplantation; UDCA = ursodeoxycholic acid In partial external biliary diversion the gallbladder apex is anastomosed to one end of a segment of bowel while the other end is used to create a cutaneous stoma from which bile is then drained and discarded, thus, interrupting the enterohepatic circulation of bile acids and reducing pruritus. Recommended Surveillance for Individuals with ATP8B1 Deficiency Standard biochemical assays of hepatocellular function & of hepatobiliary injury Liver imaging Liver biopsy if indicated by imaging studies &/or biochemical assays Assess for portal hypertension. Consider use of clinical tools to quantify itching. Consider serum bile acid quantification. Specific focus on diarrhea Review of growth parameters Consider measurements of mid-arm circumference. Standard biochemical assays Consider dedicated pancreatic imaging if concern. SNHL = sensorineural hearing loss Note: Monitoring for hepatobiliary malignancy has not been shown to be necessary in ATP8B1 deficiency. Susceptibility to sensorineural hearing loss in ATP8B1 deficiency may argue against use of aminoglycoside antibiotics or other potentially ototoxic agents. Oral contraceptive therapy can induce and/or exacerbate episodes of cholestasis. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, surveillance, and awareness of See Cystic fibrosis transmembrane conductance regulator corrector compounds improved trafficking of mutated ATP8B1 protein in cell culture studies [ Ileal bile acid transporter inhibitors have shown reduction in bile acid levels and reduced pruritus in children; various clinical trials are underway [ Search • Standard biochemical assays of hepatocellular function & hepatobiliary injury • Liver imaging • Liver biopsy if indicated by imaging studies &/or biochemical assays • Assess for portal hypertension. • Consider use of clinical tools to quantify itch. • Consider serum bile acid quantification. • Specific focus on diarrhea • Review of growth parameters • Consider measurements of mid-arm circumference. • Use of • Need for social work involvement for parental support. • Can incl partial/total external diversion, partial/total internal diversion, or ileal exclusion • Primary surgical therapy; can ↓ pruritus & slow or reverse progression to hepatic fibrosis • Consider LTX if cirrhosis is present. • In some LTX constitutes definitive therapy; in others secretory diarrhea in absence of steatorrhea continues or worsens after LTX • Consideration of diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis • Relatively ineffective & do not alter progression to end-stage liver disease. • Future efforts focusing on real-world experience w/recently FDA-approved IBAT inhibitors are needed. • Bile acid chelators • Clonidine has palliated diarrhea after LTX in some persons. • Consider diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis. • May prevent &/or treat growth failure • Nasogastric tube feeding has been helpful in some. • May not be responsive to LTX • Preparations of vitamin E (e.g., tocopheryl polyethylene glycol-1000 succinate) are useful in severe cholestasis. • Vitamin K administration in newborn period (1st 28 days of life) is essential. • Supportive care for acute pancreatitis episodes • Replacement therapy for insufficiency if documented • Standard biochemical assays of hepatocellular function & of hepatobiliary injury • Liver imaging • Liver biopsy if indicated by imaging studies &/or biochemical assays • Assess for portal hypertension. • Consider use of clinical tools to quantify itching. • Consider serum bile acid quantification. • Specific focus on diarrhea • Review of growth parameters • Consider measurements of mid-arm circumference. • Standard biochemical assays • Consider dedicated pancreatic imaging if concern. ## Evaluations at Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ATP8B1 deficiency, all possible manifestations of this disorder (if not addressed as part of the evaluation that led to the diagnosis) should be included in the initial evaluation. See Recommended Evaluations Following Initial Diagnosis in Individuals with ATP8B1 Deficiency Standard biochemical assays of hepatocellular function & hepatobiliary injury Liver imaging Liver biopsy if indicated by imaging studies &/or biochemical assays Assess for portal hypertension. Consider use of clinical tools to quantify itch. Consider serum bile acid quantification. Specific focus on diarrhea Review of growth parameters Consider measurements of mid-arm circumference. Use of Need for social work involvement for parental support. MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Standard biochemical assays of hepatocellular function & hepatobiliary injury • Liver imaging • Liver biopsy if indicated by imaging studies &/or biochemical assays • Assess for portal hypertension. • Consider use of clinical tools to quantify itch. • Consider serum bile acid quantification. • Specific focus on diarrhea • Review of growth parameters • Consider measurements of mid-arm circumference. • Use of • Need for social work involvement for parental support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with ATP8B1 Deficiency Can incl partial/total external diversion, partial/total internal diversion, or ileal exclusion Primary surgical therapy; can ↓ pruritus & slow or reverse progression to hepatic fibrosis Consider LTX if cirrhosis is present. In some LTX constitutes definitive therapy; in others secretory diarrhea in absence of steatorrhea continues or worsens after LTX Consideration of diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis Relatively ineffective & do not alter progression to end-stage liver disease. Future efforts focusing on real-world experience w/recently FDA-approved IBAT inhibitors are needed. Bile acid chelators Clonidine has palliated diarrhea after LTX in some persons. Consider diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis. May prevent &/or treat growth failure Nasogastric tube feeding has been helpful in some. May not be responsive to LTX Preparations of vitamin E (e.g., tocopheryl polyethylene glycol-1000 succinate) are useful in severe cholestasis. Vitamin K administration in newborn period (1st 28 days of life) is essential. Supportive care for acute pancreatitis episodes Replacement therapy for insufficiency if documented IBAT = ileal bile acid transporter; LTX = liver transplantation; UDCA = ursodeoxycholic acid In partial external biliary diversion the gallbladder apex is anastomosed to one end of a segment of bowel while the other end is used to create a cutaneous stoma from which bile is then drained and discarded, thus, interrupting the enterohepatic circulation of bile acids and reducing pruritus. • Can incl partial/total external diversion, partial/total internal diversion, or ileal exclusion • Primary surgical therapy; can ↓ pruritus & slow or reverse progression to hepatic fibrosis • Consider LTX if cirrhosis is present. • In some LTX constitutes definitive therapy; in others secretory diarrhea in absence of steatorrhea continues or worsens after LTX • Consideration of diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis • Relatively ineffective & do not alter progression to end-stage liver disease. • Future efforts focusing on real-world experience w/recently FDA-approved IBAT inhibitors are needed. • Bile acid chelators • Clonidine has palliated diarrhea after LTX in some persons. • Consider diversion at time of transplantation to mitigate post-transplant diarrhea & steatohepatitis. • May prevent &/or treat growth failure • Nasogastric tube feeding has been helpful in some. • May not be responsive to LTX • Preparations of vitamin E (e.g., tocopheryl polyethylene glycol-1000 succinate) are useful in severe cholestasis. • Vitamin K administration in newborn period (1st 28 days of life) is essential. • Supportive care for acute pancreatitis episodes • Replacement therapy for insufficiency if documented ## Surveillance Recommended Surveillance for Individuals with ATP8B1 Deficiency Standard biochemical assays of hepatocellular function & of hepatobiliary injury Liver imaging Liver biopsy if indicated by imaging studies &/or biochemical assays Assess for portal hypertension. Consider use of clinical tools to quantify itching. Consider serum bile acid quantification. Specific focus on diarrhea Review of growth parameters Consider measurements of mid-arm circumference. Standard biochemical assays Consider dedicated pancreatic imaging if concern. SNHL = sensorineural hearing loss Note: Monitoring for hepatobiliary malignancy has not been shown to be necessary in ATP8B1 deficiency. • Standard biochemical assays of hepatocellular function & of hepatobiliary injury • Liver imaging • Liver biopsy if indicated by imaging studies &/or biochemical assays • Assess for portal hypertension. • Consider use of clinical tools to quantify itching. • Consider serum bile acid quantification. • Specific focus on diarrhea • Review of growth parameters • Consider measurements of mid-arm circumference. • Standard biochemical assays • Consider dedicated pancreatic imaging if concern. ## Agents/Circumstances to Avoid Susceptibility to sensorineural hearing loss in ATP8B1 deficiency may argue against use of aminoglycoside antibiotics or other potentially ototoxic agents. Oral contraceptive therapy can induce and/or exacerbate episodes of cholestasis. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, surveillance, and awareness of See ## Therapies Under Investigation Cystic fibrosis transmembrane conductance regulator corrector compounds improved trafficking of mutated ATP8B1 protein in cell culture studies [ Ileal bile acid transporter inhibitors have shown reduction in bile acid levels and reduced pruritus in children; various clinical trials are underway [ Search ## Genetic Counseling ATP8B1 deficiency is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with ATP8B1 deficiency [ If both parents are known to be heterozygous for an Although disease severity generally correlates with variant type, sibs with the same biallelic Unless the reproductive partner of an affected individual also has ATP8B1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in The carrier frequencies of * See Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with ATP8B1 deficiency [ • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Although disease severity generally correlates with variant type, sibs with the same biallelic • Unless the reproductive partner of an affected individual also has ATP8B1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • The carrier frequencies of • * See • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance ATP8B1 deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with ATP8B1 deficiency [ If both parents are known to be heterozygous for an Although disease severity generally correlates with variant type, sibs with the same biallelic Unless the reproductive partner of an affected individual also has ATP8B1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in The carrier frequencies of * See • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Intrahepatic cholestasis of pregnancy has been reported occasionally in mothers of individuals with ATP8B1 deficiency [ • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Although disease severity generally correlates with variant type, sibs with the same biallelic • Unless the reproductive partner of an affected individual also has ATP8B1 deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • The carrier frequencies of • * See ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and of reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada United Kingdom • • • • Canada • • • • • United Kingdom • • • ## Molecular Genetics ATP8B1 Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ATP8B1 Deficiency ( For a broader review of this discussion, see Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis For a broader review of this discussion, see Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes Laura N Bull, PhD (2001-present)AS Knisely, MD; King's College Hospital (2001-2021) Raffaella Morotti, MD (2021-present)Benjamin L Shneider, MD; Children's Hospital of Pittsburgh (2006-2021) James E Squires, MD, MS (2021-present)Kelly A Taylor, MS, CGC; Vanderbilt University (2001-2006) 9 September 2021 (bp) Comprehensive update posted live 20 March 2014 (me) Comprehensive update posted live 15 February 2006 (me) Comprehensive update posted live 15 July 2003 (me) Comprehensive update posted live 15 October 2001 (me) Review posted live 24 April 2001 (kt) Original submission • 9 September 2021 (bp) Comprehensive update posted live • 20 March 2014 (me) Comprehensive update posted live • 15 February 2006 (me) Comprehensive update posted live • 15 July 2003 (me) Comprehensive update posted live • 15 October 2001 (me) Review posted live • 24 April 2001 (kt) Original submission ## Author Notes ## Author History Laura N Bull, PhD (2001-present)AS Knisely, MD; King's College Hospital (2001-2021) Raffaella Morotti, MD (2021-present)Benjamin L Shneider, MD; Children's Hospital of Pittsburgh (2006-2021) James E Squires, MD, MS (2021-present)Kelly A Taylor, MS, CGC; Vanderbilt University (2001-2006) ## Revision History 9 September 2021 (bp) Comprehensive update posted live 20 March 2014 (me) Comprehensive update posted live 15 February 2006 (me) Comprehensive update posted live 15 July 2003 (me) Comprehensive update posted live 15 October 2001 (me) Review posted live 24 April 2001 (kt) Original submission • 9 September 2021 (bp) Comprehensive update posted live • 20 March 2014 (me) Comprehensive update posted live • 15 February 2006 (me) Comprehensive update posted live • 15 July 2003 (me) Comprehensive update posted live • 15 October 2001 (me) Review posted live • 24 April 2001 (kt) Original submission ## References ## Literature Cited	[]	15/10/2001	9/9/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ph1	ph1	[ "Alanine-glyoxylate transaminase", "AGXT", "Primary Hyperoxaluria Type 1" ]	Primary Hyperoxaluria Type 1	Dawn S Milliner, Peter C Harris, David J Sas, Andrea G Cogal, John C Lieske	Summary Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract; often the crystals deposit in kidney parenchyma (nephrocalcinosis). The age at presentation of PH1 ranges from infancy (age <12 months) in 10% of individuals, childhood/adolescence (age 1-17 years) in 70%, and adulthood (age ≥18 years) in 20%. The natural history of untreated PH1 is (1) progressive decline in kidney function due to complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) in persons with advanced chronic kidney disease (CKD), high plasma oxalate concentrations result in other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"), most commonly in the bones, heart, and retina. In the absence of treatment, progression of oxalosis results in death from kidney failure and/or other organ involvement. The diagnosis of PH1 is established in a proband with supportive laboratory findings (excess excretion of oxalate in the urine and/or markedly increased plasma oxalate concentration) and biallelic pathogenic variants in PH1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Consensus guidelines for the diagnostic approach to individuals with a suspicion of primary hyperoxaluria and management of all types of primary hyperoxaluria have been published [ Primary hyperoxaluria type 1 (PH1) Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology [ Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. First kidney stone First kidney stone [ Multiple or recurring calcium-containing kidney stones Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function [ Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria [ Nephrocalcinosis Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis [ Hyperoxaluria resulting from increased hepatic production of oxalate is the central laboratory feature of PH1 (see CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. Primary Hyperoxaluria Type 1: Supportive Laboratory Findings Must be corrected to BSA 1.73 m At least 2 collections required to confirm abnormality Less reliable when eGFR <30 mL/min/BSA Data for normal values for children age <2 yrs are limited. POx >20 is consistent w/PH1. POx >50 µmol/L is strongly suggestive of PH1 [ Plasma samples require special handling. Results vary by method. Available only in specialty labs BSA = body surface area; eGFR = estimated glomerular filtration rate; POx = plasma oxalate; UOx = urine oxalate Accurate measurements rely on acidification of the urine to a urine pH ≤2 either during collection or in the laboratory to dissolve any calcium oxalate crystals that form in the urine in vivo or in vitro after collection. Urine oxalate:creatinine changes rapidly in infancy and childhood [ Plasma oxalate concentration, increased in individuals with kidney failure of any cause, is much greater in individuals with PH1; thus, plasma oxalate concentration in individuals with suspected PH1 should be compared with that of other individuals with kidney failure rather than healthy individuals [ Plasma oxalate concentrations are highest in individuals with PH1 on dialysis, often >100 µmol/L [ Normal Spot Urine Oxalate:Creatinine Ratio by Age Modified from The diagnosis of PH1 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Note: If an individual has clinical features of PH1 (see For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Out of more than 260 known • Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology [ • Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. • First kidney stone • First kidney stone [ • Multiple or recurring calcium-containing kidney stones • Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function [ • Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria [ • Nephrocalcinosis • Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis [ • CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. • CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. • Must be corrected to BSA 1.73 m • At least 2 collections required to confirm abnormality • Less reliable when eGFR <30 mL/min/BSA • Data for normal values for children age <2 yrs are limited. • POx >20 is consistent w/PH1. • POx >50 µmol/L is strongly suggestive of PH1 [ • Plasma samples require special handling. • Results vary by method. • Available only in specialty labs ## Suggestive Findings Primary hyperoxaluria type 1 (PH1) Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology [ Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. First kidney stone First kidney stone [ Multiple or recurring calcium-containing kidney stones Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function [ Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria [ Nephrocalcinosis Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis [ Hyperoxaluria resulting from increased hepatic production of oxalate is the central laboratory feature of PH1 (see CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. Primary Hyperoxaluria Type 1: Supportive Laboratory Findings Must be corrected to BSA 1.73 m At least 2 collections required to confirm abnormality Less reliable when eGFR <30 mL/min/BSA Data for normal values for children age <2 yrs are limited. POx >20 is consistent w/PH1. POx >50 µmol/L is strongly suggestive of PH1 [ Plasma samples require special handling. Results vary by method. Available only in specialty labs BSA = body surface area; eGFR = estimated glomerular filtration rate; POx = plasma oxalate; UOx = urine oxalate Accurate measurements rely on acidification of the urine to a urine pH ≤2 either during collection or in the laboratory to dissolve any calcium oxalate crystals that form in the urine in vivo or in vitro after collection. Urine oxalate:creatinine changes rapidly in infancy and childhood [ Plasma oxalate concentration, increased in individuals with kidney failure of any cause, is much greater in individuals with PH1; thus, plasma oxalate concentration in individuals with suspected PH1 should be compared with that of other individuals with kidney failure rather than healthy individuals [ Plasma oxalate concentrations are highest in individuals with PH1 on dialysis, often >100 µmol/L [ Normal Spot Urine Oxalate:Creatinine Ratio by Age Modified from • Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology [ • Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. • First kidney stone • First kidney stone [ • Multiple or recurring calcium-containing kidney stones • Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function [ • Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria [ • Nephrocalcinosis • Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis [ • CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. • CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. • Must be corrected to BSA 1.73 m • At least 2 collections required to confirm abnormality • Less reliable when eGFR <30 mL/min/BSA • Data for normal values for children age <2 yrs are limited. • POx >20 is consistent w/PH1. • POx >50 µmol/L is strongly suggestive of PH1 [ • Plasma samples require special handling. • Results vary by method. • Available only in specialty labs ## Clinical Findings Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology [ Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. First kidney stone First kidney stone [ Multiple or recurring calcium-containing kidney stones Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function [ Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria [ Nephrocalcinosis Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis [ • Impaired kidney function or poor weight gain and/or poor linear growth of undetermined etiology [ • Nephrocalcinosis. Renal ultrasound examination most commonly reveals diffuse nephrocalcinosis with few if any observable discrete stones. • First kidney stone • First kidney stone [ • Multiple or recurring calcium-containing kidney stones • Impairment of kidney function associated with stones or nephrocalcinosis. Nephrocalcinosis has been observed at the time of the first imaging study in 30% of individuals with preserved kidney function [ • Recurrent nephrolithiasis in which kidney imaging reveals multiple bilateral radiopaque calculi known or suspected to be calcium oxalate, especially if urinary testing is available and confirms hyperoxaluria [ • Nephrocalcinosis • Reduced kidney function or end-stage kidney disease (ESKD) with a history of kidney stones or nephrocalcinosis [ ## Supportive Laboratory Findings Hyperoxaluria resulting from increased hepatic production of oxalate is the central laboratory feature of PH1 (see CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. Primary Hyperoxaluria Type 1: Supportive Laboratory Findings Must be corrected to BSA 1.73 m At least 2 collections required to confirm abnormality Less reliable when eGFR <30 mL/min/BSA Data for normal values for children age <2 yrs are limited. POx >20 is consistent w/PH1. POx >50 µmol/L is strongly suggestive of PH1 [ Plasma samples require special handling. Results vary by method. Available only in specialty labs BSA = body surface area; eGFR = estimated glomerular filtration rate; POx = plasma oxalate; UOx = urine oxalate Accurate measurements rely on acidification of the urine to a urine pH ≤2 either during collection or in the laboratory to dissolve any calcium oxalate crystals that form in the urine in vivo or in vitro after collection. Urine oxalate:creatinine changes rapidly in infancy and childhood [ Plasma oxalate concentration, increased in individuals with kidney failure of any cause, is much greater in individuals with PH1; thus, plasma oxalate concentration in individuals with suspected PH1 should be compared with that of other individuals with kidney failure rather than healthy individuals [ Plasma oxalate concentrations are highest in individuals with PH1 on dialysis, often >100 µmol/L [ Normal Spot Urine Oxalate:Creatinine Ratio by Age Modified from • CKD stages 1 to 3b (i.e., kidney function is preserved). Because most excess oxalate is excreted in the urine and plasma oxalate concentrations are normal to mildly elevated, measurement of urine oxalate is important. • CKD stages 4 and 5 (advanced CKD or the individual is on dialysis). Because less oxalate than expected is excreted in the urine and plasma oxalate concentration is markedly increased, assessment of plasma oxalate concentration is preferred. • Must be corrected to BSA 1.73 m • At least 2 collections required to confirm abnormality • Less reliable when eGFR <30 mL/min/BSA • Data for normal values for children age <2 yrs are limited. • POx >20 is consistent w/PH1. • POx >50 µmol/L is strongly suggestive of PH1 [ • Plasma samples require special handling. • Results vary by method. • Available only in specialty labs ## Establishing the Diagnosis The diagnosis of PH1 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click Note: If an individual has clinical features of PH1 (see For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Out of more than 260 known ## Option 1 For an introduction to multigene panels click ## Option 2 Note: If an individual has clinical features of PH1 (see For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Out of more than 260 known ## Clinical Characteristics Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Crystal deposition leads to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract and often in kidney parenchyma (nephrocalcinosis). The natural history of untreated PH1 is (1) progressive decline in kidney function because of complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"). In the absence of treatment oxalosis progresses leading to death from kidney failure and/or other organ involvement [ Primary Hyperoxaluria Type 1: Clinical Presentations ± = variably present or not; + = present in some affected individuals; ++ = often present; +++ = present in most affected individuals; CKD = chronic kidney disease; ESKD = end-stage kidney disease In most reports from Europe and the United States, infantile onset accounts for 10% or less of PH1 [ In severe, early-onset (infantile) disease, the presenting signs and symptoms include nephrocalcinosis (with or without nephrolithiasis) and poor weight gain and/or poor linear growth related to advanced kidney failure. End-stage kidney disease (ESKD) can appear as early as age four to six months and typically before age 12 months. Infants who do not require dialysis at the time of diagnosis often progress to ESKD over months despite optimal supportive care [ Over time, worsening systemic oxalate deposition results in multiorgan disease including oxalate osteopathy characterized by growth delay and pathologic fractures, retinal deposition with visual impairment, and cardiomyopathy and cardiac arrythmias [ In most of the 70% of individuals with PH1 who are first diagnosed in childhood or adolescence, the initial manifestations occur before age ten years, and in 85%-90% by age 20 years [ Most often individuals with disease onset in this age group have findings related to nephrolithiasis including hematuria, dysuria, pain, urinary tract infection, and/or stone passage [ Occasionally individuals with disease onset in this age group present with moderate-to-severe chronic kidney disease (CKD) and progress to ESKD during childhood or adolescence. At the time of diagnosis, kidney function may be normal or show mild-to-moderate reduction, which worsens slowly over time [ In 54 individuals with PH1 who developed kidney failure during childhood or adolescence in the years 2000 to 2009 the five-year survival was 83% following initiation of kidney replacement therapy (i.e., dialysis and/or transplantation), an improvement when compared to the outcome of individuals with PH1 treated with kidney replacement therapy prior to 2000 (particularly in children younger than age two years). Nonetheless, outcomes in children with PH1 were less favorable when compared to children with other types of kidney disease who required kidney replacement therapy [ The 20% of individuals with PH1 first diagnosed as adults [ The finding at initial presentation in adults with PH1 may be acute kidney failure due to bilateral renal obstruction caused by calcium oxalate stones or other illnesses that compromise fluid intake and thus urine volume. Acute kidney failure can also occur following stone removal procedures [ PH1 is not correctly diagnosed in 20%-50% of individuals with adult-onset disease until later stages of CKD or after kidney failure [ In contrast, some individuals with PH1 remain free of manifestations or have minimal findings into the sixth decade of life [ Other less common clinical manifestations of oxalate deposition include: Bone marrow involvement resulting in anemia refractory to erythropoietin-stimulating agents (ESA) and splenomegaly [ Vascular involvement resulting in ischemia, most often manifesting as non-healing cutaneous ulcers; Cerebral infarcts resulting from cerebral vessel involvement [ Refractory hypotension in advanced oxalosis; Peripheral neuropathy [ Dental pain and root resorption [ Hypothyroidism [ Most manifestations of oxalosis are slowly reversible following successful liver and kidney transplantation (see Management, Note: While infantile oxalosis was observed to be rare in those homozygous for pyridoxine-responsive The age at onset and clinical manifestations can vary widely even among sibs with the same biallelic Genotype-phenotype correlations reported with specific Although individuals who are compound heterozygotes for p.Phe152Ile, p.Gly170Arg, or p.Ile244Thr and a non-pyridoxine-sensitive pathogenic variant developed kidney failure at a slightly younger age than those homozygous for either variant, it was not significantly different. Population-based analysis of Clinical estimates of prevalence of PH1, primarily from European studies, range from one to three in 1,000,000 and one in 120,000 live births [ It is estimated that PH1 accounts for 1%-2% of children with ESKD in Western Europe and North America [ The increased prevalence of PH1 in the Canary Islands is attributed to the A higher prevalence of PH1 is reported in Tunisia, Syria, and Druze communities due to high rates of consanguinity and founder variants in these populations [ When considering the above data, it is important to remember that PH1 remains underdiagnosed because of wide variability in its age of onset (infancy to adulthood) and clinical presentation (ranging from severe disease in infancy to adults with recurrent stones to advanced disease present in 20%-50% at the time of diagnosis). Additional factors contributing to underdiagnosis are lack of familiarity with PH1 among many physicians and lack of laboratory resources to measure oxalate concentration and perform genetic testing, especially in developing countries. • Bone marrow involvement resulting in anemia refractory to erythropoietin-stimulating agents (ESA) and splenomegaly [ • Vascular involvement resulting in ischemia, most often manifesting as non-healing cutaneous ulcers; • Cerebral infarcts resulting from cerebral vessel involvement [ • Refractory hypotension in advanced oxalosis; • Peripheral neuropathy [ • Dental pain and root resorption [ • Hypothyroidism [ ## Clinical Description Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Crystal deposition leads to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract and often in kidney parenchyma (nephrocalcinosis). The natural history of untreated PH1 is (1) progressive decline in kidney function because of complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"). In the absence of treatment oxalosis progresses leading to death from kidney failure and/or other organ involvement [ Primary Hyperoxaluria Type 1: Clinical Presentations ± = variably present or not; + = present in some affected individuals; ++ = often present; +++ = present in most affected individuals; CKD = chronic kidney disease; ESKD = end-stage kidney disease In most reports from Europe and the United States, infantile onset accounts for 10% or less of PH1 [ In severe, early-onset (infantile) disease, the presenting signs and symptoms include nephrocalcinosis (with or without nephrolithiasis) and poor weight gain and/or poor linear growth related to advanced kidney failure. End-stage kidney disease (ESKD) can appear as early as age four to six months and typically before age 12 months. Infants who do not require dialysis at the time of diagnosis often progress to ESKD over months despite optimal supportive care [ Over time, worsening systemic oxalate deposition results in multiorgan disease including oxalate osteopathy characterized by growth delay and pathologic fractures, retinal deposition with visual impairment, and cardiomyopathy and cardiac arrythmias [ In most of the 70% of individuals with PH1 who are first diagnosed in childhood or adolescence, the initial manifestations occur before age ten years, and in 85%-90% by age 20 years [ Most often individuals with disease onset in this age group have findings related to nephrolithiasis including hematuria, dysuria, pain, urinary tract infection, and/or stone passage [ Occasionally individuals with disease onset in this age group present with moderate-to-severe chronic kidney disease (CKD) and progress to ESKD during childhood or adolescence. At the time of diagnosis, kidney function may be normal or show mild-to-moderate reduction, which worsens slowly over time [ In 54 individuals with PH1 who developed kidney failure during childhood or adolescence in the years 2000 to 2009 the five-year survival was 83% following initiation of kidney replacement therapy (i.e., dialysis and/or transplantation), an improvement when compared to the outcome of individuals with PH1 treated with kidney replacement therapy prior to 2000 (particularly in children younger than age two years). Nonetheless, outcomes in children with PH1 were less favorable when compared to children with other types of kidney disease who required kidney replacement therapy [ The 20% of individuals with PH1 first diagnosed as adults [ The finding at initial presentation in adults with PH1 may be acute kidney failure due to bilateral renal obstruction caused by calcium oxalate stones or other illnesses that compromise fluid intake and thus urine volume. Acute kidney failure can also occur following stone removal procedures [ PH1 is not correctly diagnosed in 20%-50% of individuals with adult-onset disease until later stages of CKD or after kidney failure [ In contrast, some individuals with PH1 remain free of manifestations or have minimal findings into the sixth decade of life [ Other less common clinical manifestations of oxalate deposition include: Bone marrow involvement resulting in anemia refractory to erythropoietin-stimulating agents (ESA) and splenomegaly [ Vascular involvement resulting in ischemia, most often manifesting as non-healing cutaneous ulcers; Cerebral infarcts resulting from cerebral vessel involvement [ Refractory hypotension in advanced oxalosis; Peripheral neuropathy [ Dental pain and root resorption [ Hypothyroidism [ Most manifestations of oxalosis are slowly reversible following successful liver and kidney transplantation (see Management, Note: While infantile oxalosis was observed to be rare in those homozygous for pyridoxine-responsive The age at onset and clinical manifestations can vary widely even among sibs with the same biallelic • Bone marrow involvement resulting in anemia refractory to erythropoietin-stimulating agents (ESA) and splenomegaly [ • Vascular involvement resulting in ischemia, most often manifesting as non-healing cutaneous ulcers; • Cerebral infarcts resulting from cerebral vessel involvement [ • Refractory hypotension in advanced oxalosis; • Peripheral neuropathy [ • Dental pain and root resorption [ • Hypothyroidism [ ## Infantile Onset (age <12 months) In severe, early-onset (infantile) disease, the presenting signs and symptoms include nephrocalcinosis (with or without nephrolithiasis) and poor weight gain and/or poor linear growth related to advanced kidney failure. End-stage kidney disease (ESKD) can appear as early as age four to six months and typically before age 12 months. Infants who do not require dialysis at the time of diagnosis often progress to ESKD over months despite optimal supportive care [ Over time, worsening systemic oxalate deposition results in multiorgan disease including oxalate osteopathy characterized by growth delay and pathologic fractures, retinal deposition with visual impairment, and cardiomyopathy and cardiac arrythmias [ ## Childhood/Adolescent Onset (ages 1-17 years) In most of the 70% of individuals with PH1 who are first diagnosed in childhood or adolescence, the initial manifestations occur before age ten years, and in 85%-90% by age 20 years [ Most often individuals with disease onset in this age group have findings related to nephrolithiasis including hematuria, dysuria, pain, urinary tract infection, and/or stone passage [ Occasionally individuals with disease onset in this age group present with moderate-to-severe chronic kidney disease (CKD) and progress to ESKD during childhood or adolescence. At the time of diagnosis, kidney function may be normal or show mild-to-moderate reduction, which worsens slowly over time [ In 54 individuals with PH1 who developed kidney failure during childhood or adolescence in the years 2000 to 2009 the five-year survival was 83% following initiation of kidney replacement therapy (i.e., dialysis and/or transplantation), an improvement when compared to the outcome of individuals with PH1 treated with kidney replacement therapy prior to 2000 (particularly in children younger than age two years). Nonetheless, outcomes in children with PH1 were less favorable when compared to children with other types of kidney disease who required kidney replacement therapy [ ## Adult Onset (age ≥18 years) The 20% of individuals with PH1 first diagnosed as adults [ The finding at initial presentation in adults with PH1 may be acute kidney failure due to bilateral renal obstruction caused by calcium oxalate stones or other illnesses that compromise fluid intake and thus urine volume. Acute kidney failure can also occur following stone removal procedures [ PH1 is not correctly diagnosed in 20%-50% of individuals with adult-onset disease until later stages of CKD or after kidney failure [ In contrast, some individuals with PH1 remain free of manifestations or have minimal findings into the sixth decade of life [ ## PH1 of Any Age Other less common clinical manifestations of oxalate deposition include: Bone marrow involvement resulting in anemia refractory to erythropoietin-stimulating agents (ESA) and splenomegaly [ Vascular involvement resulting in ischemia, most often manifesting as non-healing cutaneous ulcers; Cerebral infarcts resulting from cerebral vessel involvement [ Refractory hypotension in advanced oxalosis; Peripheral neuropathy [ Dental pain and root resorption [ Hypothyroidism [ Most manifestations of oxalosis are slowly reversible following successful liver and kidney transplantation (see Management, Note: While infantile oxalosis was observed to be rare in those homozygous for pyridoxine-responsive • Bone marrow involvement resulting in anemia refractory to erythropoietin-stimulating agents (ESA) and splenomegaly [ • Vascular involvement resulting in ischemia, most often manifesting as non-healing cutaneous ulcers; • Cerebral infarcts resulting from cerebral vessel involvement [ • Refractory hypotension in advanced oxalosis; • Peripheral neuropathy [ • Dental pain and root resorption [ • Hypothyroidism [ ## Intrafamilial Variability The age at onset and clinical manifestations can vary widely even among sibs with the same biallelic ## Genotype-Phenotype Correlations Genotype-phenotype correlations reported with specific Although individuals who are compound heterozygotes for p.Phe152Ile, p.Gly170Arg, or p.Ile244Thr and a non-pyridoxine-sensitive pathogenic variant developed kidney failure at a slightly younger age than those homozygous for either variant, it was not significantly different. ## Prevalence Population-based analysis of Clinical estimates of prevalence of PH1, primarily from European studies, range from one to three in 1,000,000 and one in 120,000 live births [ It is estimated that PH1 accounts for 1%-2% of children with ESKD in Western Europe and North America [ The increased prevalence of PH1 in the Canary Islands is attributed to the A higher prevalence of PH1 is reported in Tunisia, Syria, and Druze communities due to high rates of consanguinity and founder variants in these populations [ When considering the above data, it is important to remember that PH1 remains underdiagnosed because of wide variability in its age of onset (infancy to adulthood) and clinical presentation (ranging from severe disease in infancy to adults with recurrent stones to advanced disease present in 20%-50% at the time of diagnosis). Additional factors contributing to underdiagnosis are lack of familiarity with PH1 among many physicians and lack of laboratory resources to measure oxalate concentration and perform genetic testing, especially in developing countries. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Differential diagnosis of primary hyperoxaluria type 1 (PH1) needs to take into consideration the three known causes of primary hyperoxaluria (type 1, type 2, and type 3; see All individuals with hyperoxaluria not attributable to secondary causes or who have CKD with suggestive clinical findings such as nephrolithiasis, nephrocalcinosis, or plasma oxalate concentration higher than expected for the CKD stage should undergo genetic testing for definitive diagnosis. Primary hyperoxaluria (PH) should be included in the differential diagnosis of any condition that causes calcium oxalate kidney stone disease and/or nephrocalcinosis or is associated with hyperoxaluria. The three known types of PH are PH1 (due to biallelic Of note, up to 10% of clinically suspected primary hyperoxaluria is genetically unresolved. The clinical manifestations of the three known types of PH overlap considerably (see Urinary organic acid metabolites reflect the metabolic pathways and can be useful in differentiating among PH types. Metabolites are typically measured in random urine specimens with correction for creatinine concentration. Urine glycolate is often elevated in PH1, glycerate is increased in PH2, and 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) are increased in most individuals with PH3. One recent series of predominantly North American populations found urine oxalate to be lower in PH3 than in PH1 and PH2 [ In both series urinary citrate and calcium excretion rates were normal in individuals with PH3 [ Comparison of Primary Hyperoxaluria Types 1, 2, and 3 Adapted from DHG = 2,4-dihydroxyglutarate; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HOG = 4-hydroxy-2-oxoglutarate; NC = nephrocalcinosis; nL = normal limit; PH = primary hyperoxaluria Percentage among currently diagnosed individuals with primary hyperoxaluria [ Parameters presented are the median. Although increased urinary excretion of these specific organic acids is suggestive of PH type [ Phenotypic overlap of PH1 with other monogenic stone diseases can occur [ Comparison of Primary Hyperoxaluria and Other Monogenic Stone Diseases + = present in some affected individuals; ++ = often present; +++ = present in most affected individuals; -- not recognized to be abnormal but data are limited; AR = autosomal recessive; CKD = chronic kidney disease; Conc = concentration; MOI = mode of inheritance; NC = nephrocalcinosis; PH = primary hyperoxaluria; SCa = serum total calcium; SMg = serum magnesium; SPhos = serum phosphate; UCa = urine calcium; UDHA = urine dihydroxyadenine; UMg = urine magnesium; UPhos = urine phosphate; XL = X-linked Stones comprised of dihydroxyadenine are radiolucent to intermediate density on radiographs and ultrasonography. Disorder of renal magnesium wasting; presentation in childhood or adolescence with UTIs, nephrolithiasis, nephrocalcinosis, and polydipsia/polyuria is characteristic, as is CKD progressing to ESKD in early to mid-adulthood in many [ Resulting hypercalcemia may be severe in infancy and may present as poor weight gain and/or poor linear growth. Hypercalcemia typically abates during early childhood, though serum calcium may be intermittently mildly elevated through adulthood. Many individuals first present with stones or nephrocalcinosis in childhood or as adults. Kidney cysts are often present. CKD is common and some individuals progress to ESKD [ Characterized by renal phosphate wasting, hypophosphatemia, increased 1,25-dihydroxyvitamin D, hypercalciuria, nephrolithiasis, nephrocalcinosis, and bone disease (rickets/osteomalacia) [ Secondary forms of hyperoxaluria – including excessive dietary intake of oxalate or oxalate precursors and enteric hyperoxaluria – should be considered in the differential diagnosis of all individuals who present with hyperoxaluria [ Foods high in oxalate (e.g., spinach, beetroot, dark chocolate), especially if dietary calcium intake is low; Diets markedly deficient in calcium, which result in a greater proportion of free oxalate in the intestinal lumen, thus enhancing absorption of oxalate and resulting in hyperoxaluria; Very high doses of vitamin C [ Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. Any gastrointestinal disease or surgery that impairs fat absorption [ Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) Generalized loss of peroxisomal function is observed in Nephrocalcinosis of prematurity, which occurs in a significant proportion of infants born prior to 28 weeks' gestation, is also characterized by nephrolithiasis [ • Urinary organic acid metabolites reflect the metabolic pathways and can be useful in differentiating among PH types. Metabolites are typically measured in random urine specimens with correction for creatinine concentration. Urine glycolate is often elevated in PH1, glycerate is increased in PH2, and 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) are increased in most individuals with PH3. • One recent series of predominantly North American populations found urine oxalate to be lower in PH3 than in PH1 and PH2 [ • In both series urinary citrate and calcium excretion rates were normal in individuals with PH3 [ • Foods high in oxalate (e.g., spinach, beetroot, dark chocolate), especially if dietary calcium intake is low; • Diets markedly deficient in calcium, which result in a greater proportion of free oxalate in the intestinal lumen, thus enhancing absorption of oxalate and resulting in hyperoxaluria; • Very high doses of vitamin C [ • Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. • Any gastrointestinal disease or surgery that impairs fat absorption [ • Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) ## Primary Hyperoxaluria Primary hyperoxaluria (PH) should be included in the differential diagnosis of any condition that causes calcium oxalate kidney stone disease and/or nephrocalcinosis or is associated with hyperoxaluria. The three known types of PH are PH1 (due to biallelic Of note, up to 10% of clinically suspected primary hyperoxaluria is genetically unresolved. The clinical manifestations of the three known types of PH overlap considerably (see Urinary organic acid metabolites reflect the metabolic pathways and can be useful in differentiating among PH types. Metabolites are typically measured in random urine specimens with correction for creatinine concentration. Urine glycolate is often elevated in PH1, glycerate is increased in PH2, and 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) are increased in most individuals with PH3. One recent series of predominantly North American populations found urine oxalate to be lower in PH3 than in PH1 and PH2 [ In both series urinary citrate and calcium excretion rates were normal in individuals with PH3 [ Comparison of Primary Hyperoxaluria Types 1, 2, and 3 Adapted from DHG = 2,4-dihydroxyglutarate; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HOG = 4-hydroxy-2-oxoglutarate; NC = nephrocalcinosis; nL = normal limit; PH = primary hyperoxaluria Percentage among currently diagnosed individuals with primary hyperoxaluria [ Parameters presented are the median. Although increased urinary excretion of these specific organic acids is suggestive of PH type [ Phenotypic overlap of PH1 with other monogenic stone diseases can occur [ Comparison of Primary Hyperoxaluria and Other Monogenic Stone Diseases + = present in some affected individuals; ++ = often present; +++ = present in most affected individuals; -- not recognized to be abnormal but data are limited; AR = autosomal recessive; CKD = chronic kidney disease; Conc = concentration; MOI = mode of inheritance; NC = nephrocalcinosis; PH = primary hyperoxaluria; SCa = serum total calcium; SMg = serum magnesium; SPhos = serum phosphate; UCa = urine calcium; UDHA = urine dihydroxyadenine; UMg = urine magnesium; UPhos = urine phosphate; XL = X-linked Stones comprised of dihydroxyadenine are radiolucent to intermediate density on radiographs and ultrasonography. Disorder of renal magnesium wasting; presentation in childhood or adolescence with UTIs, nephrolithiasis, nephrocalcinosis, and polydipsia/polyuria is characteristic, as is CKD progressing to ESKD in early to mid-adulthood in many [ Resulting hypercalcemia may be severe in infancy and may present as poor weight gain and/or poor linear growth. Hypercalcemia typically abates during early childhood, though serum calcium may be intermittently mildly elevated through adulthood. Many individuals first present with stones or nephrocalcinosis in childhood or as adults. Kidney cysts are often present. CKD is common and some individuals progress to ESKD [ Characterized by renal phosphate wasting, hypophosphatemia, increased 1,25-dihydroxyvitamin D, hypercalciuria, nephrolithiasis, nephrocalcinosis, and bone disease (rickets/osteomalacia) [ • Urinary organic acid metabolites reflect the metabolic pathways and can be useful in differentiating among PH types. Metabolites are typically measured in random urine specimens with correction for creatinine concentration. Urine glycolate is often elevated in PH1, glycerate is increased in PH2, and 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) are increased in most individuals with PH3. • One recent series of predominantly North American populations found urine oxalate to be lower in PH3 than in PH1 and PH2 [ • In both series urinary citrate and calcium excretion rates were normal in individuals with PH3 [ ## Secondary Hyperoxaluria Secondary forms of hyperoxaluria – including excessive dietary intake of oxalate or oxalate precursors and enteric hyperoxaluria – should be considered in the differential diagnosis of all individuals who present with hyperoxaluria [ Foods high in oxalate (e.g., spinach, beetroot, dark chocolate), especially if dietary calcium intake is low; Diets markedly deficient in calcium, which result in a greater proportion of free oxalate in the intestinal lumen, thus enhancing absorption of oxalate and resulting in hyperoxaluria; Very high doses of vitamin C [ Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. Any gastrointestinal disease or surgery that impairs fat absorption [ Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) • Foods high in oxalate (e.g., spinach, beetroot, dark chocolate), especially if dietary calcium intake is low; • Diets markedly deficient in calcium, which result in a greater proportion of free oxalate in the intestinal lumen, thus enhancing absorption of oxalate and resulting in hyperoxaluria; • Very high doses of vitamin C [ • Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. • Any gastrointestinal disease or surgery that impairs fat absorption [ • Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) ## Zellweger Spectrum Disorder Generalized loss of peroxisomal function is observed in ## Nephrocalcinosis of Prematurity Nephrocalcinosis of prematurity, which occurs in a significant proportion of infants born prior to 28 weeks' gestation, is also characterized by nephrolithiasis [ ## Management Clinical practice recommendations for management of primary hyperoxaluria (PH) have been published [ The following evaluations are recommended to establish the extent of disease and needs in an individual diagnosed with primary hyperoxaluria type 1 (PH1): Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis Baseline 24-hour urine collection with measurement of excretion rates of oxalate, calcium, and citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones Note: Baseline measurement of 24-hour excretion rates is recommended in nearly all individuals, even those requiring catheter placement for accurate collection. In rare exceptions only a spot urine with concentrations corrected for creatinine content is used (see Measurement of plasma oxalate concentration (see Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentration When chronic kidney disease (CKD) is stage 3b or higher, evaluate for systemic oxalate deposits (i.e., oxalosis) with: Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; Echocardiography for evidence of cardiomyopathy; Electrocardiogram for conduction disturbances; Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to obtain a pedigree and inform affected individuals and their families about the nature, mode of inheritance, and implications of PH1 to facilitate medical and personal decision making Assessment of need for family support and Management options for PH1 include targeted therapies and supportive care [ Targeted therapy for PH1 includes pyridoxine (for individuals with specific Note: Use of RNAi therapeutics to reduce hepatic oxalate production in pre- and post-transplantation management of kidney recipients is complicated; information to date is limited to case reports [ Because disease manifestations, including CKD or even kidney failure, are often present at the time of diagnosis, several approaches to targeted therapy are necessary (see Primary Hyperoxaluria Type 1: Targeted Therapies ~30%-50% of individuals w/PH1 are pyridoxine responsive. Since there are multiple mechanisms of pyridoxine response & only a few pathogenic variants have been tested, a trial of pyridoxine should be considered in all persons w/1 or 2 missense FDA & EMA approved for persons of all ages Experience using lumasiran in persons w/advanced CKD, on dialysis, or following kidney transplantation alone is limited. AGT = alanine-glyoxylate aminotransferase; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; EMA = European Medicines Agency; FDA = US Food and Drug Administration; GFR = glomerular filtration rate; LDHA = lactate dehydrogenase A; RNAi = RNA interference; siRNA = small interfering RNA Liver transplant is considered "targeted therapy" because it restores normal hepatic AGT function. Kidney transplant replaces kidney function but does not address the underlying cause of the disorder, and thus is considered supportive care. Pyridoxine response is assessed by comparing the 24-hour urine oxalate excretion rate before treatment and after at least three months of pyridoxine treatment at a minimum dose of 5 mg/kg/day. Reduction of ≥30% or normalization of urinary oxalate excretion while receiving pyridoxine indicates responsiveness [ Most individuals who are pyridoxine responsive show maximum benefit at a dose of 5-8 mg/kg/day [ A starting pyridoxine dose of 5 mg/kg/day is recommended. Stepwise increases in pyridoxine dose to a maximum of 10-20 mg/kg/day with assessments of response by measurement of urine oxalate excretion at each step determines the minimum effective dose. Pyridoxine responsiveness can be difficult to determine in individuals with advanced CKD or end-stage kidney disease (ESKD), whose urinary oxalate excretion rates may be influenced by the low glomerular filtration rate (GFR). When the GFR is <30 mL/min/1.73 m Certain Because 30%-50% of individuals with PH1 are pyridoxine responsive (and only a few Individuals responsive to pyridoxine should continue this therapy indefinitely or until successful orthotopic liver transplantation (when a liver with normal AGT enzyme activity replaces the liver with deficient AGT enzyme activity). Additionally, the recent availability of lumasiran and nedosiran requires comparing pyridoxine and siRNA therapeutic agents regarding efficacy, durability of effect, long-term tolerability, safety, and use under special circumstances such as pregnancy (see Pyridoxine has an excellent safety profile in individuals with PH1, even after decades of use. In contrast, peripheral neuropathy (including paresthesias) has been reported in individuals who do not have PH1 who were receiving very large doses of pyridoxine (typically, adults receiving 1-2 g/day) [ Nedosiran, a second siRNA therapeutic agent approved for PH1 in late 2023, targets a separate hepatic enzyme, lactate dehydrogenase A (LDHA) [ Additional data are needed to confirm long-term safety and efficacy of lumasiran and nedosiran in reversing the kidney-related effects of hepatic overproduction of oxalate. In double-blind, placebo-controlled trials of 39 individuals with PH1 (lumasiran-treated n=26, placebo n=13), lumasiran was highly effective in reducing urine and plasma oxalate concentrations [ Lumasiran has been effective in infants and young children [ Although early clinical trials demonstrated promising reductions in plasma and urine oxalate concentrations with lumasiran treatment [ Because the currently approved lumasiran dose is administered subcutaneously on a monthly or quarterly basis (see Schedule for Weight-Based Subcutaneous Administration of Lumasiran A double-blind, placebo-controlled clinical trial that included 29 individuals with PH1 older than age six years and an eGFR >30 ml/in/1.73m Nedosiran was well tolerated without serious adverse effects. Nedosiran clinical trials are under way for individuals with PH1 and advanced CKD who are on dialysis (see Until 2020 whole liver transplantation was – despite limited organ availability, high cost, and significant morbidity and mortality – the only intervention capable of restoring normal hepatic AGT enzyme activity and thus normalizing oxalate production. Liver and kidney transplantation were often performed either as a single combined procedure or sequential procedures, with similar outcomes achieved using either approach [ With recent availability of RNAi therapeutic agents capable of reducing hepatic oxalate production, some have suggested that liver transplantation may no longer be needed [ Points to consider regarding transplantation include the following: Kidney transplantation will continue to be the option for individuals who either have progressed to advanced CKD or ESKD before being diagnosed with PH1 or have not had the benefit of RNAi agents. Pre- and post-transplant management of kidney recipients with PH1 has been challenging and will be profoundly influenced by the ability to reduce hepatic oxalate production using siRNA therapeutics. Experience with use of such agents after kidney transplantation is thus far limited to case reports [ When systemic oxalosis is present prior to transplantation, mobilization of systemic oxalate places the kidney allograft at risk until tissue oxalate stores are completely cleared [ Clearance of tissue oxalate stores by a well-functioning kidney allograft requires months to more than five years following liver transplantation or RNAi reduction of oxalate production [ Liver transplantation for PH1 should always be performed with complete removal of the native liver. Pyridoxine supplementation in individuals who have been pyridoxine responsive can be discontinued at the time of liver transplantation, since normal AGT enzyme activity will have been restored. Although most publications report transplantation of organs from deceased donors, living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an Early diagnosis of PH1 with initiation of supportive care (also referred to as conservative treatment) aims to prevent crystal injury to kidneys, reduce stone formation and stone-related kidney damage, preserve kidney function, and prevent systemic oxalosis (see Primary Hyperoxaluria Type 1: Supportive Care Maintain high oral fluid intake to assure good urine volume. Use oral citrate or pyrophosphate to inhibit calcium oxalate crystal formation. Maintain high urine volume. Minimize urine oxalate concentration. Optimize urine citrate. Consult w/urologist experienced in mgmt of PH. Ureteroscopic mgmt of symptomatic stones preferred when appropriate. Prompt attention to pain or other symptoms suggesting infection or possible urinary obstruction. Use imaging studies at regular intervals to guide mgmt. Avoid dehydration. Avoid nephrotoxins that can cause kidney injury (e.g., NSAIDs). Monitor plasma oxalate concentration during transient or permanent periods of low GFR. Initiate dialysis promptly to ↓ oxalate concentration. GFR = glomerular filtration rate; NSAID = nonsteroidal anti-inflammatory drug; PH = primary hyperoxaluria High oral fluid intake. Drinking large volumes of fluid (2-3 L/m Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. Inhibition of calcium oxalate crystallization. If the GFR is preserved, increase urine citrate excretion using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in three to four divided doses. If the GFR is reduced or blood potassium concentration is elevated, sodium citrate can be used. In individuals with good kidney function (eGFR >30 mL/min/1.73 m In PH1 excess oxalate results from endogenous metabolism, not dietary intake of oxalate, and dietary restriction of oxalate intake is of little benefit. Thus, avoiding specific foods or beverages with very high oxalate content, without strict limits, is appropriate. Since recurring symptomatic stone events requiring urologic interventions are common, consultation with a urologist experienced in the care of individuals with PH1 helps individualize care and improve outcomes, particularly when specialized equipment and techniques may be required for infants and small children [ Calcium oxalate stones can be resistant to shock wave lithotripsy (SWL); nephrocalcinosis can also complicate stone management. Because stone removal can result in acute kidney failure, interventions least likely to cause kidney injury are preferred [ Surgical modalities used for stone management include the following: Hemodialysis is the primary dialysis modality used in persons with PH1 with kidney failure to reduce plasma oxalate concentration to prevent or treat oxalosis; however, absent targeted therapy to reduce hepatic oxalate production, the high rate of oxalate production (often 2-7 mmol/1.73 m Current guidelines suggest reducing and maintaining plasma oxalate concentration below 30-45 µmol/L (the calcium oxalate supersaturation threshold at which tissue deposition occurs) as long as possible between dialysis sessions. Although most individuals with PH1 require four or more dialysis sessions per week to maintain acceptable plasma oxalate concentrations, significant individual variation in oxalate production requires individualization of dialysis prescriptions [ Following increasing clinical experience with RNAi therapeutics effective in reducing hepatic oxalate production in individuals with PH1, it is expected that guidelines for PH1 [ Individuals with PH1 require lifelong care, the frequency of which is related to kidney function [ Regular monitoring of kidney function. Serum creatinine and/or cystatin C for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease. Regular kidney ultrasound examinations at least annually, or more often as needed to monitor and manage stone-forming activity Urinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections) at least annually, more often in individuals with active stones or changes in kidney function Kidney function Kidney ultrasound for stones and incipient nephrocalcinosis Urine oxalate and plasma oxalate concentrations History and physical examination at least every three months for signs and symptoms of systemic oxalosis with assessment of growth and development (in children), bone or joint involvement, evidence of cardiomyopathy, signs of arterial insufficiency or ischemia, and skin examination for livedo reticularis, subcutaneous oxalate deposits, and/or ischemic ulcers Serum creatinine and plasma oxalate concentrations, typically monthly or more often depending on clinical circumstances Radiographs of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Obtain initially, then repeat for bone symptoms and/or pathologic fractures; more frequent bone evaluation is needed in infants and young children. Ophthalmologic examination for visual acuity testing, evidence of retinal oxalate deposits, and optical coherence tomography (OCT) if available. Retinal photographs can be valuable to monitor changes over time. Electrocardiogram to evaluate for associated atrioventricular block or other oxalate-related conduction abnormalities, repeated every six to 12 months Echocardiogram for evidence of oxalate cardiomyopathy, repeated every 6-12 months. Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate, repeated every three months Thyroid function testing once a year Regular dental examinations/care Note: Evaluations should occur more often in newly diagnosed symptomatic individuals or in children younger than ages two to three years. Avoid the following: Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized. Intake of vitamin C that exceeds the recommended daily allowance Loop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase calcium oxalate stone production High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) or any pharmacologic agent that can compromise kidney function Large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit) See Of note, women with PH1 warrant close monitoring by both an obstetrician and nephrologist during pregnancy and the postpartum period. Although pregnancy does not appear to be an important risk factor for the development of ESKD in most women with PH1 [ Women with PH1 have had successful pregnancies following kidney transplantation alone and combined liver and kidney transplantation [ Lumasiran and nedosiran, recently approved for use in individuals with PH1 (see To date, no information is available regarding lumasiran or nedosiran transmission in breast milk; thus, risk to breast-feeding infants cannot be ruled out. Several novel therapies are under investigation. Small molecule inhibitors of LDHA for treatment of PH1 are in early clinical studies. Stiripentol, administered orally, inhibits activity of LDHA and is approved by the FDA for clinical use as an anti-seizure medication in Dravet syndrome. A few case reports have suggested a possible urine oxalate-reducing effect of stiripentol in PH1. However, to date, anecdotal evidence has been scattered, with effects in one report indistinguishable from those of concomitantly administered pyridoxine, and in individuals with PH1 with CKD or kidney failure, neither plasma oxalate concentration nor urine oxalate declined significantly [ Other efforts to insert oxalate-degrading enzymes into bacteria that inhabit normal intestinal flora [ Search • Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis • Baseline 24-hour urine collection with measurement of excretion rates of oxalate, calcium, and citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones • Note: Baseline measurement of 24-hour excretion rates is recommended in nearly all individuals, even those requiring catheter placement for accurate collection. In rare exceptions only a spot urine with concentrations corrected for creatinine content is used (see • Measurement of plasma oxalate concentration (see • Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentration • When chronic kidney disease (CKD) is stage 3b or higher, evaluate for systemic oxalate deposits (i.e., oxalosis) with: • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; • Echocardiography for evidence of cardiomyopathy; • Electrocardiogram for conduction disturbances; • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; • Echocardiography for evidence of cardiomyopathy; • Electrocardiogram for conduction disturbances; • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to obtain a pedigree and inform affected individuals and their families about the nature, mode of inheritance, and implications of PH1 to facilitate medical and personal decision making • Assessment of need for family support and • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; • Echocardiography for evidence of cardiomyopathy; • Electrocardiogram for conduction disturbances; • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. • ~30%-50% of individuals w/PH1 are pyridoxine responsive. • Since there are multiple mechanisms of pyridoxine response & only a few pathogenic variants have been tested, a trial of pyridoxine should be considered in all persons w/1 or 2 missense • FDA & EMA approved for persons of all ages • Experience using lumasiran in persons w/advanced CKD, on dialysis, or following kidney transplantation alone is limited. • A starting pyridoxine dose of 5 mg/kg/day is recommended. Stepwise increases in pyridoxine dose to a maximum of 10-20 mg/kg/day with assessments of response by measurement of urine oxalate excretion at each step determines the minimum effective dose. • Pyridoxine responsiveness can be difficult to determine in individuals with advanced CKD or end-stage kidney disease (ESKD), whose urinary oxalate excretion rates may be influenced by the low glomerular filtration rate (GFR). When the GFR is <30 mL/min/1.73 m • In double-blind, placebo-controlled trials of 39 individuals with PH1 (lumasiran-treated n=26, placebo n=13), lumasiran was highly effective in reducing urine and plasma oxalate concentrations [ • Lumasiran has been effective in infants and young children [ • Although early clinical trials demonstrated promising reductions in plasma and urine oxalate concentrations with lumasiran treatment [ • Because the currently approved lumasiran dose is administered subcutaneously on a monthly or quarterly basis (see • Schedule for Weight-Based Subcutaneous Administration of Lumasiran • A double-blind, placebo-controlled clinical trial that included 29 individuals with PH1 older than age six years and an eGFR >30 ml/in/1.73m • Nedosiran was well tolerated without serious adverse effects. • Nedosiran clinical trials are under way for individuals with PH1 and advanced CKD who are on dialysis (see • Kidney transplantation will continue to be the option for individuals who either have progressed to advanced CKD or ESKD before being diagnosed with PH1 or have not had the benefit of RNAi agents. Pre- and post-transplant management of kidney recipients with PH1 has been challenging and will be profoundly influenced by the ability to reduce hepatic oxalate production using siRNA therapeutics. Experience with use of such agents after kidney transplantation is thus far limited to case reports [ • When systemic oxalosis is present prior to transplantation, mobilization of systemic oxalate places the kidney allograft at risk until tissue oxalate stores are completely cleared [ • Clearance of tissue oxalate stores by a well-functioning kidney allograft requires months to more than five years following liver transplantation or RNAi reduction of oxalate production [ • Liver transplantation for PH1 should always be performed with complete removal of the native liver. • Pyridoxine supplementation in individuals who have been pyridoxine responsive can be discontinued at the time of liver transplantation, since normal AGT enzyme activity will have been restored. • Although most publications report transplantation of organs from deceased donors, living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an • Maintain high oral fluid intake to assure good urine volume. • Use oral citrate or pyrophosphate to inhibit calcium oxalate crystal formation. • Maintain high urine volume. • Minimize urine oxalate concentration. • Optimize urine citrate. • Consult w/urologist experienced in mgmt of PH. • Ureteroscopic mgmt of symptomatic stones preferred when appropriate. • Prompt attention to pain or other symptoms suggesting infection or possible urinary obstruction. • Use imaging studies at regular intervals to guide mgmt. • Avoid dehydration. • Avoid nephrotoxins that can cause kidney injury (e.g., NSAIDs). • Monitor plasma oxalate concentration during transient or permanent periods of low GFR. • Initiate dialysis promptly to ↓ oxalate concentration. • High oral fluid intake. Drinking large volumes of fluid (2-3 L/m • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Inhibition of calcium oxalate crystallization. If the GFR is preserved, increase urine citrate excretion using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in three to four divided doses. If the GFR is reduced or blood potassium concentration is elevated, sodium citrate can be used. • In individuals with good kidney function (eGFR >30 mL/min/1.73 m • In PH1 excess oxalate results from endogenous metabolism, not dietary intake of oxalate, and dietary restriction of oxalate intake is of little benefit. Thus, avoiding specific foods or beverages with very high oxalate content, without strict limits, is appropriate. • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Regular monitoring of kidney function. Serum creatinine and/or cystatin C for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease. • Regular kidney ultrasound examinations at least annually, or more often as needed to monitor and manage stone-forming activity • Urinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections) at least annually, more often in individuals with active stones or changes in kidney function • Kidney function • Kidney ultrasound for stones and incipient nephrocalcinosis • Urine oxalate and plasma oxalate concentrations • History and physical examination at least every three months for signs and symptoms of systemic oxalosis with assessment of growth and development (in children), bone or joint involvement, evidence of cardiomyopathy, signs of arterial insufficiency or ischemia, and skin examination for livedo reticularis, subcutaneous oxalate deposits, and/or ischemic ulcers • Serum creatinine and plasma oxalate concentrations, typically monthly or more often depending on clinical circumstances • Radiographs of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Obtain initially, then repeat for bone symptoms and/or pathologic fractures; more frequent bone evaluation is needed in infants and young children. • Ophthalmologic examination for visual acuity testing, evidence of retinal oxalate deposits, and optical coherence tomography (OCT) if available. Retinal photographs can be valuable to monitor changes over time. • Electrocardiogram to evaluate for associated atrioventricular block or other oxalate-related conduction abnormalities, repeated every six to 12 months • Echocardiogram for evidence of oxalate cardiomyopathy, repeated every 6-12 months. • Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate, repeated every three months • Thyroid function testing once a year • Regular dental examinations/care • Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized. • Intake of vitamin C that exceeds the recommended daily allowance • Loop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase calcium oxalate stone production • High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) or any pharmacologic agent that can compromise kidney function • Large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit) ## Evaluations Following Initial Diagnosis The following evaluations are recommended to establish the extent of disease and needs in an individual diagnosed with primary hyperoxaluria type 1 (PH1): Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis Baseline 24-hour urine collection with measurement of excretion rates of oxalate, calcium, and citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones Note: Baseline measurement of 24-hour excretion rates is recommended in nearly all individuals, even those requiring catheter placement for accurate collection. In rare exceptions only a spot urine with concentrations corrected for creatinine content is used (see Measurement of plasma oxalate concentration (see Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentration When chronic kidney disease (CKD) is stage 3b or higher, evaluate for systemic oxalate deposits (i.e., oxalosis) with: Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; Echocardiography for evidence of cardiomyopathy; Electrocardiogram for conduction disturbances; Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to obtain a pedigree and inform affected individuals and their families about the nature, mode of inheritance, and implications of PH1 to facilitate medical and personal decision making Assessment of need for family support and • Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis • Baseline 24-hour urine collection with measurement of excretion rates of oxalate, calcium, and citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones • Note: Baseline measurement of 24-hour excretion rates is recommended in nearly all individuals, even those requiring catheter placement for accurate collection. In rare exceptions only a spot urine with concentrations corrected for creatinine content is used (see • Measurement of plasma oxalate concentration (see • Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentration • When chronic kidney disease (CKD) is stage 3b or higher, evaluate for systemic oxalate deposits (i.e., oxalosis) with: • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; • Echocardiography for evidence of cardiomyopathy; • Electrocardiogram for conduction disturbances; • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; • Echocardiography for evidence of cardiomyopathy; • Electrocardiogram for conduction disturbances; • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to obtain a pedigree and inform affected individuals and their families about the nature, mode of inheritance, and implications of PH1 to facilitate medical and personal decision making • Assessment of need for family support and • Bone imaging for evidence of sclerosis and/or pathologic fractures due to oxalate osteodystrophy; • Ophthalmologic examination including visual acuity and retinal examination for retinal oxalate deposition; • Echocardiography for evidence of cardiomyopathy; • Electrocardiogram for conduction disturbances; • Complete blood count for evidence of anemia, with further studies as needed to determine if erythropoietin resistance is the cause. ## Treatment of Manifestations Management options for PH1 include targeted therapies and supportive care [ Targeted therapy for PH1 includes pyridoxine (for individuals with specific Note: Use of RNAi therapeutics to reduce hepatic oxalate production in pre- and post-transplantation management of kidney recipients is complicated; information to date is limited to case reports [ Because disease manifestations, including CKD or even kidney failure, are often present at the time of diagnosis, several approaches to targeted therapy are necessary (see Primary Hyperoxaluria Type 1: Targeted Therapies ~30%-50% of individuals w/PH1 are pyridoxine responsive. Since there are multiple mechanisms of pyridoxine response & only a few pathogenic variants have been tested, a trial of pyridoxine should be considered in all persons w/1 or 2 missense FDA & EMA approved for persons of all ages Experience using lumasiran in persons w/advanced CKD, on dialysis, or following kidney transplantation alone is limited. AGT = alanine-glyoxylate aminotransferase; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; EMA = European Medicines Agency; FDA = US Food and Drug Administration; GFR = glomerular filtration rate; LDHA = lactate dehydrogenase A; RNAi = RNA interference; siRNA = small interfering RNA Liver transplant is considered "targeted therapy" because it restores normal hepatic AGT function. Kidney transplant replaces kidney function but does not address the underlying cause of the disorder, and thus is considered supportive care. Pyridoxine response is assessed by comparing the 24-hour urine oxalate excretion rate before treatment and after at least three months of pyridoxine treatment at a minimum dose of 5 mg/kg/day. Reduction of ≥30% or normalization of urinary oxalate excretion while receiving pyridoxine indicates responsiveness [ Most individuals who are pyridoxine responsive show maximum benefit at a dose of 5-8 mg/kg/day [ A starting pyridoxine dose of 5 mg/kg/day is recommended. Stepwise increases in pyridoxine dose to a maximum of 10-20 mg/kg/day with assessments of response by measurement of urine oxalate excretion at each step determines the minimum effective dose. Pyridoxine responsiveness can be difficult to determine in individuals with advanced CKD or end-stage kidney disease (ESKD), whose urinary oxalate excretion rates may be influenced by the low glomerular filtration rate (GFR). When the GFR is <30 mL/min/1.73 m Certain Because 30%-50% of individuals with PH1 are pyridoxine responsive (and only a few Individuals responsive to pyridoxine should continue this therapy indefinitely or until successful orthotopic liver transplantation (when a liver with normal AGT enzyme activity replaces the liver with deficient AGT enzyme activity). Additionally, the recent availability of lumasiran and nedosiran requires comparing pyridoxine and siRNA therapeutic agents regarding efficacy, durability of effect, long-term tolerability, safety, and use under special circumstances such as pregnancy (see Pyridoxine has an excellent safety profile in individuals with PH1, even after decades of use. In contrast, peripheral neuropathy (including paresthesias) has been reported in individuals who do not have PH1 who were receiving very large doses of pyridoxine (typically, adults receiving 1-2 g/day) [ Nedosiran, a second siRNA therapeutic agent approved for PH1 in late 2023, targets a separate hepatic enzyme, lactate dehydrogenase A (LDHA) [ Additional data are needed to confirm long-term safety and efficacy of lumasiran and nedosiran in reversing the kidney-related effects of hepatic overproduction of oxalate. In double-blind, placebo-controlled trials of 39 individuals with PH1 (lumasiran-treated n=26, placebo n=13), lumasiran was highly effective in reducing urine and plasma oxalate concentrations [ Lumasiran has been effective in infants and young children [ Although early clinical trials demonstrated promising reductions in plasma and urine oxalate concentrations with lumasiran treatment [ Because the currently approved lumasiran dose is administered subcutaneously on a monthly or quarterly basis (see Schedule for Weight-Based Subcutaneous Administration of Lumasiran A double-blind, placebo-controlled clinical trial that included 29 individuals with PH1 older than age six years and an eGFR >30 ml/in/1.73m Nedosiran was well tolerated without serious adverse effects. Nedosiran clinical trials are under way for individuals with PH1 and advanced CKD who are on dialysis (see Until 2020 whole liver transplantation was – despite limited organ availability, high cost, and significant morbidity and mortality – the only intervention capable of restoring normal hepatic AGT enzyme activity and thus normalizing oxalate production. Liver and kidney transplantation were often performed either as a single combined procedure or sequential procedures, with similar outcomes achieved using either approach [ With recent availability of RNAi therapeutic agents capable of reducing hepatic oxalate production, some have suggested that liver transplantation may no longer be needed [ Points to consider regarding transplantation include the following: Kidney transplantation will continue to be the option for individuals who either have progressed to advanced CKD or ESKD before being diagnosed with PH1 or have not had the benefit of RNAi agents. Pre- and post-transplant management of kidney recipients with PH1 has been challenging and will be profoundly influenced by the ability to reduce hepatic oxalate production using siRNA therapeutics. Experience with use of such agents after kidney transplantation is thus far limited to case reports [ When systemic oxalosis is present prior to transplantation, mobilization of systemic oxalate places the kidney allograft at risk until tissue oxalate stores are completely cleared [ Clearance of tissue oxalate stores by a well-functioning kidney allograft requires months to more than five years following liver transplantation or RNAi reduction of oxalate production [ Liver transplantation for PH1 should always be performed with complete removal of the native liver. Pyridoxine supplementation in individuals who have been pyridoxine responsive can be discontinued at the time of liver transplantation, since normal AGT enzyme activity will have been restored. Although most publications report transplantation of organs from deceased donors, living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an Early diagnosis of PH1 with initiation of supportive care (also referred to as conservative treatment) aims to prevent crystal injury to kidneys, reduce stone formation and stone-related kidney damage, preserve kidney function, and prevent systemic oxalosis (see Primary Hyperoxaluria Type 1: Supportive Care Maintain high oral fluid intake to assure good urine volume. Use oral citrate or pyrophosphate to inhibit calcium oxalate crystal formation. Maintain high urine volume. Minimize urine oxalate concentration. Optimize urine citrate. Consult w/urologist experienced in mgmt of PH. Ureteroscopic mgmt of symptomatic stones preferred when appropriate. Prompt attention to pain or other symptoms suggesting infection or possible urinary obstruction. Use imaging studies at regular intervals to guide mgmt. Avoid dehydration. Avoid nephrotoxins that can cause kidney injury (e.g., NSAIDs). Monitor plasma oxalate concentration during transient or permanent periods of low GFR. Initiate dialysis promptly to ↓ oxalate concentration. GFR = glomerular filtration rate; NSAID = nonsteroidal anti-inflammatory drug; PH = primary hyperoxaluria High oral fluid intake. Drinking large volumes of fluid (2-3 L/m Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. Inhibition of calcium oxalate crystallization. If the GFR is preserved, increase urine citrate excretion using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in three to four divided doses. If the GFR is reduced or blood potassium concentration is elevated, sodium citrate can be used. In individuals with good kidney function (eGFR >30 mL/min/1.73 m In PH1 excess oxalate results from endogenous metabolism, not dietary intake of oxalate, and dietary restriction of oxalate intake is of little benefit. Thus, avoiding specific foods or beverages with very high oxalate content, without strict limits, is appropriate. Since recurring symptomatic stone events requiring urologic interventions are common, consultation with a urologist experienced in the care of individuals with PH1 helps individualize care and improve outcomes, particularly when specialized equipment and techniques may be required for infants and small children [ Calcium oxalate stones can be resistant to shock wave lithotripsy (SWL); nephrocalcinosis can also complicate stone management. Because stone removal can result in acute kidney failure, interventions least likely to cause kidney injury are preferred [ Surgical modalities used for stone management include the following: Hemodialysis is the primary dialysis modality used in persons with PH1 with kidney failure to reduce plasma oxalate concentration to prevent or treat oxalosis; however, absent targeted therapy to reduce hepatic oxalate production, the high rate of oxalate production (often 2-7 mmol/1.73 m Current guidelines suggest reducing and maintaining plasma oxalate concentration below 30-45 µmol/L (the calcium oxalate supersaturation threshold at which tissue deposition occurs) as long as possible between dialysis sessions. Although most individuals with PH1 require four or more dialysis sessions per week to maintain acceptable plasma oxalate concentrations, significant individual variation in oxalate production requires individualization of dialysis prescriptions [ Following increasing clinical experience with RNAi therapeutics effective in reducing hepatic oxalate production in individuals with PH1, it is expected that guidelines for PH1 [ • ~30%-50% of individuals w/PH1 are pyridoxine responsive. • Since there are multiple mechanisms of pyridoxine response & only a few pathogenic variants have been tested, a trial of pyridoxine should be considered in all persons w/1 or 2 missense • FDA & EMA approved for persons of all ages • Experience using lumasiran in persons w/advanced CKD, on dialysis, or following kidney transplantation alone is limited. • A starting pyridoxine dose of 5 mg/kg/day is recommended. Stepwise increases in pyridoxine dose to a maximum of 10-20 mg/kg/day with assessments of response by measurement of urine oxalate excretion at each step determines the minimum effective dose. • Pyridoxine responsiveness can be difficult to determine in individuals with advanced CKD or end-stage kidney disease (ESKD), whose urinary oxalate excretion rates may be influenced by the low glomerular filtration rate (GFR). When the GFR is <30 mL/min/1.73 m • In double-blind, placebo-controlled trials of 39 individuals with PH1 (lumasiran-treated n=26, placebo n=13), lumasiran was highly effective in reducing urine and plasma oxalate concentrations [ • Lumasiran has been effective in infants and young children [ • Although early clinical trials demonstrated promising reductions in plasma and urine oxalate concentrations with lumasiran treatment [ • Because the currently approved lumasiran dose is administered subcutaneously on a monthly or quarterly basis (see • Schedule for Weight-Based Subcutaneous Administration of Lumasiran • A double-blind, placebo-controlled clinical trial that included 29 individuals with PH1 older than age six years and an eGFR >30 ml/in/1.73m • Nedosiran was well tolerated without serious adverse effects. • Nedosiran clinical trials are under way for individuals with PH1 and advanced CKD who are on dialysis (see • Kidney transplantation will continue to be the option for individuals who either have progressed to advanced CKD or ESKD before being diagnosed with PH1 or have not had the benefit of RNAi agents. Pre- and post-transplant management of kidney recipients with PH1 has been challenging and will be profoundly influenced by the ability to reduce hepatic oxalate production using siRNA therapeutics. Experience with use of such agents after kidney transplantation is thus far limited to case reports [ • When systemic oxalosis is present prior to transplantation, mobilization of systemic oxalate places the kidney allograft at risk until tissue oxalate stores are completely cleared [ • Clearance of tissue oxalate stores by a well-functioning kidney allograft requires months to more than five years following liver transplantation or RNAi reduction of oxalate production [ • Liver transplantation for PH1 should always be performed with complete removal of the native liver. • Pyridoxine supplementation in individuals who have been pyridoxine responsive can be discontinued at the time of liver transplantation, since normal AGT enzyme activity will have been restored. • Although most publications report transplantation of organs from deceased donors, living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an • Maintain high oral fluid intake to assure good urine volume. • Use oral citrate or pyrophosphate to inhibit calcium oxalate crystal formation. • Maintain high urine volume. • Minimize urine oxalate concentration. • Optimize urine citrate. • Consult w/urologist experienced in mgmt of PH. • Ureteroscopic mgmt of symptomatic stones preferred when appropriate. • Prompt attention to pain or other symptoms suggesting infection or possible urinary obstruction. • Use imaging studies at regular intervals to guide mgmt. • Avoid dehydration. • Avoid nephrotoxins that can cause kidney injury (e.g., NSAIDs). • Monitor plasma oxalate concentration during transient or permanent periods of low GFR. • Initiate dialysis promptly to ↓ oxalate concentration. • High oral fluid intake. Drinking large volumes of fluid (2-3 L/m • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Inhibition of calcium oxalate crystallization. If the GFR is preserved, increase urine citrate excretion using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in three to four divided doses. If the GFR is reduced or blood potassium concentration is elevated, sodium citrate can be used. • In individuals with good kidney function (eGFR >30 mL/min/1.73 m • In PH1 excess oxalate results from endogenous metabolism, not dietary intake of oxalate, and dietary restriction of oxalate intake is of little benefit. Thus, avoiding specific foods or beverages with very high oxalate content, without strict limits, is appropriate. • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. ## Targeted Therapies Targeted therapy for PH1 includes pyridoxine (for individuals with specific Note: Use of RNAi therapeutics to reduce hepatic oxalate production in pre- and post-transplantation management of kidney recipients is complicated; information to date is limited to case reports [ Because disease manifestations, including CKD or even kidney failure, are often present at the time of diagnosis, several approaches to targeted therapy are necessary (see Primary Hyperoxaluria Type 1: Targeted Therapies ~30%-50% of individuals w/PH1 are pyridoxine responsive. Since there are multiple mechanisms of pyridoxine response & only a few pathogenic variants have been tested, a trial of pyridoxine should be considered in all persons w/1 or 2 missense FDA & EMA approved for persons of all ages Experience using lumasiran in persons w/advanced CKD, on dialysis, or following kidney transplantation alone is limited. AGT = alanine-glyoxylate aminotransferase; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; EMA = European Medicines Agency; FDA = US Food and Drug Administration; GFR = glomerular filtration rate; LDHA = lactate dehydrogenase A; RNAi = RNA interference; siRNA = small interfering RNA Liver transplant is considered "targeted therapy" because it restores normal hepatic AGT function. Kidney transplant replaces kidney function but does not address the underlying cause of the disorder, and thus is considered supportive care. Pyridoxine response is assessed by comparing the 24-hour urine oxalate excretion rate before treatment and after at least three months of pyridoxine treatment at a minimum dose of 5 mg/kg/day. Reduction of ≥30% or normalization of urinary oxalate excretion while receiving pyridoxine indicates responsiveness [ Most individuals who are pyridoxine responsive show maximum benefit at a dose of 5-8 mg/kg/day [ A starting pyridoxine dose of 5 mg/kg/day is recommended. Stepwise increases in pyridoxine dose to a maximum of 10-20 mg/kg/day with assessments of response by measurement of urine oxalate excretion at each step determines the minimum effective dose. Pyridoxine responsiveness can be difficult to determine in individuals with advanced CKD or end-stage kidney disease (ESKD), whose urinary oxalate excretion rates may be influenced by the low glomerular filtration rate (GFR). When the GFR is <30 mL/min/1.73 m Certain Because 30%-50% of individuals with PH1 are pyridoxine responsive (and only a few Individuals responsive to pyridoxine should continue this therapy indefinitely or until successful orthotopic liver transplantation (when a liver with normal AGT enzyme activity replaces the liver with deficient AGT enzyme activity). Additionally, the recent availability of lumasiran and nedosiran requires comparing pyridoxine and siRNA therapeutic agents regarding efficacy, durability of effect, long-term tolerability, safety, and use under special circumstances such as pregnancy (see Pyridoxine has an excellent safety profile in individuals with PH1, even after decades of use. In contrast, peripheral neuropathy (including paresthesias) has been reported in individuals who do not have PH1 who were receiving very large doses of pyridoxine (typically, adults receiving 1-2 g/day) [ Nedosiran, a second siRNA therapeutic agent approved for PH1 in late 2023, targets a separate hepatic enzyme, lactate dehydrogenase A (LDHA) [ Additional data are needed to confirm long-term safety and efficacy of lumasiran and nedosiran in reversing the kidney-related effects of hepatic overproduction of oxalate. In double-blind, placebo-controlled trials of 39 individuals with PH1 (lumasiran-treated n=26, placebo n=13), lumasiran was highly effective in reducing urine and plasma oxalate concentrations [ Lumasiran has been effective in infants and young children [ Although early clinical trials demonstrated promising reductions in plasma and urine oxalate concentrations with lumasiran treatment [ Because the currently approved lumasiran dose is administered subcutaneously on a monthly or quarterly basis (see Schedule for Weight-Based Subcutaneous Administration of Lumasiran A double-blind, placebo-controlled clinical trial that included 29 individuals with PH1 older than age six years and an eGFR >30 ml/in/1.73m Nedosiran was well tolerated without serious adverse effects. Nedosiran clinical trials are under way for individuals with PH1 and advanced CKD who are on dialysis (see Until 2020 whole liver transplantation was – despite limited organ availability, high cost, and significant morbidity and mortality – the only intervention capable of restoring normal hepatic AGT enzyme activity and thus normalizing oxalate production. Liver and kidney transplantation were often performed either as a single combined procedure or sequential procedures, with similar outcomes achieved using either approach [ With recent availability of RNAi therapeutic agents capable of reducing hepatic oxalate production, some have suggested that liver transplantation may no longer be needed [ Points to consider regarding transplantation include the following: Kidney transplantation will continue to be the option for individuals who either have progressed to advanced CKD or ESKD before being diagnosed with PH1 or have not had the benefit of RNAi agents. Pre- and post-transplant management of kidney recipients with PH1 has been challenging and will be profoundly influenced by the ability to reduce hepatic oxalate production using siRNA therapeutics. Experience with use of such agents after kidney transplantation is thus far limited to case reports [ When systemic oxalosis is present prior to transplantation, mobilization of systemic oxalate places the kidney allograft at risk until tissue oxalate stores are completely cleared [ Clearance of tissue oxalate stores by a well-functioning kidney allograft requires months to more than five years following liver transplantation or RNAi reduction of oxalate production [ Liver transplantation for PH1 should always be performed with complete removal of the native liver. Pyridoxine supplementation in individuals who have been pyridoxine responsive can be discontinued at the time of liver transplantation, since normal AGT enzyme activity will have been restored. Although most publications report transplantation of organs from deceased donors, living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an • ~30%-50% of individuals w/PH1 are pyridoxine responsive. • Since there are multiple mechanisms of pyridoxine response & only a few pathogenic variants have been tested, a trial of pyridoxine should be considered in all persons w/1 or 2 missense • FDA & EMA approved for persons of all ages • Experience using lumasiran in persons w/advanced CKD, on dialysis, or following kidney transplantation alone is limited. • A starting pyridoxine dose of 5 mg/kg/day is recommended. Stepwise increases in pyridoxine dose to a maximum of 10-20 mg/kg/day with assessments of response by measurement of urine oxalate excretion at each step determines the minimum effective dose. • Pyridoxine responsiveness can be difficult to determine in individuals with advanced CKD or end-stage kidney disease (ESKD), whose urinary oxalate excretion rates may be influenced by the low glomerular filtration rate (GFR). When the GFR is <30 mL/min/1.73 m • In double-blind, placebo-controlled trials of 39 individuals with PH1 (lumasiran-treated n=26, placebo n=13), lumasiran was highly effective in reducing urine and plasma oxalate concentrations [ • Lumasiran has been effective in infants and young children [ • Although early clinical trials demonstrated promising reductions in plasma and urine oxalate concentrations with lumasiran treatment [ • Because the currently approved lumasiran dose is administered subcutaneously on a monthly or quarterly basis (see • Schedule for Weight-Based Subcutaneous Administration of Lumasiran • A double-blind, placebo-controlled clinical trial that included 29 individuals with PH1 older than age six years and an eGFR >30 ml/in/1.73m • Nedosiran was well tolerated without serious adverse effects. • Nedosiran clinical trials are under way for individuals with PH1 and advanced CKD who are on dialysis (see • Kidney transplantation will continue to be the option for individuals who either have progressed to advanced CKD or ESKD before being diagnosed with PH1 or have not had the benefit of RNAi agents. Pre- and post-transplant management of kidney recipients with PH1 has been challenging and will be profoundly influenced by the ability to reduce hepatic oxalate production using siRNA therapeutics. Experience with use of such agents after kidney transplantation is thus far limited to case reports [ • When systemic oxalosis is present prior to transplantation, mobilization of systemic oxalate places the kidney allograft at risk until tissue oxalate stores are completely cleared [ • Clearance of tissue oxalate stores by a well-functioning kidney allograft requires months to more than five years following liver transplantation or RNAi reduction of oxalate production [ • Liver transplantation for PH1 should always be performed with complete removal of the native liver. • Pyridoxine supplementation in individuals who have been pyridoxine responsive can be discontinued at the time of liver transplantation, since normal AGT enzyme activity will have been restored. • Although most publications report transplantation of organs from deceased donors, living donor kidney or liver allografts are viable alternatives in some situations. It is important to note that the appropriateness of using a parent or sib who is heterozygous for an ## Supportive Care Early diagnosis of PH1 with initiation of supportive care (also referred to as conservative treatment) aims to prevent crystal injury to kidneys, reduce stone formation and stone-related kidney damage, preserve kidney function, and prevent systemic oxalosis (see Primary Hyperoxaluria Type 1: Supportive Care Maintain high oral fluid intake to assure good urine volume. Use oral citrate or pyrophosphate to inhibit calcium oxalate crystal formation. Maintain high urine volume. Minimize urine oxalate concentration. Optimize urine citrate. Consult w/urologist experienced in mgmt of PH. Ureteroscopic mgmt of symptomatic stones preferred when appropriate. Prompt attention to pain or other symptoms suggesting infection or possible urinary obstruction. Use imaging studies at regular intervals to guide mgmt. Avoid dehydration. Avoid nephrotoxins that can cause kidney injury (e.g., NSAIDs). Monitor plasma oxalate concentration during transient or permanent periods of low GFR. Initiate dialysis promptly to ↓ oxalate concentration. GFR = glomerular filtration rate; NSAID = nonsteroidal anti-inflammatory drug; PH = primary hyperoxaluria High oral fluid intake. Drinking large volumes of fluid (2-3 L/m Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. Inhibition of calcium oxalate crystallization. If the GFR is preserved, increase urine citrate excretion using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in three to four divided doses. If the GFR is reduced or blood potassium concentration is elevated, sodium citrate can be used. In individuals with good kidney function (eGFR >30 mL/min/1.73 m In PH1 excess oxalate results from endogenous metabolism, not dietary intake of oxalate, and dietary restriction of oxalate intake is of little benefit. Thus, avoiding specific foods or beverages with very high oxalate content, without strict limits, is appropriate. Since recurring symptomatic stone events requiring urologic interventions are common, consultation with a urologist experienced in the care of individuals with PH1 helps individualize care and improve outcomes, particularly when specialized equipment and techniques may be required for infants and small children [ Calcium oxalate stones can be resistant to shock wave lithotripsy (SWL); nephrocalcinosis can also complicate stone management. Because stone removal can result in acute kidney failure, interventions least likely to cause kidney injury are preferred [ Surgical modalities used for stone management include the following: Hemodialysis is the primary dialysis modality used in persons with PH1 with kidney failure to reduce plasma oxalate concentration to prevent or treat oxalosis; however, absent targeted therapy to reduce hepatic oxalate production, the high rate of oxalate production (often 2-7 mmol/1.73 m Current guidelines suggest reducing and maintaining plasma oxalate concentration below 30-45 µmol/L (the calcium oxalate supersaturation threshold at which tissue deposition occurs) as long as possible between dialysis sessions. Although most individuals with PH1 require four or more dialysis sessions per week to maintain acceptable plasma oxalate concentrations, significant individual variation in oxalate production requires individualization of dialysis prescriptions [ Following increasing clinical experience with RNAi therapeutics effective in reducing hepatic oxalate production in individuals with PH1, it is expected that guidelines for PH1 [ • Maintain high oral fluid intake to assure good urine volume. • Use oral citrate or pyrophosphate to inhibit calcium oxalate crystal formation. • Maintain high urine volume. • Minimize urine oxalate concentration. • Optimize urine citrate. • Consult w/urologist experienced in mgmt of PH. • Ureteroscopic mgmt of symptomatic stones preferred when appropriate. • Prompt attention to pain or other symptoms suggesting infection or possible urinary obstruction. • Use imaging studies at regular intervals to guide mgmt. • Avoid dehydration. • Avoid nephrotoxins that can cause kidney injury (e.g., NSAIDs). • Monitor plasma oxalate concentration during transient or permanent periods of low GFR. • Initiate dialysis promptly to ↓ oxalate concentration. • High oral fluid intake. Drinking large volumes of fluid (2-3 L/m • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. • Inhibition of calcium oxalate crystallization. If the GFR is preserved, increase urine citrate excretion using oral potassium citrate at a dose of 0.1-0.15 mg/kg or 0.3-0.5 mmol/kg/day in three to four divided doses. If the GFR is reduced or blood potassium concentration is elevated, sodium citrate can be used. • In individuals with good kidney function (eGFR >30 mL/min/1.73 m • In PH1 excess oxalate results from endogenous metabolism, not dietary intake of oxalate, and dietary restriction of oxalate intake is of little benefit. Thus, avoiding specific foods or beverages with very high oxalate content, without strict limits, is appropriate. • Small children may require gastrostomy tube placement or nasogastric tube for feeding and fluid supplementation. • Extreme care should be taken during any illness that could lead to hypovolemia or decreased oral fluid intake; individuals should be advised to seek early medical attention to initiate intravenous fluids if needed to maintain urine volume. ## Surveillance Individuals with PH1 require lifelong care, the frequency of which is related to kidney function [ Regular monitoring of kidney function. Serum creatinine and/or cystatin C for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease. Regular kidney ultrasound examinations at least annually, or more often as needed to monitor and manage stone-forming activity Urinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections) at least annually, more often in individuals with active stones or changes in kidney function Kidney function Kidney ultrasound for stones and incipient nephrocalcinosis Urine oxalate and plasma oxalate concentrations History and physical examination at least every three months for signs and symptoms of systemic oxalosis with assessment of growth and development (in children), bone or joint involvement, evidence of cardiomyopathy, signs of arterial insufficiency or ischemia, and skin examination for livedo reticularis, subcutaneous oxalate deposits, and/or ischemic ulcers Serum creatinine and plasma oxalate concentrations, typically monthly or more often depending on clinical circumstances Radiographs of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Obtain initially, then repeat for bone symptoms and/or pathologic fractures; more frequent bone evaluation is needed in infants and young children. Ophthalmologic examination for visual acuity testing, evidence of retinal oxalate deposits, and optical coherence tomography (OCT) if available. Retinal photographs can be valuable to monitor changes over time. Electrocardiogram to evaluate for associated atrioventricular block or other oxalate-related conduction abnormalities, repeated every six to 12 months Echocardiogram for evidence of oxalate cardiomyopathy, repeated every 6-12 months. Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate, repeated every three months Thyroid function testing once a year Regular dental examinations/care Note: Evaluations should occur more often in newly diagnosed symptomatic individuals or in children younger than ages two to three years. • Regular monitoring of kidney function. Serum creatinine and/or cystatin C for determination of eGFR should be performed at least annually and more frequently in children and adolescents and in individuals with changing kidney function or clinically active stone disease. • Regular kidney ultrasound examinations at least annually, or more often as needed to monitor and manage stone-forming activity • Urinalysis and measurements of urine oxalate excretion, urine volume, and calcium oxalate saturation (spot and 24-hour collections) at least annually, more often in individuals with active stones or changes in kidney function • Kidney function • Kidney ultrasound for stones and incipient nephrocalcinosis • Urine oxalate and plasma oxalate concentrations • History and physical examination at least every three months for signs and symptoms of systemic oxalosis with assessment of growth and development (in children), bone or joint involvement, evidence of cardiomyopathy, signs of arterial insufficiency or ischemia, and skin examination for livedo reticularis, subcutaneous oxalate deposits, and/or ischemic ulcers • Serum creatinine and plasma oxalate concentrations, typically monthly or more often depending on clinical circumstances • Radiographs of the long bones to evaluate for radiodense metaphyseal bands and diffuse demineralization. Obtain initially, then repeat for bone symptoms and/or pathologic fractures; more frequent bone evaluation is needed in infants and young children. • Ophthalmologic examination for visual acuity testing, evidence of retinal oxalate deposits, and optical coherence tomography (OCT) if available. Retinal photographs can be valuable to monitor changes over time. • Electrocardiogram to evaluate for associated atrioventricular block or other oxalate-related conduction abnormalities, repeated every six to 12 months • Echocardiogram for evidence of oxalate cardiomyopathy, repeated every 6-12 months. • Hemoglobin to evaluate for anemia associated with either renal dysfunction or marrow deposition of oxalate, repeated every three months • Thyroid function testing once a year • Regular dental examinations/care ## Agents/Circumstances to Avoid Avoid the following: Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized. Intake of vitamin C that exceeds the recommended daily allowance Loop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase calcium oxalate stone production High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) or any pharmacologic agent that can compromise kidney function Large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit) • Intravascular volume depletion. The importance of maintaining dilute urine cannot be overemphasized. • Intake of vitamin C that exceeds the recommended daily allowance • Loop diuretics to maintain dilute urine, as they can lead to hypercalciuria and increase calcium oxalate stone production • High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) or any pharmacologic agent that can compromise kidney function • Large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit) ## Evaluation of Relatives at Risk See ## Pregnancy Management Of note, women with PH1 warrant close monitoring by both an obstetrician and nephrologist during pregnancy and the postpartum period. Although pregnancy does not appear to be an important risk factor for the development of ESKD in most women with PH1 [ Women with PH1 have had successful pregnancies following kidney transplantation alone and combined liver and kidney transplantation [ Lumasiran and nedosiran, recently approved for use in individuals with PH1 (see To date, no information is available regarding lumasiran or nedosiran transmission in breast milk; thus, risk to breast-feeding infants cannot be ruled out. ## Therapies Under Investigation Several novel therapies are under investigation. Small molecule inhibitors of LDHA for treatment of PH1 are in early clinical studies. Stiripentol, administered orally, inhibits activity of LDHA and is approved by the FDA for clinical use as an anti-seizure medication in Dravet syndrome. A few case reports have suggested a possible urine oxalate-reducing effect of stiripentol in PH1. However, to date, anecdotal evidence has been scattered, with effects in one report indistinguishable from those of concomitantly administered pyridoxine, and in individuals with PH1 with CKD or kidney failure, neither plasma oxalate concentration nor urine oxalate declined significantly [ Other efforts to insert oxalate-degrading enzymes into bacteria that inhabit normal intestinal flora [ Search ## Genetic Counseling Primary hyperoxaluria type 1 (PH1) is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for an Targeted molecular genetic testing for the If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an The age at onset and clinical manifestations can vary widely among sibs with the same biallelic Given the variability in clinical expression, significant disease risk in asymptomatic individuals [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has PH1 or is a carrier of an One family with pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported: offspring of an affected individual and a carrier were affected [ Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an • Targeted molecular genetic testing for the • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ • If both parents are known to be heterozygous for an • The age at onset and clinical manifestations can vary widely among sibs with the same biallelic • Given the variability in clinical expression, significant disease risk in asymptomatic individuals [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has PH1 or is a carrier of an • One family with pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported: offspring of an affected individual and a carrier were affected [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Primary hyperoxaluria type 1 (PH1) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an Targeted molecular genetic testing for the If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an The age at onset and clinical manifestations can vary widely among sibs with the same biallelic Given the variability in clinical expression, significant disease risk in asymptomatic individuals [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has PH1 or is a carrier of an One family with pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported: offspring of an affected individual and a carrier were affected [ • The parents of an affected individual are presumed to be heterozygous for an • Targeted molecular genetic testing for the • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • One individual with PH1 caused by maternal chromosome 2 telomeric isodisomy has been reported. The affected individual was homozygous for the common p.Lys12GlnfsTer156 pathogenic variant. The mother was heterozygous for the variant; the variant was absent in the father [ • If both parents are known to be heterozygous for an • The age at onset and clinical manifestations can vary widely among sibs with the same biallelic • Given the variability in clinical expression, significant disease risk in asymptomatic individuals [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has PH1 or is a carrier of an • One family with pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported: offspring of an affected individual and a carrier were affected [ ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • United Kingdom • • • • • • • ## Molecular Genetics Primary Hyperoxaluria Type 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Primary Hyperoxaluria Type 1 ( Abnormal AGT function can also result from: Family segregation studies can sometimes be helpful to classify a VUS as pathogenic or benign. Enzyme analysis can be used to identify alanine-glyoxylate aminotransferase (AGT) enzyme deficiency. Note that such testing requires use of liver tissue obtained by liver biopsy. Variants listed in the table have been provided by the authors. • Family segregation studies can sometimes be helpful to classify a VUS as pathogenic or benign. • Enzyme analysis can be used to identify alanine-glyoxylate aminotransferase (AGT) enzyme deficiency. Note that such testing requires use of liver tissue obtained by liver biopsy. ## Molecular Pathogenesis Abnormal AGT function can also result from: Family segregation studies can sometimes be helpful to classify a VUS as pathogenic or benign. Enzyme analysis can be used to identify alanine-glyoxylate aminotransferase (AGT) enzyme deficiency. Note that such testing requires use of liver tissue obtained by liver biopsy. Variants listed in the table have been provided by the authors. • Family segregation studies can sometimes be helpful to classify a VUS as pathogenic or benign. • Enzyme analysis can be used to identify alanine-glyoxylate aminotransferase (AGT) enzyme deficiency. Note that such testing requires use of liver tissue obtained by liver biopsy. ## Chapter Notes The Oxalosis and Hyperoxaluria Foundation (OHF; The OHF and RKSC are also interested in hearing from clinicians treating families affected by frequent kidney stones, nephrocalcinosis, and/or kidney failure in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Peter C Harris ( The authors gratefully acknowledge research support from the NIDDK and NCATS (U54KD083908, and DK133171) and support from the OHF for the RKSC OHF Primary Hyperoxaluria Registry. We are indebted to the many referring physicians, patients, and families for their contributions to the PH Registry. Ben H Chew, MD, MSc, FRCSC; University of British Columbia (2009-2017)Andrea G Cogal (2017-present)Marion B Coulter-Mackie, PhD; BC Children's Hospital and BC Women's Hospital & Health Centre (2002-2017)Peter C Harris, PhD (2017-present)R Morrison Hurley, MD, MSc, FRCPC; BC Children's Hospital (2002-2014)Dirk Lange, PhD; University of British Columbia (2009-2017)John C Lieske, MD (2017-present)Dawn S Milliner, MD (2017-present)David J Sas, DO (2022-present)Colin T White, MD; BC Children's Hospital and BC Women's Hospital & Health Centre (2002-2017) 15 August 2024 (bp) Comprehensive update posted live 30 November 2017 (sw) Comprehensive update posted live 17 July 2014 (me) Comprehensive update posted live 17 November 2011 (me) Comprehensive update posted live 11 August 2009 (me) Comprehensive update posted live 21 December 2006 (me) Comprehensive update posted live 25 June 2004 (me) Comprehensive update posted live 19 June 2002 (me) Review posted live 4 January 2002 (rmh) Original submission • 15 August 2024 (bp) Comprehensive update posted live • 30 November 2017 (sw) Comprehensive update posted live • 17 July 2014 (me) Comprehensive update posted live • 17 November 2011 (me) Comprehensive update posted live • 11 August 2009 (me) Comprehensive update posted live • 21 December 2006 (me) Comprehensive update posted live • 25 June 2004 (me) Comprehensive update posted live • 19 June 2002 (me) Review posted live • 4 January 2002 (rmh) Original submission ## Author Notes The Oxalosis and Hyperoxaluria Foundation (OHF; The OHF and RKSC are also interested in hearing from clinicians treating families affected by frequent kidney stones, nephrocalcinosis, and/or kidney failure in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Peter C Harris ( ## Acknowledgments The authors gratefully acknowledge research support from the NIDDK and NCATS (U54KD083908, and DK133171) and support from the OHF for the RKSC OHF Primary Hyperoxaluria Registry. We are indebted to the many referring physicians, patients, and families for their contributions to the PH Registry. ## Author History Ben H Chew, MD, MSc, FRCSC; University of British Columbia (2009-2017)Andrea G Cogal (2017-present)Marion B Coulter-Mackie, PhD; BC Children's Hospital and BC Women's Hospital & Health Centre (2002-2017)Peter C Harris, PhD (2017-present)R Morrison Hurley, MD, MSc, FRCPC; BC Children's Hospital (2002-2014)Dirk Lange, PhD; University of British Columbia (2009-2017)John C Lieske, MD (2017-present)Dawn S Milliner, MD (2017-present)David J Sas, DO (2022-present)Colin T White, MD; BC Children's Hospital and BC Women's Hospital & Health Centre (2002-2017) ## Revision History 15 August 2024 (bp) Comprehensive update posted live 30 November 2017 (sw) Comprehensive update posted live 17 July 2014 (me) Comprehensive update posted live 17 November 2011 (me) Comprehensive update posted live 11 August 2009 (me) Comprehensive update posted live 21 December 2006 (me) Comprehensive update posted live 25 June 2004 (me) Comprehensive update posted live 19 June 2002 (me) Review posted live 4 January 2002 (rmh) Original submission • 15 August 2024 (bp) Comprehensive update posted live • 30 November 2017 (sw) Comprehensive update posted live • 17 July 2014 (me) Comprehensive update posted live • 17 November 2011 (me) Comprehensive update posted live • 11 August 2009 (me) Comprehensive update posted live • 21 December 2006 (me) Comprehensive update posted live • 25 June 2004 (me) Comprehensive update posted live • 19 June 2002 (me) Review posted live • 4 January 2002 (rmh) Original submission ## Key Sections in This ## References ## Literature Cited Algorithm for diagnostic evaluation of primary hyperoxaluria Reproduced with permission from	[]	19/6/2002	15/8/2024	10/2/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ph2	ph2	[ "Glyoxylate Reductase/Hydroxypyruvate Reductase Deficiency", "Glyoxylate Reductase/Hydroxypyruvate Reductase Deficiency", "Glyoxylate reductase/hydroxypyruvate reductase", "GRHPR", "Primary Hyperoxaluria Type 2" ]	Primary Hyperoxaluria Type 2	Gill Rumsby, Sally-Anne Hulton	Summary Primary hyperoxaluria type 2 (PH2), caused by deficiency of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GR/HPR), is characterized by recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis / urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), and end-stage kidney disease (ESKD). After ESKD, oxalosis (widespread tissue deposition of calcium oxalate) usually develops. Symptom onset is typically in childhood. The diagnosis of PH2 is established in a proband by identification of biallelic pathogenic variants in PH2 is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.	## Diagnosis Primary hyperoxaluria type 2 (PH2) Symptoms of nephrolithiasis (e.g., hematuria, renal colic, obstruction of the urinary tract) Frequent recurrent nephrolithiasis Nephrocalcinosis End-stage kidney disease with a history of nephrolithiasis The diagnosis of PH2 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 2 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Author, personal communication Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. The enzyme is primarily expressed in the liver [ Note: The enzyme has also been shown to be expressed in leukocytes [ • Symptoms of nephrolithiasis (e.g., hematuria, renal colic, obstruction of the urinary tract) • Frequent recurrent nephrolithiasis • Nephrocalcinosis • End-stage kidney disease with a history of nephrolithiasis • For an introduction to multigene panels click • The enzyme is primarily expressed in the liver [ • Note: The enzyme has also been shown to be expressed in leukocytes [ ## Suggestive Findings Primary hyperoxaluria type 2 (PH2) Symptoms of nephrolithiasis (e.g., hematuria, renal colic, obstruction of the urinary tract) Frequent recurrent nephrolithiasis Nephrocalcinosis End-stage kidney disease with a history of nephrolithiasis • Symptoms of nephrolithiasis (e.g., hematuria, renal colic, obstruction of the urinary tract) • Frequent recurrent nephrolithiasis • Nephrocalcinosis • End-stage kidney disease with a history of nephrolithiasis ## Establishing the Diagnosis The diagnosis of PH2 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 2 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Author, personal communication Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. The enzyme is primarily expressed in the liver [ Note: The enzyme has also been shown to be expressed in leukocytes [ • For an introduction to multigene panels click • The enzyme is primarily expressed in the liver [ • Note: The enzyme has also been shown to be expressed in leukocytes [ ## Clinical Characteristics The age of onset of primary hyperoxaluria type 2 (PH2) is typically in childhood [ Presenting symptoms are typically those associated with the presence of kidney stones including hematuria, renal colic, or obstruction of the urinary tract [ The majority of individuals have kidney stones composed of calcium oxalate [ Nephrocalcinosis, observed on ultrasound examination, abdominal radiograph, or CT examination, is a much less common finding in PH2 than in PH1. The disease can progress to ESKD although this outcome appears to be later in PH2 than in PH1, in which 50% of affected individuals have ESKD by age 25 years [ Oxalate deposition in bone results in radiograph findings of transverse translucent symmetric bands with fixed sclerotic margins at the end of long bones followed by cystic rarefaction of the bones. Osteodystrophy causes bone pain and multiple pathologic fractures occur in advanced disease. Involvement of the bone marrow can result in anemia refractory to erythropoietin-stimulating agents. Additional clinical manifestations of oxalosis may include visual disturbance due to retinopathy and/or maculopathy, cardiac conduction disturbances such as heart block, cardiomyopathy, and synovitis secondary to oxalate deposition in the joints. Vascular involvement can lead to ischemia, most often manifest as non-healing cutaneous ulcers. Dental complications include periodontal disease. Hypothyroidism is also reported. The low prevalence of PH2 does not allow genotype-phenotype correlations at the present time. Primary hyperoxaluria type 2 was originally described as: L-glyceric aciduria, referring to the excessive production of urinary L-glycerate; D-glycerate dehydrogenase deficiency, referring to the non-physiologic action of the enzyme in catalyzing the dehydrogenation of D-glycerate. As the more important enzyme reaction appears to be that of glyoxylate reduction, the name glyoxylate reductase is now favored. No data regarding the prevalence of PH2 exist. It is thought to be less common than • L-glyceric aciduria, referring to the excessive production of urinary L-glycerate; • D-glycerate dehydrogenase deficiency, referring to the non-physiologic action of the enzyme in catalyzing the dehydrogenation of D-glycerate. ## Clinical Description The age of onset of primary hyperoxaluria type 2 (PH2) is typically in childhood [ Presenting symptoms are typically those associated with the presence of kidney stones including hematuria, renal colic, or obstruction of the urinary tract [ The majority of individuals have kidney stones composed of calcium oxalate [ Nephrocalcinosis, observed on ultrasound examination, abdominal radiograph, or CT examination, is a much less common finding in PH2 than in PH1. The disease can progress to ESKD although this outcome appears to be later in PH2 than in PH1, in which 50% of affected individuals have ESKD by age 25 years [ Oxalate deposition in bone results in radiograph findings of transverse translucent symmetric bands with fixed sclerotic margins at the end of long bones followed by cystic rarefaction of the bones. Osteodystrophy causes bone pain and multiple pathologic fractures occur in advanced disease. Involvement of the bone marrow can result in anemia refractory to erythropoietin-stimulating agents. Additional clinical manifestations of oxalosis may include visual disturbance due to retinopathy and/or maculopathy, cardiac conduction disturbances such as heart block, cardiomyopathy, and synovitis secondary to oxalate deposition in the joints. Vascular involvement can lead to ischemia, most often manifest as non-healing cutaneous ulcers. Dental complications include periodontal disease. Hypothyroidism is also reported. ## Genotype-Phenotype Correlations The low prevalence of PH2 does not allow genotype-phenotype correlations at the present time. ## Nomenclature Primary hyperoxaluria type 2 was originally described as: L-glyceric aciduria, referring to the excessive production of urinary L-glycerate; D-glycerate dehydrogenase deficiency, referring to the non-physiologic action of the enzyme in catalyzing the dehydrogenation of D-glycerate. As the more important enzyme reaction appears to be that of glyoxylate reduction, the name glyoxylate reductase is now favored. • L-glyceric aciduria, referring to the excessive production of urinary L-glycerate; • D-glycerate dehydrogenase deficiency, referring to the non-physiologic action of the enzyme in catalyzing the dehydrogenation of D-glycerate. ## Prevalence No data regarding the prevalence of PH2 exist. It is thought to be less common than ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with pathogenic variants in ## Differential Diagnosis Megadoses of vitamin C (4 g/day) have led to hyperoxaluria [ ## Management To establish the extent of disease in an individual diagnosed with primary hyperoxaluria type 2 (PH2), the following evaluations, originally outlined for PH1, are recommended if they have not already been completed [ Assessment of kidney function If moderate to advanced ESKD is present, assessment of systemic oxalate deposition in tissue and bone: Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones Ophthalmic examination of the retina to look for oxalate crystals Evaluation of cardiac function by echocardiography and EKG Consultation with a clinical geneticist and/or genetic counselor Management follows general guidance for that of kidney stones: to relieve obstruction, and to manage symptoms of renal impairment as they arise. As with PH1, conservative therapy is applied with the aim of minimizing oxalate-related renal injury and preserving renal function. Treatment of persons with preserved renal function, reviewed by Adequate fluid intake (>2.5 L/m Urinary inhibitors of calcium oxalate crystallization: Orthophosphate treatment (20-30 mg/kg body weight/day) Potassium citrate (0.1-0.15 g/kg body weight/day) Because the plasma oxalate concentration begins to rise when the renal clearance is less than 40 mL/min/1.73 m Oxalate clearance on hemodialysis is greater than on peritoneal dialysis (120 mL/min on hemodialysis vs 7 mL/min on peritoneal dialysis): standard hemodialysis programs will result in clearance of oxalate of 6-9 mmol/1.73 m For individuals in ESKD, intensive (daily) dialysis is required to maximize oxalate removal. As in PH1, the longer the individual with PH2 is on dialysis the more likely systemic oxalate deposition will occur. Kidney transplantation alone has been used in PH2 with varying success. Careful management in the postoperative period, with attention to brisk urine output and use of calcium oxalate urinary inhibitors, minimizes the risk of allograft loss as a result of oxalate deposition. As it is not unusual for such transplants to fail in individuals with PH2 and as there is more enzyme present in the liver than in other tissues [ To date, there is just one published report of a successful liver-kidney transplantation in an individual with PH2 with a previously failed kidney allograft [ Pharmacologic doses of pyridoxine are used as a treatment in individuals with PH1 because of its role as a cofactor for the defective enzyme. There is no supportive evidence for the use of pyridoxine in individuals with PH2. The main preventive treatment is to maintain adequate hydration status and to enhance calcium oxalate solubility with exogenous citrate and neutral phosphates as described in Frequency of recommended screening can vary; however, as a guide, the following are recommended. Individuals with preserved renal function (i.e., measured or estimated GFR ≥60 mL/min/1.73 m Individuals with a GFR <60 mL/min/1.73 m The following should be avoided: Dehydration Excessive ascorbate (i.e. vitamin C; >1000 mg/day) Foods rich in oxalate (chocolate, rhubarb, spinach, and star fruit in particular) High salt (sodium) diet should be discouraged. Excessive stone interventions with extracorporal shock wave lithotripsy In order to delay disease onset in asymptomatic relatives, it is prudent to evaluate at-risk family members before symptoms occur. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Measurement of urinary oxalate excretion if the pathogenic variants in the family are not known. Molecular genetic testing tends to be more reliable as urine oxalate output can be variable in childhood. See For pregnant women with PH2, close monitoring by both an obstetrician and nephrologist is indicated because of the increased risk of decline in kidney function together with developing nephrolithiasis during pregnancy or after delivery. See Other proposed trials include the use of inhibitors of glycolate oxidase (ALN-GO1) to reduce the amount of glyoxylate produced, although this treatment would be mainly relevant to treatment of individuals with PH1. Search • Assessment of kidney function • If moderate to advanced ESKD is present, assessment of systemic oxalate deposition in tissue and bone: • Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones • Ophthalmic examination of the retina to look for oxalate crystals • Evaluation of cardiac function by echocardiography and EKG • Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones • Ophthalmic examination of the retina to look for oxalate crystals • Evaluation of cardiac function by echocardiography and EKG • Consultation with a clinical geneticist and/or genetic counselor • Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones • Ophthalmic examination of the retina to look for oxalate crystals • Evaluation of cardiac function by echocardiography and EKG • Adequate fluid intake (>2.5 L/m • Urinary inhibitors of calcium oxalate crystallization: • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Dehydration • Excessive ascorbate (i.e. vitamin C; >1000 mg/day) • Foods rich in oxalate (chocolate, rhubarb, spinach, and star fruit in particular) • High salt (sodium) diet should be discouraged. • Excessive stone interventions with extracorporal shock wave lithotripsy • Molecular genetic testing if the pathogenic variants in the family are known; • Measurement of urinary oxalate excretion if the pathogenic variants in the family are not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with primary hyperoxaluria type 2 (PH2), the following evaluations, originally outlined for PH1, are recommended if they have not already been completed [ Assessment of kidney function If moderate to advanced ESKD is present, assessment of systemic oxalate deposition in tissue and bone: Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones Ophthalmic examination of the retina to look for oxalate crystals Evaluation of cardiac function by echocardiography and EKG Consultation with a clinical geneticist and/or genetic counselor • Assessment of kidney function • If moderate to advanced ESKD is present, assessment of systemic oxalate deposition in tissue and bone: • Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones • Ophthalmic examination of the retina to look for oxalate crystals • Evaluation of cardiac function by echocardiography and EKG • Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones • Ophthalmic examination of the retina to look for oxalate crystals • Evaluation of cardiac function by echocardiography and EKG • Consultation with a clinical geneticist and/or genetic counselor • Bone radiographs to look for radiodense metaphyseal bands followed by cystic rarefaction of bones • Ophthalmic examination of the retina to look for oxalate crystals • Evaluation of cardiac function by echocardiography and EKG ## Treatment of Manifestations Management follows general guidance for that of kidney stones: to relieve obstruction, and to manage symptoms of renal impairment as they arise. As with PH1, conservative therapy is applied with the aim of minimizing oxalate-related renal injury and preserving renal function. Treatment of persons with preserved renal function, reviewed by Adequate fluid intake (>2.5 L/m Urinary inhibitors of calcium oxalate crystallization: Orthophosphate treatment (20-30 mg/kg body weight/day) Potassium citrate (0.1-0.15 g/kg body weight/day) Because the plasma oxalate concentration begins to rise when the renal clearance is less than 40 mL/min/1.73 m Oxalate clearance on hemodialysis is greater than on peritoneal dialysis (120 mL/min on hemodialysis vs 7 mL/min on peritoneal dialysis): standard hemodialysis programs will result in clearance of oxalate of 6-9 mmol/1.73 m For individuals in ESKD, intensive (daily) dialysis is required to maximize oxalate removal. As in PH1, the longer the individual with PH2 is on dialysis the more likely systemic oxalate deposition will occur. Kidney transplantation alone has been used in PH2 with varying success. Careful management in the postoperative period, with attention to brisk urine output and use of calcium oxalate urinary inhibitors, minimizes the risk of allograft loss as a result of oxalate deposition. As it is not unusual for such transplants to fail in individuals with PH2 and as there is more enzyme present in the liver than in other tissues [ To date, there is just one published report of a successful liver-kidney transplantation in an individual with PH2 with a previously failed kidney allograft [ Pharmacologic doses of pyridoxine are used as a treatment in individuals with PH1 because of its role as a cofactor for the defective enzyme. There is no supportive evidence for the use of pyridoxine in individuals with PH2. • Adequate fluid intake (>2.5 L/m • Urinary inhibitors of calcium oxalate crystallization: • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) ## Reduction of Calcium Oxalate Supersaturation As with PH1, conservative therapy is applied with the aim of minimizing oxalate-related renal injury and preserving renal function. Treatment of persons with preserved renal function, reviewed by Adequate fluid intake (>2.5 L/m Urinary inhibitors of calcium oxalate crystallization: Orthophosphate treatment (20-30 mg/kg body weight/day) Potassium citrate (0.1-0.15 g/kg body weight/day) • Adequate fluid intake (>2.5 L/m • Urinary inhibitors of calcium oxalate crystallization: • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) • Orthophosphate treatment (20-30 mg/kg body weight/day) • Potassium citrate (0.1-0.15 g/kg body weight/day) ## Dialysis Because the plasma oxalate concentration begins to rise when the renal clearance is less than 40 mL/min/1.73 m Oxalate clearance on hemodialysis is greater than on peritoneal dialysis (120 mL/min on hemodialysis vs 7 mL/min on peritoneal dialysis): standard hemodialysis programs will result in clearance of oxalate of 6-9 mmol/1.73 m For individuals in ESKD, intensive (daily) dialysis is required to maximize oxalate removal. As in PH1, the longer the individual with PH2 is on dialysis the more likely systemic oxalate deposition will occur. ## Organ Transplantation Kidney transplantation alone has been used in PH2 with varying success. Careful management in the postoperative period, with attention to brisk urine output and use of calcium oxalate urinary inhibitors, minimizes the risk of allograft loss as a result of oxalate deposition. As it is not unusual for such transplants to fail in individuals with PH2 and as there is more enzyme present in the liver than in other tissues [ To date, there is just one published report of a successful liver-kidney transplantation in an individual with PH2 with a previously failed kidney allograft [ ## Other Pharmacologic doses of pyridoxine are used as a treatment in individuals with PH1 because of its role as a cofactor for the defective enzyme. There is no supportive evidence for the use of pyridoxine in individuals with PH2. ## Prevention of Primary Manifestations The main preventive treatment is to maintain adequate hydration status and to enhance calcium oxalate solubility with exogenous citrate and neutral phosphates as described in ## Surveillance Frequency of recommended screening can vary; however, as a guide, the following are recommended. Individuals with preserved renal function (i.e., measured or estimated GFR ≥60 mL/min/1.73 m Individuals with a GFR <60 mL/min/1.73 m ## Agents/Circumstances to Avoid The following should be avoided: Dehydration Excessive ascorbate (i.e. vitamin C; >1000 mg/day) Foods rich in oxalate (chocolate, rhubarb, spinach, and star fruit in particular) High salt (sodium) diet should be discouraged. Excessive stone interventions with extracorporal shock wave lithotripsy • Dehydration • Excessive ascorbate (i.e. vitamin C; >1000 mg/day) • Foods rich in oxalate (chocolate, rhubarb, spinach, and star fruit in particular) • High salt (sodium) diet should be discouraged. • Excessive stone interventions with extracorporal shock wave lithotripsy ## Evaluation of Relatives at Risk In order to delay disease onset in asymptomatic relatives, it is prudent to evaluate at-risk family members before symptoms occur. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Measurement of urinary oxalate excretion if the pathogenic variants in the family are not known. Molecular genetic testing tends to be more reliable as urine oxalate output can be variable in childhood. See • Molecular genetic testing if the pathogenic variants in the family are known; • Measurement of urinary oxalate excretion if the pathogenic variants in the family are not known. ## Pregnancy Management For pregnant women with PH2, close monitoring by both an obstetrician and nephrologist is indicated because of the increased risk of decline in kidney function together with developing nephrolithiasis during pregnancy or after delivery. See ## Therapies Under Investigation Other proposed trials include the use of inhibitors of glycolate oxidase (ALN-GO1) to reduce the amount of glyoxylate produced, although this treatment would be mainly relevant to treatment of individuals with PH1. Search ## Genetic Counseling Primary hyperoxaluria type 2 (PH2) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., carriers of Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. Complications relating to kidney and/or liver transplantation and scarcity of suitable organs for transplantation may be a consideration for parents who already have one affected child. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Primary hyperoxaluria type 2 (PH2) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., carriers of Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. Complications relating to kidney and/or liver transplantation and scarcity of suitable organs for transplantation may be a consideration for parents who already have one affected child. ## Resources United Kingdom • • • • • • • • United Kingdom • • • • • ## Molecular Genetics Primary Hyperoxaluria Type 2: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Primary Hyperoxaluria Type 2 ( Selected Variants listed in the table have been provided by the authors. ## Chapter Notes 21 December 2017 (sw) Comprehensive update posted live 5 May 2011 (me) Comprehensive update posed live 2 December 2008 (me) Review posted live 9 September 2008 (gr) Original submission • 21 December 2017 (sw) Comprehensive update posted live • 5 May 2011 (me) Comprehensive update posed live • 2 December 2008 (me) Review posted live • 9 September 2008 (gr) Original submission ## Revision History 21 December 2017 (sw) Comprehensive update posted live 5 May 2011 (me) Comprehensive update posed live 2 December 2008 (me) Review posted live 9 September 2008 (gr) Original submission • 21 December 2017 (sw) Comprehensive update posted live • 5 May 2011 (me) Comprehensive update posed live • 2 December 2008 (me) Review posted live • 9 September 2008 (gr) Original submission ## References ## Literature Cited	[]	2/12/2008	21/12/2017		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ph3	ph3	[ "Probable 4-hydroxy-2-oxoglutarate aldolase, mitochondrial", "HOGA1", "Primary Hyperoxaluria Type 3" ]	Primary Hyperoxaluria Type 3	Dawn S Milliner, Peter C Harris, David J Sas, John C Lieske	Summary Primary hyperoxaluria type 3 (PH3) is characterized by recurring calcium oxalate stones beginning in childhood or adolescence and, on occasion, nephrocalcinosis or reduced kidney function. PH3 most often presents in childhood (median age 2 to 3 years) with signs or symptoms related to stones including hematuria, frequent urination, dysuria, blood visible in the urine, or stone-associated pain. Some individuals with PH3 do not present until adulthood, usually with stone-related symptoms or findings. Over time, frequent stones and/or nephrocalcinosis may compromise kidney function, resulting in chronic kidney disease. To date, systemic oxalosis has not been reported in PH3. The diagnosis of PH3 is established in a proband with suggestive findings and biallelic pathogenic variants in More frequent assessments are required for: children under age four years, individuals with complex stone problems, and individuals with reduced kidney function. PH3 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis For recently published algorithms for the diagnosis of the primary hyperoxalurias (PH), see Primary hyperoxaluria type 3 (PH3) Calcium oxalate stones, especially when in both kidneys Recurring calcium oxalate stones Onset of stone disease in childhood or adolescence Reduced kidney function in the presence of calcium stones or nephrocalcinosis (crystal deposition in renal parenchyma) Nephrocalcinosis Note: (1) Normal urine oxalate is <0.46 mmol per 1.73 m Note: (1) Normal plasma oxalate concentration varies depending on methods of sample preparation and measurement [ Random Urine Oxalate-to-Creatinine Ratio in Children by Age Based on Urine oxalate-to-creatinine ratios are higher in very premature infants than in term infants, especially when they are receiving parenteral nutrition containing amino acids. The ratio falls when premature infants are receiving only glucose and electrolyte solutions [ When very high dietary intake of oxalate or low dietary intake of calcium is suspected as the cause of the hyperoxaluria, the diet should be corrected and the urine oxalate remeasured for verification. The diagnosis of PH3 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 3 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. • Calcium oxalate stones, especially when in both kidneys • Recurring calcium oxalate stones • Onset of stone disease in childhood or adolescence • Reduced kidney function in the presence of calcium stones or nephrocalcinosis (crystal deposition in renal parenchyma) • Nephrocalcinosis • Note: (1) Normal urine oxalate is <0.46 mmol per 1.73 m • Note: (1) Normal plasma oxalate concentration varies depending on methods of sample preparation and measurement [ ## Suggestive Findings Primary hyperoxaluria type 3 (PH3) Calcium oxalate stones, especially when in both kidneys Recurring calcium oxalate stones Onset of stone disease in childhood or adolescence Reduced kidney function in the presence of calcium stones or nephrocalcinosis (crystal deposition in renal parenchyma) Nephrocalcinosis Note: (1) Normal urine oxalate is <0.46 mmol per 1.73 m Note: (1) Normal plasma oxalate concentration varies depending on methods of sample preparation and measurement [ Random Urine Oxalate-to-Creatinine Ratio in Children by Age Based on Urine oxalate-to-creatinine ratios are higher in very premature infants than in term infants, especially when they are receiving parenteral nutrition containing amino acids. The ratio falls when premature infants are receiving only glucose and electrolyte solutions [ When very high dietary intake of oxalate or low dietary intake of calcium is suspected as the cause of the hyperoxaluria, the diet should be corrected and the urine oxalate remeasured for verification. • Calcium oxalate stones, especially when in both kidneys • Recurring calcium oxalate stones • Onset of stone disease in childhood or adolescence • Reduced kidney function in the presence of calcium stones or nephrocalcinosis (crystal deposition in renal parenchyma) • Nephrocalcinosis • Note: (1) Normal urine oxalate is <0.46 mmol per 1.73 m • Note: (1) Normal plasma oxalate concentration varies depending on methods of sample preparation and measurement [ ## Establishing the Diagnosis The diagnosis of PH3 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 3 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primary Hyperoxaluria Type 3 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Primary hyperoxaluria type 3 (PH3) is characterized by recurring calcium oxalate kidney stones beginning in childhood or adolescence and, on occasion, nephrocalcinosis or reduced kidney function. In individuals with PH3, stone formation typically begins prior to age five years, though in some individuals stones may not be clinically evident until adulthood [ PH3 most often presents in childhood (median age 2 to 3 years) with signs or symptoms related to stones including hematuria, frequent urination, dysuria, blood visible in the urine, or stone-associated pain. In one large study the median number of stones present at first imaging in individuals with PH3 was four [ The lifelong clinical stone burden is substantial, as symptomatic stone events recur through the sixth decade of life [ Some individuals with PH3 do not present until adulthood, usually with stone-related symptoms or findings. Although stones are likely to be discovered due to symptoms, they may also be detected incidentally on imaging studies performed for other purposes. Over time, frequent stones and/or nephrocalcinosis may compromise kidney function, resulting in chronic kidney disease (CKD). Individuals with PH3 who are older than age 40 years may have CKD stage 3 or higher that exceeds the expected age-related glomerular filtration rate (GFR) decline [ To date, the only three individuals with PH3 reported to progress to kidney failure also had other factors that may have contributed to CKD progression. These individuals were: An eight-year-old who had multiple stone removal procedures and urinary tract obstruction [ A 33-year-old who had bladder dysfunction [ A 78-year-old male who had a 30-year history of nephrolithiasis who developed end-stage kidney disease after unilateral nephrectomy for clear cell carcinoma [ Systemic oxalosis has not been reported, though the number of individuals with PH3 with advanced CKD reported to date is small. No genotype-phenotype correlations for Surveys of clinicians in central Europe led to estimates of the prevalence of primary hyperoxaluria (PH) of all causes of one to three in 1,000,000 [ Among individuals with primary hyperoxaluria, approximately 70% have PH1, 10% have PH2, 7%-12% have PH3, and 10% have an unidentified genetic cause [ Registry data from the Rare Kidney Stone Consortium and OxalEurope suggest that the prevalence of PH3 is similar to that of PH2 and approximately one sixth that of PH1. By contrast, estimates from publicly available population data ( The PH3 carrier frequency is one in 185 [ PH3 has been observed more commonly among individuals of Ashkenazi Jewish descent, and a 3-bp deletion founder variant has been identified [ • An eight-year-old who had multiple stone removal procedures and urinary tract obstruction [ • A 33-year-old who had bladder dysfunction [ • A 78-year-old male who had a 30-year history of nephrolithiasis who developed end-stage kidney disease after unilateral nephrectomy for clear cell carcinoma [ ## Clinical Description Primary hyperoxaluria type 3 (PH3) is characterized by recurring calcium oxalate kidney stones beginning in childhood or adolescence and, on occasion, nephrocalcinosis or reduced kidney function. In individuals with PH3, stone formation typically begins prior to age five years, though in some individuals stones may not be clinically evident until adulthood [ PH3 most often presents in childhood (median age 2 to 3 years) with signs or symptoms related to stones including hematuria, frequent urination, dysuria, blood visible in the urine, or stone-associated pain. In one large study the median number of stones present at first imaging in individuals with PH3 was four [ The lifelong clinical stone burden is substantial, as symptomatic stone events recur through the sixth decade of life [ Some individuals with PH3 do not present until adulthood, usually with stone-related symptoms or findings. Although stones are likely to be discovered due to symptoms, they may also be detected incidentally on imaging studies performed for other purposes. Over time, frequent stones and/or nephrocalcinosis may compromise kidney function, resulting in chronic kidney disease (CKD). Individuals with PH3 who are older than age 40 years may have CKD stage 3 or higher that exceeds the expected age-related glomerular filtration rate (GFR) decline [ To date, the only three individuals with PH3 reported to progress to kidney failure also had other factors that may have contributed to CKD progression. These individuals were: An eight-year-old who had multiple stone removal procedures and urinary tract obstruction [ A 33-year-old who had bladder dysfunction [ A 78-year-old male who had a 30-year history of nephrolithiasis who developed end-stage kidney disease after unilateral nephrectomy for clear cell carcinoma [ Systemic oxalosis has not been reported, though the number of individuals with PH3 with advanced CKD reported to date is small. • An eight-year-old who had multiple stone removal procedures and urinary tract obstruction [ • A 33-year-old who had bladder dysfunction [ • A 78-year-old male who had a 30-year history of nephrolithiasis who developed end-stage kidney disease after unilateral nephrectomy for clear cell carcinoma [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Prevalence Surveys of clinicians in central Europe led to estimates of the prevalence of primary hyperoxaluria (PH) of all causes of one to three in 1,000,000 [ Among individuals with primary hyperoxaluria, approximately 70% have PH1, 10% have PH2, 7%-12% have PH3, and 10% have an unidentified genetic cause [ Registry data from the Rare Kidney Stone Consortium and OxalEurope suggest that the prevalence of PH3 is similar to that of PH2 and approximately one sixth that of PH1. By contrast, estimates from publicly available population data ( The PH3 carrier frequency is one in 185 [ PH3 has been observed more commonly among individuals of Ashkenazi Jewish descent, and a 3-bp deletion founder variant has been identified [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Primary hyperoxaluria (PH) should be included in the differential diagnosis of any condition that causes calcium oxalate kidney stone disease or nephrocalcinosis and is associated with hyperoxaluria. The three known types of PH are Of the primary hyperoxalurias, PH1 accounts for approximately 70%, PH2 for 10%, PH3 for 10%, and 10% do not have an identified genetic cause to date [ Although increased urinary excretion of the following specific organic acids are suggestive of PH type [ PH1: increased glycolate PH2: increased glycerate PH3: increased 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) Comparison of Primary Hyperoxaluria Types 1, 2, and 3 Adapted from eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; nL = normal limit Parameters presented are the median. Secondary forms of hyperoxaluria should be systematically considered in the differential diagnosis [ Foods high in oxalate, especially if dietary calcium intake is low; Marked deficiency of dietary calcium, which leaves a greater proportion of oxalate free in the intestinal lumen, resulting in increased absorption of oxalate and hyperoxaluria; Very high doses of vitamin C; Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. Any gastrointestinal disease or surgery that impairs fat absorption is a potential cause of enteric hyperoxaluria [ Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) can cause of enteric hyperoxaluria. Phenotypic overlap with other monogenic stone diseases can occur [ Nephrocalcinosis of prematurity, which occurs in a significant proportion of infants born prior to 28 weeks' gestation, is also characterized by nephrolithiasis [ • PH1: increased glycolate • PH2: increased glycerate • PH3: increased 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) • Foods high in oxalate, especially if dietary calcium intake is low; • Marked deficiency of dietary calcium, which leaves a greater proportion of oxalate free in the intestinal lumen, resulting in increased absorption of oxalate and hyperoxaluria; • Very high doses of vitamin C; • Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. • Any gastrointestinal disease or surgery that impairs fat absorption is a potential cause of enteric hyperoxaluria [ • Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) can cause of enteric hyperoxaluria. ## Primary Hyperoxalurias Primary hyperoxaluria (PH) should be included in the differential diagnosis of any condition that causes calcium oxalate kidney stone disease or nephrocalcinosis and is associated with hyperoxaluria. The three known types of PH are Of the primary hyperoxalurias, PH1 accounts for approximately 70%, PH2 for 10%, PH3 for 10%, and 10% do not have an identified genetic cause to date [ Although increased urinary excretion of the following specific organic acids are suggestive of PH type [ PH1: increased glycolate PH2: increased glycerate PH3: increased 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) Comparison of Primary Hyperoxaluria Types 1, 2, and 3 Adapted from eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; nL = normal limit Parameters presented are the median. • PH1: increased glycolate • PH2: increased glycerate • PH3: increased 4-hydroxy-2-oxoglutarate (HOG) and 2,4-dihydroxyglutarate (DHG) ## Secondary Hyperoxalurias Secondary forms of hyperoxaluria should be systematically considered in the differential diagnosis [ Foods high in oxalate, especially if dietary calcium intake is low; Marked deficiency of dietary calcium, which leaves a greater proportion of oxalate free in the intestinal lumen, resulting in increased absorption of oxalate and hyperoxaluria; Very high doses of vitamin C; Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. Any gastrointestinal disease or surgery that impairs fat absorption is a potential cause of enteric hyperoxaluria [ Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) can cause of enteric hyperoxaluria. • Foods high in oxalate, especially if dietary calcium intake is low; • Marked deficiency of dietary calcium, which leaves a greater proportion of oxalate free in the intestinal lumen, resulting in increased absorption of oxalate and hyperoxaluria; • Very high doses of vitamin C; • Toxins, such as ethylene glycol, which can cause marked hyperoxaluria and associated acute kidney failure. • Any gastrointestinal disease or surgery that impairs fat absorption is a potential cause of enteric hyperoxaluria [ • Medications that interfere with fat absorption from the gastrointestinal tract (e.g., orlistat) can cause of enteric hyperoxaluria. ## Other Monogenic Stone Diseases Phenotypic overlap with other monogenic stone diseases can occur [ ## Nephrocalcinosis of Prematurity Nephrocalcinosis of prematurity, which occurs in a significant proportion of infants born prior to 28 weeks' gestation, is also characterized by nephrolithiasis [ ## Management No clinical practice guidelines specific to primary hyperoxaluria type 3 (PH3) have been published, though general recommendations for individuals with all forms of PH are relevant [ The following evaluations are recommended to establish the extent of disease and therapeutic needs in an individual diagnosed with PH3: Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis Baseline 24-hour urine collection with measurement of oxalate, calcium, citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones, information that is valuable in guiding treatment Measurement of plasma oxalate concentration to assess the degree of oxalate overproduction Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentrations If chronic kidney disease (CKD stage 3B or higher) is present, evaluation for systemic oxalosis deposits with the following: Echocardiography for evidence of cardiomyopathy Complete blood count for evidence of erythropoietin-resistant anemia Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy Retinal examination for retinal oxalate deposition Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PH3 in order to facilitate medical and personal decision making Assessment of need for family support and resources from patient advocacy groups such as There is no cure for PH3. Maintenance of high oral fluid intake (>2.5 L per m Oral administration of an inhibitor of calcium oxalate crystallization. Most individuals are treated with potassium and/or sodium citrate at a daily total of 1-3 mEq/kg per day divided into two or three doses a day. Individuals with PH3 with active calcium oxalate stone formation who have hypercalciuria or urine calcium that is in the upper range of normal may benefit from the addition of a thiazide medication. Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. Attention to lifelong ongoing care, including adherence to high fluid intake and medication schedule, is essential to favorable outcomes. Individuals with PH3 should be counseled to promptly report stone-related symptoms to their health care provider. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in those who are stable and doing well (except very young individuals; see Clinical assessment of stone-related symptoms including pain, frequency of passage of stones or gravel in the urine, and urinary tract infections Renal ultrasound examination or other imaging to monitor for stone formation Note: Given the need for lifelong repeated kidney imaging, care should be taken to minimize radiation exposure. Assessment of kidney function (serum creatinine and eGFR) and electrolytes Measurement of plasma oxalate concentration, particularly in individuals with any impairment of GFR 24-hour urine oxalate and supersaturation study. During follow up, changes in the urine supersaturation can be used to monitor the effectiveness of therapy by confirming that the crystallization potential has decreased. Note: In young children or other individuals unable to complete an accurate 24-hour urine collection, random urine specimens may be used for comparative measurements. Children under age four years; Individuals with complex stone problems; Individuals with reduced kidney function. Individuals with PH3 should avoid the following: Intravascular volume contraction Note: Liberal use of intravenous fluids is indicated whenever oral fluid intake is inadequate or there is loss of body fluids due to diarrhea or other causes. Delays in treatment of acute stone episodes Nephrotoxic agents High-dose ascorbic acid (more than 250 mg daily) Marked dietary oxalate excess by moderation of intake of high-oxalate foods Targeted molecular genetic testing for the familial Sibs found to have biallelic See In the few reports available to date, pregnancy outcomes in women with PH3 appear to be similar to those in women with PH1 or PH2 [ Nonetheless, mothers with PH3 should be managed as a higher-risk pregnancy with closer monitoring, given the increased risk of acute kidney injury due to hypovolemia or an obstructing or infected stone [ Stones that become symptomatic during pregnancy may require routine (but specialized) techniques for management. Urinary tract infections in individuals who have stones should be treated promptly and thoroughly due to the potential complications of pyelonephritis or infected stones. Evidence suggests that inhibition of the hepatic isoform of lactate dehydrogenase, LDHa, could reduce oxalate generation in PH1, PH2, and PH3. The siRNA therapeutic nedosiran, which targets hepatic LDHa, has been shown to reduce urinary oxalate excretion in individuals with PH1 [ Preclinical studies have also demonstrated the potential for hepatically directed gene editing of the LDHa enzyme [ Stiripentol, a pharmacologic inhibitor of LDH used to treat Dravet syndrome, a rare form of myoclonic epilepsy, is also being investigated as a therapy for PH [ Search • Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis • Baseline 24-hour urine collection with measurement of oxalate, calcium, citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones, information that is valuable in guiding treatment • Measurement of plasma oxalate concentration to assess the degree of oxalate overproduction • Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentrations • If chronic kidney disease (CKD stage 3B or higher) is present, evaluation for systemic oxalosis deposits with the following: • Echocardiography for evidence of cardiomyopathy • Complete blood count for evidence of erythropoietin-resistant anemia • Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy • Retinal examination for retinal oxalate deposition • Echocardiography for evidence of cardiomyopathy • Complete blood count for evidence of erythropoietin-resistant anemia • Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy • Retinal examination for retinal oxalate deposition • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PH3 in order to facilitate medical and personal decision making • Assessment of need for family support and resources from patient advocacy groups such as • Echocardiography for evidence of cardiomyopathy • Complete blood count for evidence of erythropoietin-resistant anemia • Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy • Retinal examination for retinal oxalate deposition • Maintenance of high oral fluid intake (>2.5 L per m • Oral administration of an inhibitor of calcium oxalate crystallization. Most individuals are treated with potassium and/or sodium citrate at a daily total of 1-3 mEq/kg per day divided into two or three doses a day. • Individuals with PH3 with active calcium oxalate stone formation who have hypercalciuria or urine calcium that is in the upper range of normal may benefit from the addition of a thiazide medication. • Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. • Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. • Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. • Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. • Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. • Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. • Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. • Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. • Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. • Clinical assessment of stone-related symptoms including pain, frequency of passage of stones or gravel in the urine, and urinary tract infections • Renal ultrasound examination or other imaging to monitor for stone formation • Note: Given the need for lifelong repeated kidney imaging, care should be taken to minimize radiation exposure. • Assessment of kidney function (serum creatinine and eGFR) and electrolytes • Measurement of plasma oxalate concentration, particularly in individuals with any impairment of GFR • 24-hour urine oxalate and supersaturation study. During follow up, changes in the urine supersaturation can be used to monitor the effectiveness of therapy by confirming that the crystallization potential has decreased. • Note: In young children or other individuals unable to complete an accurate 24-hour urine collection, random urine specimens may be used for comparative measurements. • Children under age four years; • Individuals with complex stone problems; • Individuals with reduced kidney function. • Intravascular volume contraction • Note: Liberal use of intravenous fluids is indicated whenever oral fluid intake is inadequate or there is loss of body fluids due to diarrhea or other causes. • Delays in treatment of acute stone episodes • Nephrotoxic agents • High-dose ascorbic acid (more than 250 mg daily) • Marked dietary oxalate excess by moderation of intake of high-oxalate foods • The siRNA therapeutic nedosiran, which targets hepatic LDHa, has been shown to reduce urinary oxalate excretion in individuals with PH1 [ • Preclinical studies have also demonstrated the potential for hepatically directed gene editing of the LDHa enzyme [ ## Evaluations Following Initial Diagnosis The following evaluations are recommended to establish the extent of disease and therapeutic needs in an individual diagnosed with PH3: Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis Baseline 24-hour urine collection with measurement of oxalate, calcium, citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones, information that is valuable in guiding treatment Measurement of plasma oxalate concentration to assess the degree of oxalate overproduction Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentrations If chronic kidney disease (CKD stage 3B or higher) is present, evaluation for systemic oxalosis deposits with the following: Echocardiography for evidence of cardiomyopathy Complete blood count for evidence of erythropoietin-resistant anemia Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy Retinal examination for retinal oxalate deposition Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PH3 in order to facilitate medical and personal decision making Assessment of need for family support and resources from patient advocacy groups such as • Kidney imaging for assessment of number and location of stones and presence of nephrocalcinosis • Baseline 24-hour urine collection with measurement of oxalate, calcium, citrate, pH, urine volume, and other components of a supersaturation profile to identify specific risk factors for stones, information that is valuable in guiding treatment • Measurement of plasma oxalate concentration to assess the degree of oxalate overproduction • Assessment of kidney function (estimated glomerular filtration rate [eGFR]) by serum creatinine concentration, blood urea nitrogen, and/or cystatin C concentrations • If chronic kidney disease (CKD stage 3B or higher) is present, evaluation for systemic oxalosis deposits with the following: • Echocardiography for evidence of cardiomyopathy • Complete blood count for evidence of erythropoietin-resistant anemia • Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy • Retinal examination for retinal oxalate deposition • Echocardiography for evidence of cardiomyopathy • Complete blood count for evidence of erythropoietin-resistant anemia • Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy • Retinal examination for retinal oxalate deposition • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PH3 in order to facilitate medical and personal decision making • Assessment of need for family support and resources from patient advocacy groups such as • Echocardiography for evidence of cardiomyopathy • Complete blood count for evidence of erythropoietin-resistant anemia • Bone imaging for evidence of sclerosis and pathologic fractures due to oxalate osteodystrophy • Retinal examination for retinal oxalate deposition ## Treatment of Manifestations There is no cure for PH3. Maintenance of high oral fluid intake (>2.5 L per m Oral administration of an inhibitor of calcium oxalate crystallization. Most individuals are treated with potassium and/or sodium citrate at a daily total of 1-3 mEq/kg per day divided into two or three doses a day. Individuals with PH3 with active calcium oxalate stone formation who have hypercalciuria or urine calcium that is in the upper range of normal may benefit from the addition of a thiazide medication. Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. • Maintenance of high oral fluid intake (>2.5 L per m • Oral administration of an inhibitor of calcium oxalate crystallization. Most individuals are treated with potassium and/or sodium citrate at a daily total of 1-3 mEq/kg per day divided into two or three doses a day. • Individuals with PH3 with active calcium oxalate stone formation who have hypercalciuria or urine calcium that is in the upper range of normal may benefit from the addition of a thiazide medication. • Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. • Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. • Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. • Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. • Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. • Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. • Promptly alleviating obstruction of the urinary tract by a stone through stent placement and/or stone removal. Stone removal procedures should minimize kidney injury as much as possible. For example, ureteroscopic or percutaneous nephrolithotomy may be preferable to repeated extracorporeal shockwave lithotripsy. • Maintaining continuous fluid intake and urine flow before, during, and for several days after stone removal procedures. • Treating urinary tract infections promptly and thoroughly, as bacteria may cause pyelonephritis or infect stones and complicate management. ## Surveillance Attention to lifelong ongoing care, including adherence to high fluid intake and medication schedule, is essential to favorable outcomes. Individuals with PH3 should be counseled to promptly report stone-related symptoms to their health care provider. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in those who are stable and doing well (except very young individuals; see Clinical assessment of stone-related symptoms including pain, frequency of passage of stones or gravel in the urine, and urinary tract infections Renal ultrasound examination or other imaging to monitor for stone formation Note: Given the need for lifelong repeated kidney imaging, care should be taken to minimize radiation exposure. Assessment of kidney function (serum creatinine and eGFR) and electrolytes Measurement of plasma oxalate concentration, particularly in individuals with any impairment of GFR 24-hour urine oxalate and supersaturation study. During follow up, changes in the urine supersaturation can be used to monitor the effectiveness of therapy by confirming that the crystallization potential has decreased. Note: In young children or other individuals unable to complete an accurate 24-hour urine collection, random urine specimens may be used for comparative measurements. Children under age four years; Individuals with complex stone problems; Individuals with reduced kidney function. • Clinical assessment of stone-related symptoms including pain, frequency of passage of stones or gravel in the urine, and urinary tract infections • Renal ultrasound examination or other imaging to monitor for stone formation • Note: Given the need for lifelong repeated kidney imaging, care should be taken to minimize radiation exposure. • Assessment of kidney function (serum creatinine and eGFR) and electrolytes • Measurement of plasma oxalate concentration, particularly in individuals with any impairment of GFR • 24-hour urine oxalate and supersaturation study. During follow up, changes in the urine supersaturation can be used to monitor the effectiveness of therapy by confirming that the crystallization potential has decreased. • Note: In young children or other individuals unable to complete an accurate 24-hour urine collection, random urine specimens may be used for comparative measurements. • Children under age four years; • Individuals with complex stone problems; • Individuals with reduced kidney function. ## Agents/Circumstances to Avoid Individuals with PH3 should avoid the following: Intravascular volume contraction Note: Liberal use of intravenous fluids is indicated whenever oral fluid intake is inadequate or there is loss of body fluids due to diarrhea or other causes. Delays in treatment of acute stone episodes Nephrotoxic agents High-dose ascorbic acid (more than 250 mg daily) Marked dietary oxalate excess by moderation of intake of high-oxalate foods • Intravascular volume contraction • Note: Liberal use of intravenous fluids is indicated whenever oral fluid intake is inadequate or there is loss of body fluids due to diarrhea or other causes. • Delays in treatment of acute stone episodes • Nephrotoxic agents • High-dose ascorbic acid (more than 250 mg daily) • Marked dietary oxalate excess by moderation of intake of high-oxalate foods ## Evaluation of Relatives at Risk Targeted molecular genetic testing for the familial Sibs found to have biallelic See ## Pregnancy Management In the few reports available to date, pregnancy outcomes in women with PH3 appear to be similar to those in women with PH1 or PH2 [ Nonetheless, mothers with PH3 should be managed as a higher-risk pregnancy with closer monitoring, given the increased risk of acute kidney injury due to hypovolemia or an obstructing or infected stone [ Stones that become symptomatic during pregnancy may require routine (but specialized) techniques for management. Urinary tract infections in individuals who have stones should be treated promptly and thoroughly due to the potential complications of pyelonephritis or infected stones. ## Therapies Under Investigation Evidence suggests that inhibition of the hepatic isoform of lactate dehydrogenase, LDHa, could reduce oxalate generation in PH1, PH2, and PH3. The siRNA therapeutic nedosiran, which targets hepatic LDHa, has been shown to reduce urinary oxalate excretion in individuals with PH1 [ Preclinical studies have also demonstrated the potential for hepatically directed gene editing of the LDHa enzyme [ Stiripentol, a pharmacologic inhibitor of LDH used to treat Dravet syndrome, a rare form of myoclonic epilepsy, is also being investigated as a therapy for PH [ Search • The siRNA therapeutic nedosiran, which targets hepatic LDHa, has been shown to reduce urinary oxalate excretion in individuals with PH1 [ • Preclinical studies have also demonstrated the potential for hepatically directed gene editing of the LDHa enzyme [ ## Genetic Counseling Primary hyperoxaluria type 3 (PH3) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are usually asymptomatic [ If both parents are known to be heterozygous for a Heterozygotes (carriers) are usually asymptomatic [ Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are usually asymptomatic [ • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are usually asymptomatic [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. ## Mode of Inheritance Primary hyperoxaluria type 3 (PH3) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are usually asymptomatic [ If both parents are known to be heterozygous for a Heterozygotes (carriers) are usually asymptomatic [ • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are usually asymptomatic [ • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are usually asymptomatic [ ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • ## Molecular Genetics Primary Hyperoxaluria Type 3: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Primary Hyperoxaluria Type 3 ( Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Dr John Lieske and Dr David J Sas are actively involved in clinical research regarding individuals with primary hyperoxaluria 3. They would be happy to communicate with persons who have any questions regarding diagnosis of PH3 or other considerations. Dr Lieske and Dr Sas are also interested in hearing from clinicians treating families affected by monogenic stone diseases in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Peter Harris to inquire about review of NIH grants U54 DK083908, R21 TR03174, and R01 DK133171 and the Oxalosis and Hyperoxaluria Foundation (OHF) have provided funding for our work. We also thank the OHF for partnership and funding support for the RKSC PH Registry. We express our appreciation to the dedicated staff of the Mayo Clinic Hyperoxaluria Center and to all the physicians and patients who have contributed to the RKSC PH Registry. 9 February 2023 (bp) Comprehensive update posted live 24 September 2015 (me) Review posted live 13 February 2015 (dsm) Original submission • 9 February 2023 (bp) Comprehensive update posted live • 24 September 2015 (me) Review posted live • 13 February 2015 (dsm) Original submission ## Author Notes Dr John Lieske and Dr David J Sas are actively involved in clinical research regarding individuals with primary hyperoxaluria 3. They would be happy to communicate with persons who have any questions regarding diagnosis of PH3 or other considerations. Dr Lieske and Dr Sas are also interested in hearing from clinicians treating families affected by monogenic stone diseases in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Peter Harris to inquire about review of ## Acknowledgments NIH grants U54 DK083908, R21 TR03174, and R01 DK133171 and the Oxalosis and Hyperoxaluria Foundation (OHF) have provided funding for our work. We also thank the OHF for partnership and funding support for the RKSC PH Registry. We express our appreciation to the dedicated staff of the Mayo Clinic Hyperoxaluria Center and to all the physicians and patients who have contributed to the RKSC PH Registry. ## Revision History 9 February 2023 (bp) Comprehensive update posted live 24 September 2015 (me) Review posted live 13 February 2015 (dsm) Original submission • 9 February 2023 (bp) Comprehensive update posted live • 24 September 2015 (me) Review posted live • 13 February 2015 (dsm) Original submission ## References ## Literature Cited Algorithm for the diagnostic evaluation of primary hyperoxaluria in an affected individual * Random oxalate-to-creatinine ratios vary significantly by age. Consult pediatric reference range tables for interpretation. Since it is often difficult to interpret the treatment impact for secondary causes when glomerular filtration rate is markedly reduced, genetic testing should also be strongly considered in this group of patients if the cause remains unclear. * Interpretive report includes an overview of results and of their significance along with a recommendation for confirmatory molecular testing for either Reproduced with permission from	[]	24/9/2015	9/2/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pha2	pha2	[ "Familial Hyperkalemic Hypertension", "Gordon's Syndrome", "PHAII", "PHAII", "Gordon’s Syndrome", "Familial Hyperkalemic Hypertension", "Cullin-3", "Kelch-like protein 3", "Serine/threonine-protein kinase WNK1", "Serine/threonine-protein kinase WNK4", "CUL3", "KLHL3", "WNK1", "WNK4", "Pseudohypoaldosteronism Type II" ]	Pseudohypoaldosteronism Type II	David H Ellison	Summary Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is well described. The diagnosis of PHAII is established in a proband: With hyperkalemia (in the setting of normal glomerular filtration), hypertension, metabolic acidosis, hyperchloremia, and suppressed plasma renin levels; AND/OR By the identification of a heterozygous pathogenic variant in PHAII is frequently inherited in an autosomal dominant manner; PHAIID (caused by pathogenic variants in	## Diagnosis No formal diagnostic criteria for PHAII have been published. Pseudohypoaldosteronism type II (PHAII) Hyperkalemia in the absence of impaired glomerular filtration Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). This finding is nearly universal in affected individuals at all ages. Metabolic acidosis: serum concentration of bicarbonate ranging from 14 to 24 mmol/L (normal range: ~22-29 mmol/L) Hyperchloremia: serum concentration of chloride ranging from 105 to 117 mmol/L (normal range: ~99-108 mmol/L) Suppressed plasma renin levels Variable serum aldosterone levels that tend to be relatively suppressed in the context of hyperkalemia Serum calcium and parathyroid hormone levels that are normal. However, hypercalciuria is noted in at least a subset of individuals. The diagnosis of PHAII Molecular genetic testing approaches can include It is reasonable to perform sequence analysis for pathogenic variants in If only one pathogenic variant in Sequence analysis of If no pathogenic variant is identified through sequencing of If no disease-causing deletion or duplication is found in For an introduction to multigene panels click Molecular Genetic Testing Used in Pseudohypoaldosteronism Type II AD = autosomal dominant; AR = autosomal recessive See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Both heterozygous (autosomal dominant) and biallelic (autosomal recessive) pathogenic variants in No data on detection rate of gene-targeted deletion/duplication analysis are available. Recently, six kindreds (9 individuals) were reported in preliminary results to have pathogenic missense variants in Two large deletions have been reported (see An additional locus on 1q31-q42 has been identified as harboring a gene associated with PHAII [ Denominator is from the only report to document the number of PHAII individuals who did not have variants in • Hyperkalemia in the absence of impaired glomerular filtration • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). • This finding is nearly universal in affected individuals at all ages. • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). • This finding is nearly universal in affected individuals at all ages. • Metabolic acidosis: serum concentration of bicarbonate ranging from 14 to 24 mmol/L (normal range: ~22-29 mmol/L) • Hyperchloremia: serum concentration of chloride ranging from 105 to 117 mmol/L (normal range: ~99-108 mmol/L) • Suppressed plasma renin levels • Variable serum aldosterone levels that tend to be relatively suppressed in the context of hyperkalemia • Serum calcium and parathyroid hormone levels that are normal. However, hypercalciuria is noted in at least a subset of individuals. • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). • This finding is nearly universal in affected individuals at all ages. • It is reasonable to perform sequence analysis for pathogenic variants in • If only one pathogenic variant in • Sequence analysis of • If no pathogenic variant is identified through sequencing of • If no disease-causing deletion or duplication is found in ## Suggestive Findings Pseudohypoaldosteronism type II (PHAII) Hyperkalemia in the absence of impaired glomerular filtration Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). This finding is nearly universal in affected individuals at all ages. Metabolic acidosis: serum concentration of bicarbonate ranging from 14 to 24 mmol/L (normal range: ~22-29 mmol/L) Hyperchloremia: serum concentration of chloride ranging from 105 to 117 mmol/L (normal range: ~99-108 mmol/L) Suppressed plasma renin levels Variable serum aldosterone levels that tend to be relatively suppressed in the context of hyperkalemia Serum calcium and parathyroid hormone levels that are normal. However, hypercalciuria is noted in at least a subset of individuals. • Hyperkalemia in the absence of impaired glomerular filtration • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). • This finding is nearly universal in affected individuals at all ages. • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). • This finding is nearly universal in affected individuals at all ages. • Metabolic acidosis: serum concentration of bicarbonate ranging from 14 to 24 mmol/L (normal range: ~22-29 mmol/L) • Hyperchloremia: serum concentration of chloride ranging from 105 to 117 mmol/L (normal range: ~99-108 mmol/L) • Suppressed plasma renin levels • Variable serum aldosterone levels that tend to be relatively suppressed in the context of hyperkalemia • Serum calcium and parathyroid hormone levels that are normal. However, hypercalciuria is noted in at least a subset of individuals. • Serum concentration of potassium ranges from mildly (serum K ~5.0-6.0 mmol/L) to severely elevated (>8.0 mmol/L) (normal range: ~3.5-5.1 mmol/L). • This finding is nearly universal in affected individuals at all ages. ## Establishing the Diagnosis The diagnosis of PHAII Molecular genetic testing approaches can include It is reasonable to perform sequence analysis for pathogenic variants in If only one pathogenic variant in Sequence analysis of If no pathogenic variant is identified through sequencing of If no disease-causing deletion or duplication is found in For an introduction to multigene panels click Molecular Genetic Testing Used in Pseudohypoaldosteronism Type II AD = autosomal dominant; AR = autosomal recessive See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Both heterozygous (autosomal dominant) and biallelic (autosomal recessive) pathogenic variants in No data on detection rate of gene-targeted deletion/duplication analysis are available. Recently, six kindreds (9 individuals) were reported in preliminary results to have pathogenic missense variants in Two large deletions have been reported (see An additional locus on 1q31-q42 has been identified as harboring a gene associated with PHAII [ Denominator is from the only report to document the number of PHAII individuals who did not have variants in • It is reasonable to perform sequence analysis for pathogenic variants in • If only one pathogenic variant in • Sequence analysis of • If no pathogenic variant is identified through sequencing of • If no disease-causing deletion or duplication is found in ## Clinical Characteristics Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. More than 180 individuals and families with PHAII have been reported. The clinical presentation of PHAII is heterogeneous. The most consistent clinical feature in both children and young adults is hyperkalemia [ Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is also well described in PHAII [ Other features reported in a subset of individuals with PHAII include short stature, myalgias, periodic paralysis, and dental abnormalities [ Individuals with a heterozygous In general, clinical manifestations of PHAII appear to be milder in individuals with a heterozygous Individuals with biallelic The term "pseudohypoaldosteronism" has historically been used to describe the finding of persistent hyperkalemia despite the presence of normal or elevated serum levels of aldosterone [ Therefore, the term "pseudohypoaldosteronism" is a misnomer in the context of PHAII, as affected individuals have hyperkalemia with hypertension (instead of volume depletion). Some authorities prefer the descriptive name familial hyperkalemic hypertension (FHHt) for this reason. PHAII is sometimes referred to by a subtype designation based on the associated gene, as follows: PHA type IIA (PHA2A): Unknown genetic cause (see PHA type IIB (PHA2B): PHA type IIC (PHA2C): PHA type IIE (PHA2E): PHA type IID (PHA2D): The prevalence of the disorder is unknown. To date more than 180 individuals and families with PHAII have been reported. • PHA type IIA (PHA2A): Unknown genetic cause (see • PHA type IIB (PHA2B): • PHA type IIC (PHA2C): • PHA type IIE (PHA2E): • PHA type IID (PHA2D): ## Clinical Description Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia despite normal glomerular filtration rate (GFR) and frequently by hypertension. More than 180 individuals and families with PHAII have been reported. The clinical presentation of PHAII is heterogeneous. The most consistent clinical feature in both children and young adults is hyperkalemia [ Other associated findings in both children and adults include hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. Aldosterone levels are variable, but are relatively low given the degree of hyperkalemia (elevated serum potassium is a potent stimulus for aldosterone secretion). Hypercalciuria is also well described in PHAII [ Other features reported in a subset of individuals with PHAII include short stature, myalgias, periodic paralysis, and dental abnormalities [ ## Phenotype Correlations by Gene Individuals with a heterozygous In general, clinical manifestations of PHAII appear to be milder in individuals with a heterozygous Individuals with biallelic ## Nomenclature The term "pseudohypoaldosteronism" has historically been used to describe the finding of persistent hyperkalemia despite the presence of normal or elevated serum levels of aldosterone [ Therefore, the term "pseudohypoaldosteronism" is a misnomer in the context of PHAII, as affected individuals have hyperkalemia with hypertension (instead of volume depletion). Some authorities prefer the descriptive name familial hyperkalemic hypertension (FHHt) for this reason. PHAII is sometimes referred to by a subtype designation based on the associated gene, as follows: PHA type IIA (PHA2A): Unknown genetic cause (see PHA type IIB (PHA2B): PHA type IIC (PHA2C): PHA type IIE (PHA2E): PHA type IID (PHA2D): • PHA type IIA (PHA2A): Unknown genetic cause (see • PHA type IIB (PHA2B): • PHA type IIC (PHA2C): • PHA type IIE (PHA2E): • PHA type IID (PHA2D): ## Prevalence The prevalence of the disorder is unknown. To date more than 180 individuals and families with PHAII have been reported. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Chronic kidney disease, especially when secondary to diabetes, is the most commonly identified cause of hyperkalemia. When renal function is normal, consider the following: Hypoaldosteronism or acquired renal tubular acidosis (type 4), particularly in the setting of marked volume depletion Medication effects. Examples include potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin inhibitors, trimethoprim, and cyclosporine. Primary adrenal insufficiency or deficiency of an adrenal synthetic enzyme • Chronic kidney disease, especially when secondary to diabetes, is the most commonly identified cause of hyperkalemia. • When renal function is normal, consider the following: • Hypoaldosteronism or acquired renal tubular acidosis (type 4), particularly in the setting of marked volume depletion • Medication effects. Examples include potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin inhibitors, trimethoprim, and cyclosporine. • Primary adrenal insufficiency or deficiency of an adrenal synthetic enzyme • Hypoaldosteronism or acquired renal tubular acidosis (type 4), particularly in the setting of marked volume depletion • Medication effects. Examples include potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin inhibitors, trimethoprim, and cyclosporine. • Primary adrenal insufficiency or deficiency of an adrenal synthetic enzyme • Hypoaldosteronism or acquired renal tubular acidosis (type 4), particularly in the setting of marked volume depletion • Medication effects. Examples include potassium-sparing diuretics (e.g., spironolactone), nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin inhibitors, trimethoprim, and cyclosporine. • Primary adrenal insufficiency or deficiency of an adrenal synthetic enzyme ## Management To establish the extent of disease and needs of an individual diagnosed with pseudohypoaldosteronism type II (PHAII), the following evaluations (if not performed as part of the diagnostic evaluation) are recommended: Serum electrolyte analysis Noninvasive blood pressure measurement Consultation with a clinical geneticist and/or genetic counselor Electrolyte and blood pressure abnormalities of PHAII are often corrected with thiazide diuretics. Metabolic abnormalities and hypertension generally improve within one week. Different thiazide diuretics exist, with different dosing regimens. In general dosing is titrated to normalization of blood pressure. It is possible that dosing will need to be increased over time or that additional anti-hypertensives will be required to adequately control blood pressure. There are no established guidelines regarding age at which treatment should begin for individuals with PHAII, but affected children who have hypertension are generally treated. See Control of blood pressure is important to reduce the risk for cardiovascular and renal disease and stroke. Appropriate surveillance includes routine electrolyte and blood pressure measurements, monitored in the same manner as for any person treated with a thiazide diuretic. Untreated individuals with PHAII should avoid excessive intake of foods high in salt and potassium as these may exacerbate hypertension and hyperkalemia. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Evaluations can include: Measurement of serum potassium concentration and blood pressure; Molecular genetic testing if the pathogenic variant(s) in the family are known. See During the pregnancy of a woman with PHAII, electrolytes and blood pressure should be monitored regularly and blood pressure medication adjusted as needed. Some antihypertensive medications (including thiazide diuretics) have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy. The best time to discuss the risk to the fetus associated with a maternal medication is prior to conception. Women with PHAII who become pregnant should be referred to an obstetrics group with expertise in high-risk pregnancies. See Search • Serum electrolyte analysis • Noninvasive blood pressure measurement • Consultation with a clinical geneticist and/or genetic counselor • Measurement of serum potassium concentration and blood pressure; • Molecular genetic testing if the pathogenic variant(s) in the family are known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with pseudohypoaldosteronism type II (PHAII), the following evaluations (if not performed as part of the diagnostic evaluation) are recommended: Serum electrolyte analysis Noninvasive blood pressure measurement Consultation with a clinical geneticist and/or genetic counselor • Serum electrolyte analysis • Noninvasive blood pressure measurement • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Electrolyte and blood pressure abnormalities of PHAII are often corrected with thiazide diuretics. Metabolic abnormalities and hypertension generally improve within one week. Different thiazide diuretics exist, with different dosing regimens. In general dosing is titrated to normalization of blood pressure. It is possible that dosing will need to be increased over time or that additional anti-hypertensives will be required to adequately control blood pressure. There are no established guidelines regarding age at which treatment should begin for individuals with PHAII, but affected children who have hypertension are generally treated. ## Prevention of Primary Manifestations See ## Prevention of Secondary Complications Control of blood pressure is important to reduce the risk for cardiovascular and renal disease and stroke. ## Surveillance Appropriate surveillance includes routine electrolyte and blood pressure measurements, monitored in the same manner as for any person treated with a thiazide diuretic. ## Agents/Circumstances to Avoid Untreated individuals with PHAII should avoid excessive intake of foods high in salt and potassium as these may exacerbate hypertension and hyperkalemia. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Evaluations can include: Measurement of serum potassium concentration and blood pressure; Molecular genetic testing if the pathogenic variant(s) in the family are known. See • Measurement of serum potassium concentration and blood pressure; • Molecular genetic testing if the pathogenic variant(s) in the family are known. ## Pregnancy Management During the pregnancy of a woman with PHAII, electrolytes and blood pressure should be monitored regularly and blood pressure medication adjusted as needed. Some antihypertensive medications (including thiazide diuretics) have been associated with adverse fetal outcome, especially when taken during the first trimester of pregnancy. The best time to discuss the risk to the fetus associated with a maternal medication is prior to conception. Women with PHAII who become pregnant should be referred to an obstetrics group with expertise in high-risk pregnancies. See ## Therapies Under Investigation Search ## Genetic Counseling Pseudohypoaldosteronism type II (PHAII) is most commonly inherited in an autosomal dominant manner. PHAIID can also be inherited in an autosomal recessive manner. Many individuals diagnosed with PHAII have an affected parent. A proband with PHAII may have the disorder as the result of a Fifteen of 182 reported cases have been Recommendations for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome as a result of a milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for PHAII because of the possibility of reduced penetrance in a parent. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. The parents of an affected child are obligate heterozygotes (i.e., carriers of one Carriers of a At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carriers of a Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal choice, discussion of these issues may be helpful. • Many individuals diagnosed with PHAII have an affected parent. • A proband with PHAII may have the disorder as the result of a • Fifteen of 182 reported cases have been • Recommendations for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome as a result of a milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for PHAII because of the possibility of reduced penetrance in a parent. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Carriers of a • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Carriers of a • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Pseudohypoaldosteronism type II (PHAII) is most commonly inherited in an autosomal dominant manner. PHAIID can also be inherited in an autosomal recessive manner. ## Autosomal Dominant Inheritance – Risk to Family Members Many individuals diagnosed with PHAII have an affected parent. A proband with PHAII may have the disorder as the result of a Fifteen of 182 reported cases have been Recommendations for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome as a result of a milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for PHAII because of the possibility of reduced penetrance in a parent. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. • Many individuals diagnosed with PHAII have an affected parent. • A proband with PHAII may have the disorder as the result of a • Fifteen of 182 reported cases have been • Recommendations for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome as a result of a milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed. • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for PHAII because of the possibility of reduced penetrance in a parent. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Carriers of a At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carriers of a Carrier testing for at-risk relatives requires prior identification of the • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Carriers of a • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Carriers of a ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal choice, discussion of these issues may be helpful. ## Resources United Kingdom • • • • United Kingdom • ## Molecular Genetics Pseudohypoaldosteronism Type II: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pseudohypoaldosteronism Type II ( Pathogenic variants in the genes encoding two members of the WNK protein family of serine-threonine kinases, Alterations in The electrolyte and blood pressure abnormalities in individuals with PHAII are readily corrected with thiazide diuretics, inhibitors of the Na-Cl cotransporter (NCC; encoded by Recessive Wild type KLHL3 has been shown to bind to WNK4 and WNK1 [ Immunostaining of mouse kidney demonstrates that KLHL3 is predominantly present in the distal convoluted tubule and collecting duct [ Selected Variants listed in the table have been provided by the author. Deletion within intron 1 (also known as NG_007984.2:c.759+12272_760-5774del) No amino acid change is expected. The L-Wnk1 isoform can activate the kinase SPAK (encoded by As a multifunctional regulator of ion channels and transporters, WNK1 also inhibits the K A knockout mouse model of L-WNK1 has also been generated, and mice with a heterozygous targeted disruption of the L- Selected Variants listed in the table have been provided by the authors. WNK4 has been shown to regulate the activity of a number of ion transporters through heterologous expression in Important information about the mechanisms underlying Most PHAII-causing variants in WNK4 cluster within a highly conserved noncatalytic domain just distal to the kinase domain. Recent in vitro studies have demonstrated that this segment is critical for binding to KLHL3, and PHAII-associated variants within this domain disrupt interactions between WNK4 and KLHL3 [ It has also been suggested that pathogenic variants within this segment disrupt a calcium-sensing mechanism important in the regulation of WNK4 kinase activity [ ## Molecular Pathogenesis Pathogenic variants in the genes encoding two members of the WNK protein family of serine-threonine kinases, Alterations in The electrolyte and blood pressure abnormalities in individuals with PHAII are readily corrected with thiazide diuretics, inhibitors of the Na-Cl cotransporter (NCC; encoded by Recessive Wild type KLHL3 has been shown to bind to WNK4 and WNK1 [ Immunostaining of mouse kidney demonstrates that KLHL3 is predominantly present in the distal convoluted tubule and collecting duct [ Selected Variants listed in the table have been provided by the author. Deletion within intron 1 (also known as NG_007984.2:c.759+12272_760-5774del) No amino acid change is expected. The L-Wnk1 isoform can activate the kinase SPAK (encoded by As a multifunctional regulator of ion channels and transporters, WNK1 also inhibits the K A knockout mouse model of L-WNK1 has also been generated, and mice with a heterozygous targeted disruption of the L- Selected Variants listed in the table have been provided by the authors. WNK4 has been shown to regulate the activity of a number of ion transporters through heterologous expression in Important information about the mechanisms underlying Most PHAII-causing variants in WNK4 cluster within a highly conserved noncatalytic domain just distal to the kinase domain. Recent in vitro studies have demonstrated that this segment is critical for binding to KLHL3, and PHAII-associated variants within this domain disrupt interactions between WNK4 and KLHL3 [ It has also been suggested that pathogenic variants within this segment disrupt a calcium-sensing mechanism important in the regulation of WNK4 kinase activity [ ## ## Recessive Wild type KLHL3 has been shown to bind to WNK4 and WNK1 [ Immunostaining of mouse kidney demonstrates that KLHL3 is predominantly present in the distal convoluted tubule and collecting duct [ ## Selected Variants listed in the table have been provided by the author. Deletion within intron 1 (also known as NG_007984.2:c.759+12272_760-5774del) No amino acid change is expected. The L-Wnk1 isoform can activate the kinase SPAK (encoded by As a multifunctional regulator of ion channels and transporters, WNK1 also inhibits the K A knockout mouse model of L-WNK1 has also been generated, and mice with a heterozygous targeted disruption of the L- ## Selected Variants listed in the table have been provided by the authors. WNK4 has been shown to regulate the activity of a number of ion transporters through heterologous expression in Important information about the mechanisms underlying Most PHAII-causing variants in WNK4 cluster within a highly conserved noncatalytic domain just distal to the kinase domain. Recent in vitro studies have demonstrated that this segment is critical for binding to KLHL3, and PHAII-associated variants within this domain disrupt interactions between WNK4 and KLHL3 [ It has also been suggested that pathogenic variants within this segment disrupt a calcium-sensing mechanism important in the regulation of WNK4 kinase activity [ ## References ## Literature Cited ## Chapter Notes David H Ellison, MD (2017-present)Kristopher T Kahle, MD, PhD; Harvard Medical School (2011-2017)Frederick H Wilson, MD, PhD; Harvard Medical School (2011-2017) 16 February 2017 (ma) Comprehensive update posted live 16 January 2014 (me) Comprehensive update posted live 10 November 2011 (me) Review posted live 25 April 2011 (ktk) Original submission • 16 February 2017 (ma) Comprehensive update posted live • 16 January 2014 (me) Comprehensive update posted live • 10 November 2011 (me) Review posted live • 25 April 2011 (ktk) Original submission ## Author History David H Ellison, MD (2017-present)Kristopher T Kahle, MD, PhD; Harvard Medical School (2011-2017)Frederick H Wilson, MD, PhD; Harvard Medical School (2011-2017) ## Revision History 16 February 2017 (ma) Comprehensive update posted live 16 January 2014 (me) Comprehensive update posted live 10 November 2011 (me) Review posted live 25 April 2011 (ktk) Original submission • 16 February 2017 (ma) Comprehensive update posted live • 16 January 2014 (me) Comprehensive update posted live • 10 November 2011 (me) Review posted live • 25 April 2011 (ktk) Original submission	[ "LM Boyden, M Choi, KA Choate, CJ Nelson-Williams, A Farhi, HR Toka, IR Tikhonova, R Bjornson, SM Mane, G Colussi, M Lebel, RD Gordon, BA Semmekrot, A Poujol, MJ Valimaki, ME De Ferrari, SA Sanjad, M Gutkin, FE Karet, JR Tucci, JR Stockigt, KM Keppler-Noreuil, CC Porter, SK Anand, ML Whiteford, ID David, SB Dewar, A Bettinelli, JJ Fadrowski, CW Belsha, TE Hunley, RD Nelson, H Trachtman, TRP Cole, M Pinsk, D Bockenhauer, M Shenoy, P Vaidyanathan, JW Foreman, M Rasoulpour, F Thameem, HZ Al-Shahrouri, J Radhakrishnan, AG Gharavi, B Goilav, RP Lifton. 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WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia.. Proc Natl Acad Sci USA 2004a;101:2064-9", "KT Kahle, GG Macgregor, FH Wilson, AN Van Hoek, D Brown, T Ardito, M Kashgarian, G Giebisch, SC Hebert, EL Boulpaep, RP Lifton. Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.. Proc Natl Acad Sci USA 2004b;101:14877-82", "KT Kahle, J Rinehart, G Giebisch, G Gamba, SC Hebert, RP Lifton. A novel protein kinase signaling pathway essential for blood pressure regulation in humans.. Trends Endocrinol Metab 2008;19:91-5", "KT Kahle, FH Wilson, Q Leng, MD Lalioti, AD O'Connell, K Dong, AK Rapson, GG MacGregor, G Giebisch, SC Hebert, RP Lifton. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.. Nat Genet 2003;35:372-6", "MD Lalioti, J Zhang, HM Volkman, KT Kahle, KE Hoffmann, HR Toka, C Nelson-Williams, DH Ellison, R Flavell, CJ Booth, Y Lu, DS Geller, RP Lifton. 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Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation.. J Clin Endocrinol Metab 2004;89:4025-30", "M Mitani, M Furuichi, S Narumi, T Hasegawa, M Chiga, S Uchida, S. Sato. A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation.. Clin Pediatr Endocrinol. 2016;25:127-34", "Y Mori, M Wakabayashi, T Mori, Y Araki, E Sohara, T Rai, S Sasaki, S Uchida. Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms.. Biochem Biophys Res Commun 2013;439:30-4", "T Na, G Wu, J Peng. Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions.. Biochem Biophys Res Commun 2012;419:293-8", "T Na, G Wu, W Zhang, W Dong, J Peng. Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites.. Am J Physiol Renal Physiol. 2013;304:F8-F18", "A Ohta, F Schumacher, Y Mehellou, C Johnson, A Knebel, TJ Macartney, NT Wood, DR Alessi, T Kurz. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.. Biochem J. 2013;451:111-22", "M O'Reilly, E Marshall, HJ Speirs, RW Brown. WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain.. J Am Soc Nephrol 2003;14:2447-56", "HL Picard, S Latreche, N Thurairajasingam, C Auzan, B Fiquet, R Frayssinet, A Garnier, V Jendruchova, T Lobbedez, L Martorell, G Mortier, I Pela, S Taque, R Vargas-Poussou, E Clauser, X Jeunemaitre. 6C.01: CULLIN-3 mutations leading to skipping of exon 9 are responsible for severe cases of familial hyperkalaemic hypertension.. J Hypertens. 2015a;33", "HL Picard, N Thurairajasingam, S Decramer, X Girerd, K Oshaugnessy, P Mulatero, G Roussey, I Tack, R Unwin, R Vargas-Poussou, X Jeunemaitre. 1A.01: mutations affecting the conserved acidic motif of WNK1 cause inherited normotensive hyperkalemic acidosis.. J Hypertens. 2015b;33", "AM Ring, SX Cheng, Q Leng, KT Kahle, J Rinehart, MD Lalioti, HM Volkman, FH Wilson, SC Hebert, RP Lifton. WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo.. Proc Natl Acad Sci U S A. 2007a;104:4020-4", "AM Ring, Q Leng, J Rinehart, FH Wilson, KT Kahle, SC Hebert, RP Lifton. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.. Proc Natl Acad Sci U S A. 2007b;104:4025-9", "M Schambelan, A Sebastian, FC Rector. Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of increased renal chloride reabsorption.. Kidney Int 1981;19:716-27", "M Shekarabi, N Girard, JB Rivière, P Dion, M Houle, A Toulouse, RG Lafrenière, F Vercauteren, P Hince, J Laganiere, D Rochefort, L Faivre, M Samuels, GA Rouleau. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.. J Clin Invest. 2008;118:2496-505", "S Shibata, J Zhang, J Puthumana, KL Stone, RP Lifton. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4.. Proc Natl Acad Sci U S A. 2013;110:7838-43", "AR Subramanya, CL Yang, X Zhu, DH Ellison. Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.. Am J Physiol Renal Physiol. 2006;290:F619-24", "D Takahashi, T Mori, N Nomura, MZ Khan, Y Araki, M Zeniya, E Sohara, T Rai, S Sasaki, S Uchida. WNK4 is the major WNK positively regulating NCC in the mouse kidney.. Biosci Rep. 2014;34", "R Tatum, Y Zhang, Q Lu, K Kim, BG Jeansonne, YH Chen. WNK4 phosphorylates ser(206) of claudin-7 and promotes paracellular Cl(-) permeability.. FEBS Lett. 2007;581:3887-91", "S Tsuji, M Yamashita, G Unishi, R Takewa, T Kimata, K Isobe, M Chiga, S Uchida, K. Kaneko. A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3.. BMC Nephrol. 2013;14:166", "E Vidal-Petiot, E Elvira-Matelot, K Mutig, C Soukaseum, V Baudrie, S Wu, L Cheval, E Huc, M Cambillau, S Bachmann, A Doucet, X Jeunemaitre, J Hadchouel. WNK1-related familial hyperkalemic hypertension results from an increased expression of L-WNK1 specifically in the distal nephron.. Proc Natl Acad Sci U S A. 2013;110:14366-71", "M Wakabayashi, T Mori, K Isobe, E Sohara, K Susa, Y Araki, M Chiga, E Kikuchi, N Nomura, Y Mori, H Matsuo, T Murata, S Nomura, T Asano, H Kawaguchi, S Nonoyama, T Rai, S Sasaki, S Uchida. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.. Cell Rep. 2013;3:858-68", "FH Wilson, S Disse-Nicodème, KA Choate, K Ishikawa, C Nelson-Williams, I Desitter, M Gunel, DV Milford, GW Lipkin, JM Achard, MP Feely, B Dussol, Y Berland, RJ Unwin, H Mayan, DB Simon, Z Farfel, X Jeunemaitre, RP Lifton. Human hypertension caused by mutations in WNK kinases.. Science. 2001;293:1107-12", "FH Wilson, KT Kahle, E Sabath, MD Lalioti, AK Rapson, RS Hoover, SC Hebert, G Gamba, RP Lifton. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.. Proc Natl Acad Sci U S A. 2003;100:680-4", "G Wu, J Peng. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.. FEBS Lett. 2013;587:1717-22", "B Xu, JM English, JL Wilsbacher, S Stippec, EJ Goldsmith, MH Cobb. WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.. J Biol Chem. 2000;275:16795-801", "BE Xu, S Stippec, PY Chu, A Lazrak, XJ Li, BH Lee, JM English, B Ortega, CL Huang, MH Cobb. WNK1 activates SGK1 to regulate the epithelial sodium channel.. Proc Natl Acad Sci U S A. 2005;102:10315-20", "K Yamauchi, T Rai, K Kobayashi, E Sohara, T Suzuki, T Itoh, S Suda, A Hayama, S Sasaki, S Uchida. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins.. Proc Natl Acad Sci U S A. 2004;101:4690-4", "CL Yang, J Angell, R Mitchell, DH Ellison. WNK kinases regulate thiazide-sensitive Na-Cl cotransport.. J Clin Invest. 2003;111:1039-45", "SS Yang, T Morimoto, T Rai, M Chiga, E Sohara, M Ohno, K Uchida, SH Lin, T Moriguchi, H Shibuya, Y Kondo, S Sasaki, S Uchida. Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.. Cell Metab. 2007;5:331-44", "BP Zambrowicz, A Abuin, R Ramirez-Solis, LJ Richter, J Piggott. BeltrandelRio H, Buxton EC, Edwards J, Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, Huang W, Jaing C, Key BW Jr, Kipp P, Kohlhauff B, Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst I, Vogel P, Walke W, Xu N, Zhu Q, Person C, Sands AT. Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.. Proc Natl Acad Sci U S A. 2003;100:14109-14", "C Zhang, Y Zhu, F Huang, G Jiang, J Chang, R Li. Novel missense mutations of WNK1 in patients with hypokalemic salt-losing tubulopathies.. Clin Genet. 2013;83:545-52" ]	10/11/2011	16/2/2017		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
phs	phs	[ "Transcriptional activator GLI3", "GLI3", "GLI3-Related Pallister-Hall Syndrome" ]		Leslie G Biesecker	Summary The diagnosis of	## Diagnosis Consensus clinical diagnostic criteria for Note: Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma. Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecificity of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central African descent require caution in its use as a diagnostic feature. Bifid epiglottis is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than The clinical diagnosis of Note: (1) Per ACMG/AMP variant classification guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are handled similarly in a diagnostic testing clinical setting, meaning that both can lead to a clinico-molecular diagnosis [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Combined data from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large exon or multiexon deletions or duplications have been reported in individuals with In 5% of individuals with clinical features of PHS, no pathogenic variant in • Note: Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma. • Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecificity of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central African descent require caution in its use as a diagnostic feature. • Bifid epiglottis is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than ## Suggestive Findings Note: Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma. Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecificity of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central African descent require caution in its use as a diagnostic feature. Bifid epiglottis is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than • Note: Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma. • Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecificity of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central African descent require caution in its use as a diagnostic feature. • Bifid epiglottis is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than ## Establishing the Diagnosis The clinical diagnosis of Note: (1) Per ACMG/AMP variant classification guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are handled similarly in a diagnostic testing clinical setting, meaning that both can lead to a clinico-molecular diagnosis [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Combined data from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large exon or multiexon deletions or duplications have been reported in individuals with In 5% of individuals with clinical features of PHS, no pathogenic variant in ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Combined data from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large exon or multiexon deletions or duplications have been reported in individuals with In 5% of individuals with clinical features of PHS, no pathogenic variant in ## Clinical Characteristics +++ = common; ++ = seen in many affected persons; + = seen in some or a few affected persons Even these coarse estimates of the frequency of specific features are likely to be heavily skewed by phenotypic ascertainment bias. It is likely that the overwhelming majority of diagnosed individuals were ascertained because they had a hypothalamic hamartoma and polydactyly. Therefore, to assert that these malformations are common in Note: The nonspecificity of postaxial polydactyly and the high frequency of PAP type B in persons of central African descent require caution in its use as a diagnostic feature. The mutational spectra of Note: A single truncating variant in the Two splice variants have been associated with No instances of incomplete penetrance of Other descriptors used include the following: Note: The abbreviation "HPS" is used for • Note: A single truncating variant in the • ## Clinical Description +++ = common; ++ = seen in many affected persons; + = seen in some or a few affected persons Even these coarse estimates of the frequency of specific features are likely to be heavily skewed by phenotypic ascertainment bias. It is likely that the overwhelming majority of diagnosed individuals were ascertained because they had a hypothalamic hamartoma and polydactyly. Therefore, to assert that these malformations are common in Note: The nonspecificity of postaxial polydactyly and the high frequency of PAP type B in persons of central African descent require caution in its use as a diagnostic feature. ## Genotype-Phenotype Correlations The mutational spectra of Note: A single truncating variant in the Two splice variants have been associated with • Note: A single truncating variant in the ## Penetrance No instances of incomplete penetrance of ## Nomenclature Other descriptors used include the following: Note: The abbreviation "HPS" is used for • ## Prevalence ## Genetically Related (Allelic) Disorders Other phenotypes known to be associated with germline pathogenic variants in Note: Haploinsufficiency for AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GCPS = Greig cephalopolysyndactyly syndrome; HH = hypothalamic hamartoma; MOI = mode of inheritance ## Differential Diagnosis Disorders Associated with Postaxial Polydactyly in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; ID = intellectual disability; MOI = mode of inheritance; PAP = postaxial polydactyly; PHS = Pallister-Hall syndrome Bardet-Biedl syndrome (BBS) is typically inherited in an autosomal recessive manner. ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Assessment for cortisol deficiency Consultation by endocrinologist, incl eval of growth hormone secretion, FSH & LH secretion, & serum concentration of thyroid hormone in early infancy after eval for & treatment of ACTH deficiency Assessment for cortisol deficiency must be performed urgently in persons w/no family history of Adrenal crisis can be lethal in infants who have not undergone proper eval & treatment for adrenal insufficiency. Cranial MRI to establish location & extent of hamartoma Neurologic exam to excl signs of intracranial hypertension, which is not typical of hypothalamic hamartomas Limb radiographs to distinguish postaxial polydactyly from central polydactyly Eval by hand surgeon to assess timing & surgical approach to correct polydactyly Visualization of epiglottis by laryngoscopy Urgent eval by otolaryngologist for laryngotracheal cleft when signs or symptoms of aspiration are present; elective eval by otolaryngologist in asymptomatic persons To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support; Home nursing referral. ACTH = adrenocorticotropic hormone; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with OT for manual dexterity of hands may be needed as some persons w/mesoaxial polydactyly have digital malalignment. Repair of polydactyly should be undertaken on elective basis. Mgmt of epiglottal abnormalities depends on type of abnormality & extent of respiratory compromise. Bifid epiglottis is often asymptomatic & most do not require treatment, unless accompanied by clear evidence of obstruction or assoc w/other anomalies, such as tracheal stenosis. ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; CNS = central nervous system; DD/ID = developmental delay / intellectual disability; HH = hypothalamic hamartomas; OT = occupational therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Recommended Surveillance for Individuals with Assess growth. Monitor for signs of precocious puberty. Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement. Some stimulants (commonly used for attention-deficit/hyperactivity disorder) may exacerbate seizures. Molecular genetic testing for the Clinical examination for polydactyly, laryngoscopy for bifid epiglottis, or MRI for hypothalamic hamartoma. The first-degree relative of a proband is considered affected if hypothalamic hamartoma or central or postaxial polydactyly (PAP) is present in the relative. (PAP type B can be used as a diagnostic criterion for first-degree relatives only in persons who are not of central African descent.) Note: Assessment for cortisol deficiency must be performed urgently in individuals who have family members with See Pregnancy management of a woman with In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ The management of fertility and pregnancy (which is uncommon in individuals with hypopituitarism) in individuals with hypopituitarism caused by See Search • Assessment for cortisol deficiency • Consultation by endocrinologist, incl eval of growth hormone secretion, FSH & LH secretion, & serum concentration of thyroid hormone in early infancy after eval for & treatment of ACTH deficiency • Assessment for cortisol deficiency must be performed urgently in persons w/no family history of • Adrenal crisis can be lethal in infants who have not undergone proper eval & treatment for adrenal insufficiency. • Cranial MRI to establish location & extent of hamartoma • Neurologic exam to excl signs of intracranial hypertension, which is not typical of hypothalamic hamartomas • Limb radiographs to distinguish postaxial polydactyly from central polydactyly • Eval by hand surgeon to assess timing & surgical approach to correct polydactyly • Visualization of epiglottis by laryngoscopy • Urgent eval by otolaryngologist for laryngotracheal cleft when signs or symptoms of aspiration are present; elective eval by otolaryngologist in asymptomatic persons • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support; • Home nursing referral. • OT for manual dexterity of hands may be needed as some persons w/mesoaxial polydactyly have digital malalignment. • Repair of polydactyly should be undertaken on elective basis. • Mgmt of epiglottal abnormalities depends on type of abnormality & extent of respiratory compromise. • Bifid epiglottis is often asymptomatic & most do not require treatment, unless accompanied by clear evidence of obstruction or assoc w/other anomalies, such as tracheal stenosis. • Assess growth. • Monitor for signs of precocious puberty. • Molecular genetic testing for the • Clinical examination for polydactyly, laryngoscopy for bifid epiglottis, or MRI for hypothalamic hamartoma. The first-degree relative of a proband is considered affected if hypothalamic hamartoma or central or postaxial polydactyly (PAP) is present in the relative. (PAP type B can be used as a diagnostic criterion for first-degree relatives only in persons who are not of central African descent.) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Assessment for cortisol deficiency Consultation by endocrinologist, incl eval of growth hormone secretion, FSH & LH secretion, & serum concentration of thyroid hormone in early infancy after eval for & treatment of ACTH deficiency Assessment for cortisol deficiency must be performed urgently in persons w/no family history of Adrenal crisis can be lethal in infants who have not undergone proper eval & treatment for adrenal insufficiency. Cranial MRI to establish location & extent of hamartoma Neurologic exam to excl signs of intracranial hypertension, which is not typical of hypothalamic hamartomas Limb radiographs to distinguish postaxial polydactyly from central polydactyly Eval by hand surgeon to assess timing & surgical approach to correct polydactyly Visualization of epiglottis by laryngoscopy Urgent eval by otolaryngologist for laryngotracheal cleft when signs or symptoms of aspiration are present; elective eval by otolaryngologist in asymptomatic persons To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support; Home nursing referral. ACTH = adrenocorticotropic hormone; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MOI = mode of inheritance; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assessment for cortisol deficiency • Consultation by endocrinologist, incl eval of growth hormone secretion, FSH & LH secretion, & serum concentration of thyroid hormone in early infancy after eval for & treatment of ACTH deficiency • Assessment for cortisol deficiency must be performed urgently in persons w/no family history of • Adrenal crisis can be lethal in infants who have not undergone proper eval & treatment for adrenal insufficiency. • Cranial MRI to establish location & extent of hamartoma • Neurologic exam to excl signs of intracranial hypertension, which is not typical of hypothalamic hamartomas • Limb radiographs to distinguish postaxial polydactyly from central polydactyly • Eval by hand surgeon to assess timing & surgical approach to correct polydactyly • Visualization of epiglottis by laryngoscopy • Urgent eval by otolaryngologist for laryngotracheal cleft when signs or symptoms of aspiration are present; elective eval by otolaryngologist in asymptomatic persons • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with OT for manual dexterity of hands may be needed as some persons w/mesoaxial polydactyly have digital malalignment. Repair of polydactyly should be undertaken on elective basis. Mgmt of epiglottal abnormalities depends on type of abnormality & extent of respiratory compromise. Bifid epiglottis is often asymptomatic & most do not require treatment, unless accompanied by clear evidence of obstruction or assoc w/other anomalies, such as tracheal stenosis. ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; CNS = central nervous system; DD/ID = developmental delay / intellectual disability; HH = hypothalamic hamartomas; OT = occupational therapy • OT for manual dexterity of hands may be needed as some persons w/mesoaxial polydactyly have digital malalignment. • Repair of polydactyly should be undertaken on elective basis. • Mgmt of epiglottal abnormalities depends on type of abnormality & extent of respiratory compromise. • Bifid epiglottis is often asymptomatic & most do not require treatment, unless accompanied by clear evidence of obstruction or assoc w/other anomalies, such as tracheal stenosis. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Recommended Surveillance for Individuals with Assess growth. Monitor for signs of precocious puberty. • Assess growth. • Monitor for signs of precocious puberty. ## Agents/Circumstances to Avoid Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement. Some stimulants (commonly used for attention-deficit/hyperactivity disorder) may exacerbate seizures. ## Evaluation of Relatives at Risk Molecular genetic testing for the Clinical examination for polydactyly, laryngoscopy for bifid epiglottis, or MRI for hypothalamic hamartoma. The first-degree relative of a proband is considered affected if hypothalamic hamartoma or central or postaxial polydactyly (PAP) is present in the relative. (PAP type B can be used as a diagnostic criterion for first-degree relatives only in persons who are not of central African descent.) Note: Assessment for cortisol deficiency must be performed urgently in individuals who have family members with See • Molecular genetic testing for the • Clinical examination for polydactyly, laryngoscopy for bifid epiglottis, or MRI for hypothalamic hamartoma. The first-degree relative of a proband is considered affected if hypothalamic hamartoma or central or postaxial polydactyly (PAP) is present in the relative. (PAP type B can be used as a diagnostic criterion for first-degree relatives only in persons who are not of central African descent.) ## Pregnancy Management Pregnancy management of a woman with In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ The management of fertility and pregnancy (which is uncommon in individuals with hypopituitarism) in individuals with hypopituitarism caused by See ## Therapies Under Investigation Search ## Genetic Counseling Approximately 75% of individuals diagnosed with Approximately 25% of individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a d The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The description of a single parent with germline mosaicism for a If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because intrafamilial variability appears to be low, affected sibs would be expected to have clinical findings similar to those of the proband. If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of the possibility of parental germline mosaicism. Because there has only been a single occurrence of parental germline mosaicism (and no reports of non-penetrance) reported to date, the parents of a proband with no known family history of See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Approximately 75% of individuals diagnosed with • Approximately 25% of individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a d • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The description of a single parent with germline mosaicism for a • The proband has a d • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The description of a single parent with germline mosaicism for a • The proband has a d • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The description of a single parent with germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because intrafamilial variability appears to be low, affected sibs would be expected to have clinical findings similar to those of the proband. • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of the possibility of parental germline mosaicism. Because there has only been a single occurrence of parental germline mosaicism (and no reports of non-penetrance) reported to date, the parents of a proband with no known family history of • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance ## Risk to Family Members Approximately 75% of individuals diagnosed with Approximately 25% of individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a d The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The description of a single parent with germline mosaicism for a If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because intrafamilial variability appears to be low, affected sibs would be expected to have clinical findings similar to those of the proband. If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of the possibility of parental germline mosaicism. Because there has only been a single occurrence of parental germline mosaicism (and no reports of non-penetrance) reported to date, the parents of a proband with no known family history of • Approximately 75% of individuals diagnosed with • Approximately 25% of individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a d • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The description of a single parent with germline mosaicism for a • The proband has a d • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The description of a single parent with germline mosaicism for a • The proband has a d • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The description of a single parent with germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because intrafamilial variability appears to be low, affected sibs would be expected to have clinical findings similar to those of the proband. • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of the possibility of parental germline mosaicism. Because there has only been a single occurrence of parental germline mosaicism (and no reports of non-penetrance) reported to date, the parents of a proband with no known family history of ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics GLI3-Related Pallister-Hall Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for GLI3-Related Pallister-Hall Syndrome ( ## Molecular Pathogenesis ## Chapter Notes The author is a board-certified clinical geneticist and pediatrician. He performs clinical and molecular research on genetic disorders at the National Institutes of Health. Dr Biesecker is interested in hearing from clinicians treating families affected by The author is supported by funding from the Intramural Research Program of the National Human Genome Research Institute. 22 February 2024 (aa) Revision: information about 18 August 2022 (sw) Comprehensive update posted live 18 May 2017 (sw) Comprehensive update posted live 18 December 2014 (me) Comprehensive update posted live 13 September 2012 (me) Comprehensive update posted live 18 March 2008 (me) Comprehensive update posted live 6 June 2005 (me) Comprehensive update posted live 1 May 2003 (me) Comprehensive update posted live 25 May 2000 (me) Review posted live 20 January 2000 (lb) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 22 February 2024 (aa) Revision: information about • 18 August 2022 (sw) Comprehensive update posted live • 18 May 2017 (sw) Comprehensive update posted live • 18 December 2014 (me) Comprehensive update posted live • 13 September 2012 (me) Comprehensive update posted live • 18 March 2008 (me) Comprehensive update posted live • 6 June 2005 (me) Comprehensive update posted live • 1 May 2003 (me) Comprehensive update posted live • 25 May 2000 (me) Review posted live • 20 January 2000 (lb) Original submission ## Author Notes The author is a board-certified clinical geneticist and pediatrician. He performs clinical and molecular research on genetic disorders at the National Institutes of Health. Dr Biesecker is interested in hearing from clinicians treating families affected by ## Acknowledgments The author is supported by funding from the Intramural Research Program of the National Human Genome Research Institute. ## Revision History 22 February 2024 (aa) Revision: information about 18 August 2022 (sw) Comprehensive update posted live 18 May 2017 (sw) Comprehensive update posted live 18 December 2014 (me) Comprehensive update posted live 13 September 2012 (me) Comprehensive update posted live 18 March 2008 (me) Comprehensive update posted live 6 June 2005 (me) Comprehensive update posted live 1 May 2003 (me) Comprehensive update posted live 25 May 2000 (me) Review posted live 20 January 2000 (lb) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 22 February 2024 (aa) Revision: information about • 18 August 2022 (sw) Comprehensive update posted live • 18 May 2017 (sw) Comprehensive update posted live • 18 December 2014 (me) Comprehensive update posted live • 13 September 2012 (me) Comprehensive update posted live • 18 March 2008 (me) Comprehensive update posted live • 6 June 2005 (me) Comprehensive update posted live • 1 May 2003 (me) Comprehensive update posted live • 25 May 2000 (me) Review posted live • 20 January 2000 (lb) Original submission ## References ## Literature Cited The mutational spectra of	[]	25/5/2000	18/8/2022	22/2/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
phts	phts	[ "PHTS", "Cowden Syndrome (CS)", "Bannayan-Riley-Ruvalcaba Syndrome (BRRS)", "PTEN-Related Proteus-Like Syndrome", "PTEN-Related Proteus Syndrome (PS)", "Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN", "PTEN", "PTEN Hamartoma Tumor Syndrome (PHTS)" ]		Lamis Yehia, Charis Eng	Summary The CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, kidney, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The lifetime risk for renal cell cancer (predominantly of papillary histology) is 34%. The risk for endometrial cancer may approach 28%. BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS. The diagnosis of PHTS is established in a proband by identification of a heterozygous germline Children (age <18 years). Yearly thyroid ultrasound from the time of diagnosis (earliest reported at age 7 years) and skin check with physical examination Adults. Yearly thyroid ultrasound and dermatologic evaluation Women beginning at age 30 years. Monthly breast self-examination; annual breast screening (at minimum mammogram; MRI may also be incorporated). Starting by age 35 years, consider transvaginal ultrasound or endometrial biopsy. Men and women. Colonoscopy beginning at age 35 years with frequency dependent on degree of polyposis identified or family history of early-onset colon cancer (before age 40); biennial (every 2 years) renal imaging (CT or MRI preferred) beginning at age 40 years Those with a family history of a particular cancer type at an early age. Consider initiating screening 5 to 10 years prior to the youngest age of diagnosis in the family. PHTS is inherited in an autosomal dominant manner. Because CS is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as ≥2 related affected individuals) cannot be determined. The majority of CS cases are simplex. Perhaps 10%-50% of individuals with CS have an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing PHTS. Once a	Cowden syndrome (CS) Bannayan-Riley-Ruvalcaba syndrome (BRRS) For synonyms and outdated names see For other genetic causes of these phenotypes see • Cowden syndrome (CS) • Bannayan-Riley-Ruvalcaba syndrome (BRRS) ## Diagnosis The Based on more than 3,000 prospectively accrued cases of CS or Cowden-like syndrome (CLS) from the community, a scoring system (which can be found In adults, a clinical threshold score of ten or more leads to a recommendation for referral to a genetics professional to consider PHTS. In children, macrocephaly and one or more of the following leads to the consideration of PHTS: Autism or developmental delay Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling Vascular features, such as arteriovenous malformations or hemangiomas Gastrointestinal polyps Pediatric-onset thyroid cancer or germ cell tumors Additionally, consensus clinical diagnostic criteria for CS have been developed [ Consensus clinical diagnostic criteria have been divided into three categories: pathognomonic, major, and minor. Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma [ Mucocutaneous lesions: Trichilemmomas (facial) (See Acral keratoses Papillomatous lesions (See Mucosal lesions Breast cancer Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer Macrocephaly (occipital frontal circumference ≥97th percentile) Endometrial carcinoma Other thyroid lesions (e.g., adenoma, multinodular goiter) Intellectual disability (IQ ≤75) Hamartomatous intestinal polyps Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumors (especially renal cell carcinoma) Genitourinary malformation Uterine fibroids Pathognomonic mucocutaneous lesions including one of the following: Six or more facial papules, of which three or more must be trichilemmomas Cutaneous facial papules and oral mucosal papillomatosis Oral mucosal papillomatosis and acral keratoses Six or more palmoplantar keratoses Two or more major criteria One major and three or more minor criteria Four or more minor criteria In a family in which one individual meets the diagnostic criteria for CS listed above, other relatives are considered to have a clinical diagnosis of CS if they meet A pathognomonic criterion Any one major criterion with or without minor criteria Two minor criteria History of Bannayan-Riley-Ruvalcaba syndrome Diagnostic criteria for BRRS have not been set but are based heavily on the presence of the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis [ The diagnosis of PHTS Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: In individuals with Cowden syndrome (CS) and Cowden-like syndrome (CLS), also consider a germline For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in 3% BRRS = Bannayan-Riley-Ruvalcaba syndrome; CS = Cowden syndrome; PLS = Proteus-like syndrome; PS = See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data suggest that up to 50% of individuals with a Proteus-like syndrome and 20% of individuals who meet the clinical diagnostic criteria of Proteus syndrome have Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Individuals with CS who have large deletions have been reported [ • In adults, a clinical threshold score of ten or more leads to a recommendation for referral to a genetics professional to consider PHTS. • In children, macrocephaly and one or more of the following leads to the consideration of PHTS: • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma [ • Mucocutaneous lesions: • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Breast cancer • Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer • Macrocephaly (occipital frontal circumference ≥97th percentile) • Endometrial carcinoma • Other thyroid lesions (e.g., adenoma, multinodular goiter) • Intellectual disability (IQ ≤75) • Hamartomatous intestinal polyps • Fibrocystic disease of the breast • Lipomas • Fibromas • Genitourinary tumors (especially renal cell carcinoma) • Genitourinary malformation • Uterine fibroids • Pathognomonic mucocutaneous lesions including one of the following: • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • Two or more major criteria • One major and three or more minor criteria • Four or more minor criteria • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • A pathognomonic criterion • Any one major criterion with or without minor criteria • Two minor criteria • History of Bannayan-Riley-Ruvalcaba syndrome ## Suggestive Findings The Based on more than 3,000 prospectively accrued cases of CS or Cowden-like syndrome (CLS) from the community, a scoring system (which can be found In adults, a clinical threshold score of ten or more leads to a recommendation for referral to a genetics professional to consider PHTS. In children, macrocephaly and one or more of the following leads to the consideration of PHTS: Autism or developmental delay Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling Vascular features, such as arteriovenous malformations or hemangiomas Gastrointestinal polyps Pediatric-onset thyroid cancer or germ cell tumors Additionally, consensus clinical diagnostic criteria for CS have been developed [ Consensus clinical diagnostic criteria have been divided into three categories: pathognomonic, major, and minor. Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma [ Mucocutaneous lesions: Trichilemmomas (facial) (See Acral keratoses Papillomatous lesions (See Mucosal lesions Breast cancer Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer Macrocephaly (occipital frontal circumference ≥97th percentile) Endometrial carcinoma Other thyroid lesions (e.g., adenoma, multinodular goiter) Intellectual disability (IQ ≤75) Hamartomatous intestinal polyps Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumors (especially renal cell carcinoma) Genitourinary malformation Uterine fibroids Pathognomonic mucocutaneous lesions including one of the following: Six or more facial papules, of which three or more must be trichilemmomas Cutaneous facial papules and oral mucosal papillomatosis Oral mucosal papillomatosis and acral keratoses Six or more palmoplantar keratoses Two or more major criteria One major and three or more minor criteria Four or more minor criteria In a family in which one individual meets the diagnostic criteria for CS listed above, other relatives are considered to have a clinical diagnosis of CS if they meet A pathognomonic criterion Any one major criterion with or without minor criteria Two minor criteria History of Bannayan-Riley-Ruvalcaba syndrome Diagnostic criteria for BRRS have not been set but are based heavily on the presence of the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis [ • In adults, a clinical threshold score of ten or more leads to a recommendation for referral to a genetics professional to consider PHTS. • In children, macrocephaly and one or more of the following leads to the consideration of PHTS: • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma [ • Mucocutaneous lesions: • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Breast cancer • Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer • Macrocephaly (occipital frontal circumference ≥97th percentile) • Endometrial carcinoma • Other thyroid lesions (e.g., adenoma, multinodular goiter) • Intellectual disability (IQ ≤75) • Hamartomatous intestinal polyps • Fibrocystic disease of the breast • Lipomas • Fibromas • Genitourinary tumors (especially renal cell carcinoma) • Genitourinary malformation • Uterine fibroids • Pathognomonic mucocutaneous lesions including one of the following: • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • Two or more major criteria • One major and three or more minor criteria • Four or more minor criteria • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • A pathognomonic criterion • Any one major criterion with or without minor criteria • Two minor criteria • History of Bannayan-Riley-Ruvalcaba syndrome ## Cowden Syndrome (CS) Based on more than 3,000 prospectively accrued cases of CS or Cowden-like syndrome (CLS) from the community, a scoring system (which can be found In adults, a clinical threshold score of ten or more leads to a recommendation for referral to a genetics professional to consider PHTS. In children, macrocephaly and one or more of the following leads to the consideration of PHTS: Autism or developmental delay Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling Vascular features, such as arteriovenous malformations or hemangiomas Gastrointestinal polyps Pediatric-onset thyroid cancer or germ cell tumors Additionally, consensus clinical diagnostic criteria for CS have been developed [ Consensus clinical diagnostic criteria have been divided into three categories: pathognomonic, major, and minor. Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma [ Mucocutaneous lesions: Trichilemmomas (facial) (See Acral keratoses Papillomatous lesions (See Mucosal lesions Breast cancer Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer Macrocephaly (occipital frontal circumference ≥97th percentile) Endometrial carcinoma Other thyroid lesions (e.g., adenoma, multinodular goiter) Intellectual disability (IQ ≤75) Hamartomatous intestinal polyps Fibrocystic disease of the breast Lipomas Fibromas Genitourinary tumors (especially renal cell carcinoma) Genitourinary malformation Uterine fibroids Pathognomonic mucocutaneous lesions including one of the following: Six or more facial papules, of which three or more must be trichilemmomas Cutaneous facial papules and oral mucosal papillomatosis Oral mucosal papillomatosis and acral keratoses Six or more palmoplantar keratoses Two or more major criteria One major and three or more minor criteria Four or more minor criteria In a family in which one individual meets the diagnostic criteria for CS listed above, other relatives are considered to have a clinical diagnosis of CS if they meet A pathognomonic criterion Any one major criterion with or without minor criteria Two minor criteria History of Bannayan-Riley-Ruvalcaba syndrome • In adults, a clinical threshold score of ten or more leads to a recommendation for referral to a genetics professional to consider PHTS. • In children, macrocephaly and one or more of the following leads to the consideration of PHTS: • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Autism or developmental delay • Dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling • Vascular features, such as arteriovenous malformations or hemangiomas • Gastrointestinal polyps • Pediatric-onset thyroid cancer or germ cell tumors • Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma [ • Mucocutaneous lesions: • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Trichilemmomas (facial) (See • Acral keratoses • Papillomatous lesions (See • Mucosal lesions • Breast cancer • Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer • Macrocephaly (occipital frontal circumference ≥97th percentile) • Endometrial carcinoma • Other thyroid lesions (e.g., adenoma, multinodular goiter) • Intellectual disability (IQ ≤75) • Hamartomatous intestinal polyps • Fibrocystic disease of the breast • Lipomas • Fibromas • Genitourinary tumors (especially renal cell carcinoma) • Genitourinary malformation • Uterine fibroids • Pathognomonic mucocutaneous lesions including one of the following: • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • Two or more major criteria • One major and three or more minor criteria • Four or more minor criteria • Six or more facial papules, of which three or more must be trichilemmomas • Cutaneous facial papules and oral mucosal papillomatosis • Oral mucosal papillomatosis and acral keratoses • Six or more palmoplantar keratoses • A pathognomonic criterion • Any one major criterion with or without minor criteria • Two minor criteria • History of Bannayan-Riley-Ruvalcaba syndrome ## Bannayan-Riley-Ruvalcaba Syndrome (BRRS) Diagnostic criteria for BRRS have not been set but are based heavily on the presence of the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis [ ## Establishing the Diagnosis The diagnosis of PHTS Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: In individuals with Cowden syndrome (CS) and Cowden-like syndrome (CLS), also consider a germline For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in 3% BRRS = Bannayan-Riley-Ruvalcaba syndrome; CS = Cowden syndrome; PLS = Proteus-like syndrome; PS = See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data suggest that up to 50% of individuals with a Proteus-like syndrome and 20% of individuals who meet the clinical diagnostic criteria of Proteus syndrome have Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Individuals with CS who have large deletions have been reported [ ## Option 1 Note: In individuals with Cowden syndrome (CS) and Cowden-like syndrome (CLS), also consider a germline For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in 3% BRRS = Bannayan-Riley-Ruvalcaba syndrome; CS = Cowden syndrome; PLS = Proteus-like syndrome; PS = See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data suggest that up to 50% of individuals with a Proteus-like syndrome and 20% of individuals who meet the clinical diagnostic criteria of Proteus syndrome have Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Individuals with CS who have large deletions have been reported [ ## Clinical Characteristics CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Renal cell carcinoma and colorectal carcinoma have also been shown to be in the PHTS spectrum. BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS. More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [ Hamartomatous and mixed gastrointestinal polyps, seen frequently in the majority of people with PHTS, do confer an increased risk for colorectal cancers [ Based on anecdotal observations, glycogenic acanthosis in the presence of features of CS appears to be associated with a high likelihood of finding a Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. An analysis of prospectively accrued and followed probands and family members with a Although breast cancer has been described in males with a Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ The lifetime risk for epithelial thyroid cancer is approximately 35% [ Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. Benign uterine fibroids are common. Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ More than 90% of individuals with a Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. Common features of BRRS, in addition to those mentioned Individuals with BRRS and a The gastrointestinal hamartomatous polyps in BRRS (seen in 45% of affected individuals) may occasionally be associated with intussusception, but rectal bleeding and oozing of "serum" is more common. These polyps are not believed to increase the risk for colorectal cancer. PHTS hamartomatous polyps are different in histomorphology from the polyps seen in PS is characterized by progressive segmental or patchy overgrowth of diverse tissues of all germ layers, most commonly affecting the skeleton, skin, adipose tissue, and central nervous system. In most individuals, Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. See Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS who do not meet the PS diagnostic criteria. The two most serious clinical manifestations in individuals with germline For purposes of More than 90% of families that included individuals with CS and also individuals with BRRS were found to have a germline An individual presenting as a simplex case (i.e., one with no known family history) of Proteus-like syndrome comprising hemihypertrophy, macrocephaly, lipomas, connective tissue nevi, and multiple arteriovenous malformations had a germline Two of nine individuals who met the clinical diagnostic criteria of Proteus syndrome and three of six with Proteus-like syndrome were found to have germline More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [ Cowden syndrome, Cowden disease, and multiple hamartoma syndrome have been used interchangeably. Bannayan-Riley-Ruvalcaba syndrome, Bannayan-Ruvalcaba-Riley syndrome, Bannayan-Zonana syndrome, and Myhre-Riley-Smith syndrome refer to a similar constellation of signs that comprise what the authors refer to as BRRS. When a One form of Proteus-like syndrome, with a clinical presentation similar to that first described by Estimating the prevalence of PHTS has historically been challenging, mainly due to the wide phenotypic and genotypic variability, as well as the association with clinical features, such as benign breast and uterine lesions, that are relatively common in the general population. Because of the variable and often subtle external manifestations, many individuals remain undiagnosed, resulting in underestimated prevalence [ A recent study evaluated the prevalence of germline pathogenic or likely pathogenic • CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Renal cell carcinoma and colorectal carcinoma have also been shown to be in the PHTS spectrum. • BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis. • PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues. • Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS. • • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. ## Clinical Description CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Renal cell carcinoma and colorectal carcinoma have also been shown to be in the PHTS spectrum. BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS. More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [ Hamartomatous and mixed gastrointestinal polyps, seen frequently in the majority of people with PHTS, do confer an increased risk for colorectal cancers [ Based on anecdotal observations, glycogenic acanthosis in the presence of features of CS appears to be associated with a high likelihood of finding a Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. An analysis of prospectively accrued and followed probands and family members with a Although breast cancer has been described in males with a Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ The lifetime risk for epithelial thyroid cancer is approximately 35% [ Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. Benign uterine fibroids are common. Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ More than 90% of individuals with a Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. Common features of BRRS, in addition to those mentioned Individuals with BRRS and a The gastrointestinal hamartomatous polyps in BRRS (seen in 45% of affected individuals) may occasionally be associated with intussusception, but rectal bleeding and oozing of "serum" is more common. These polyps are not believed to increase the risk for colorectal cancer. PHTS hamartomatous polyps are different in histomorphology from the polyps seen in PS is characterized by progressive segmental or patchy overgrowth of diverse tissues of all germ layers, most commonly affecting the skeleton, skin, adipose tissue, and central nervous system. In most individuals, Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. See Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS who do not meet the PS diagnostic criteria. • CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Renal cell carcinoma and colorectal carcinoma have also been shown to be in the PHTS spectrum. • BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis. • PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues. • Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS. • • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. ## Cowden Syndrome (CS) More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [ Hamartomatous and mixed gastrointestinal polyps, seen frequently in the majority of people with PHTS, do confer an increased risk for colorectal cancers [ Based on anecdotal observations, glycogenic acanthosis in the presence of features of CS appears to be associated with a high likelihood of finding a Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. An analysis of prospectively accrued and followed probands and family members with a Although breast cancer has been described in males with a Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ The lifetime risk for epithelial thyroid cancer is approximately 35% [ Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. Benign uterine fibroids are common. Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ More than 90% of individuals with a Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. • Women with Cowden syndrome are at as high as a 67% risk for benign breast disease. • An analysis of prospectively accrued and followed probands and family members with a • Although breast cancer has been described in males with a • Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [ • The lifetime risk for epithelial thyroid cancer is approximately 35% [ • Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS. • Benign uterine fibroids are common. • Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [ • More than 90% of individuals with a • Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [ • Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. • Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS. • A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), is also found in CS and may be pathognomonic. ## Bannayan-Riley-Ruvalcaba Syndrome (BRRS) Common features of BRRS, in addition to those mentioned Individuals with BRRS and a The gastrointestinal hamartomatous polyps in BRRS (seen in 45% of affected individuals) may occasionally be associated with intussusception, but rectal bleeding and oozing of "serum" is more common. These polyps are not believed to increase the risk for colorectal cancer. PHTS hamartomatous polyps are different in histomorphology from the polyps seen in PS is characterized by progressive segmental or patchy overgrowth of diverse tissues of all germ layers, most commonly affecting the skeleton, skin, adipose tissue, and central nervous system. In most individuals, Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. See Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS who do not meet the PS diagnostic criteria. ## Clinical Implications of All PHTS Phenotypes The two most serious clinical manifestations in individuals with germline ## Genotype-Phenotype Correlations For purposes of More than 90% of families that included individuals with CS and also individuals with BRRS were found to have a germline An individual presenting as a simplex case (i.e., one with no known family history) of Proteus-like syndrome comprising hemihypertrophy, macrocephaly, lipomas, connective tissue nevi, and multiple arteriovenous malformations had a germline Two of nine individuals who met the clinical diagnostic criteria of Proteus syndrome and three of six with Proteus-like syndrome were found to have germline ## Penetrance More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [ ## Nomenclature Cowden syndrome, Cowden disease, and multiple hamartoma syndrome have been used interchangeably. Bannayan-Riley-Ruvalcaba syndrome, Bannayan-Ruvalcaba-Riley syndrome, Bannayan-Zonana syndrome, and Myhre-Riley-Smith syndrome refer to a similar constellation of signs that comprise what the authors refer to as BRRS. When a One form of Proteus-like syndrome, with a clinical presentation similar to that first described by ## Prevalence Estimating the prevalence of PHTS has historically been challenging, mainly due to the wide phenotypic and genotypic variability, as well as the association with clinical features, such as benign breast and uterine lesions, that are relatively common in the general population. Because of the variable and often subtle external manifestations, many individuals remain undiagnosed, resulting in underestimated prevalence [ A recent study evaluated the prevalence of germline pathogenic or likely pathogenic ## Genetically Related (Allelic) Disorders Other phenotypes that can be associated with ASD = autism spectrum disorder; BRRS = Bannayan-Riley-Ruvalcaba syndrome; CS = Cowden syndrome; GI = gastrointestinal; path var = pathogenic variant ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of BRRS = Bannayan-Riley-Ruvalcaba syndrome; CS = Cowden syndrome; DVT = deep vein thrombosis; GI = gastrointestinal; PHTS = Birt-Hogg-Dubé syndrome, neurofibromatosis type 1, and nevoid basal cell carcinoma (Gorlin) syndrome are inherited in an autosomal dominant manner. All individuals with clinically confirmed Proteus syndrome (known to authors of the Since ## Management To establish the extent of disease and needs of an individual diagnosed with Recommended Evaluations and Surveillance Following Initial Diagnosis in Individuals with Complete medical history & family history for features of PHTS Annual comprehensive physical exam starting at age 18 yrs, or 5 yrs before youngest age of diagnosis of a component cancer in family (whichever comes 1st), w/particular attention to thyroid exam Encourage education re signs & symptoms of cancer. Starting at age 18 yrs: consistent breast awareness & self-exam; report changes to health care provider. Starting at age 25 yrs Starting at ages 30-35 yrs Discuss mastectomy as needed. Starting at age 40 yrs: consider renal US every 1-2 yrs Renal imaging (CT or MRI preferred) Consider endometrial cancer screening by age 35 yrs. Encourage education & prompt response to symptoms (e.g., abnormal bleeding). Consider endometrial biopsy screening every 1-2 yrs. Transvaginal US in postmenopausal women at clinician's discretion & as needed Discuss hysterectomy on completion of childbearing & as needed. Starting at age of diagnosis: at clinician's recommendation, consider psychomotor assessment in children; brain MRI if symptomatic Eval for early intervention / special education where indicated By genetics professionals To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PHTS to facilitate medical & personal decision making Refer to psychosocial support as needed (e.g., to address the diagnosis, family planning, risk-reducing mastectomy). MOI = mode of inheritance; PHTS = Adapted with permission from the NCCN Guidelines® for For individuals with a family history of a particular cancer type at an early age, screening should be considered five to ten years prior to the youngest diagnosis in the family. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Note: Screening recommendations have not been established for BRRS. Given recent molecular epidemiologic studies, however, individuals with BRRS and a germline Note: Although the observation of germline Treatment of Manifestations in Individuals with Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome Developmental support services Early intervention &/or special education services Thyroid US to monitor for ↑ in size of nodules, or multinodular goiter If results of fine needle aspirate are suspicious for malignancy, perform total thyroidectomy. US = ultrasound Individuals with a germline Some women at increased risk for breast cancer consider prophylactic mastectomy, especially if breast tissue is dense or if repeated breast biopsies have been necessary. Prophylactic mastectomy reduces the risk of breast cancer by 90% in women at high risk [ No Because of the propensity for rapid tissue regrowth and the propensity to form keloid tissue, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms (e.g., pain, deformity) are significant. It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the Molecular testing is appropriate for at-risk individuals younger than age 18 years, given the possible early disease presentation in individuals with BRRS and Family members who have not inherited the See Although mTOR inhibitors show promise for treatment of malignancies in individuals who have a germline Search • Complete medical history & family history for features of PHTS • Annual comprehensive physical exam starting at age 18 yrs, or 5 yrs before youngest age of diagnosis of a component cancer in family (whichever comes 1st), w/particular attention to thyroid exam • Encourage education re signs & symptoms of cancer. • Starting at age 18 yrs: consistent breast awareness & self-exam; report changes to health care provider. • Starting at age 25 yrs • Starting at ages 30-35 yrs • Discuss mastectomy as needed. • Starting at age 40 yrs: consider renal US every 1-2 yrs • Renal imaging (CT or MRI preferred) • Consider endometrial cancer screening by age 35 yrs. • Encourage education & prompt response to symptoms (e.g., abnormal bleeding). • Consider endometrial biopsy screening every 1-2 yrs. • Transvaginal US in postmenopausal women at clinician's discretion & as needed • Discuss hysterectomy on completion of childbearing & as needed. • Starting at age of diagnosis: at clinician's recommendation, consider psychomotor assessment in children; brain MRI if symptomatic • Eval for early intervention / special education where indicated • By genetics professionals • To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PHTS to facilitate medical & personal decision making • Refer to psychosocial support as needed (e.g., to address the diagnosis, family planning, risk-reducing mastectomy). • Developmental support services • Early intervention &/or special education services • Thyroid US to monitor for ↑ in size of nodules, or multinodular goiter • If results of fine needle aspirate are suspicious for malignancy, perform total thyroidectomy. ## Evaluations and Surveillance Guidelines Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Recommended Evaluations and Surveillance Following Initial Diagnosis in Individuals with Complete medical history & family history for features of PHTS Annual comprehensive physical exam starting at age 18 yrs, or 5 yrs before youngest age of diagnosis of a component cancer in family (whichever comes 1st), w/particular attention to thyroid exam Encourage education re signs & symptoms of cancer. Starting at age 18 yrs: consistent breast awareness & self-exam; report changes to health care provider. Starting at age 25 yrs Starting at ages 30-35 yrs Discuss mastectomy as needed. Starting at age 40 yrs: consider renal US every 1-2 yrs Renal imaging (CT or MRI preferred) Consider endometrial cancer screening by age 35 yrs. Encourage education & prompt response to symptoms (e.g., abnormal bleeding). Consider endometrial biopsy screening every 1-2 yrs. Transvaginal US in postmenopausal women at clinician's discretion & as needed Discuss hysterectomy on completion of childbearing & as needed. Starting at age of diagnosis: at clinician's recommendation, consider psychomotor assessment in children; brain MRI if symptomatic Eval for early intervention / special education where indicated By genetics professionals To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PHTS to facilitate medical & personal decision making Refer to psychosocial support as needed (e.g., to address the diagnosis, family planning, risk-reducing mastectomy). MOI = mode of inheritance; PHTS = Adapted with permission from the NCCN Guidelines® for For individuals with a family history of a particular cancer type at an early age, screening should be considered five to ten years prior to the youngest diagnosis in the family. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Note: Screening recommendations have not been established for BRRS. Given recent molecular epidemiologic studies, however, individuals with BRRS and a germline Note: Although the observation of germline • Complete medical history & family history for features of PHTS • Annual comprehensive physical exam starting at age 18 yrs, or 5 yrs before youngest age of diagnosis of a component cancer in family (whichever comes 1st), w/particular attention to thyroid exam • Encourage education re signs & symptoms of cancer. • Starting at age 18 yrs: consistent breast awareness & self-exam; report changes to health care provider. • Starting at age 25 yrs • Starting at ages 30-35 yrs • Discuss mastectomy as needed. • Starting at age 40 yrs: consider renal US every 1-2 yrs • Renal imaging (CT or MRI preferred) • Consider endometrial cancer screening by age 35 yrs. • Encourage education & prompt response to symptoms (e.g., abnormal bleeding). • Consider endometrial biopsy screening every 1-2 yrs. • Transvaginal US in postmenopausal women at clinician's discretion & as needed • Discuss hysterectomy on completion of childbearing & as needed. • Starting at age of diagnosis: at clinician's recommendation, consider psychomotor assessment in children; brain MRI if symptomatic • Eval for early intervention / special education where indicated • By genetics professionals • To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PHTS to facilitate medical & personal decision making • Refer to psychosocial support as needed (e.g., to address the diagnosis, family planning, risk-reducing mastectomy). ## Bannayan-Riley-Ruvalcaba Syndrome (BRRS) Note: Screening recommendations have not been established for BRRS. Given recent molecular epidemiologic studies, however, individuals with BRRS and a germline ## Proteus Syndrome / Proteus-Like Syndrome Note: Although the observation of germline ## Treatment of Manifestations Treatment of Manifestations in Individuals with Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome Developmental support services Early intervention &/or special education services Thyroid US to monitor for ↑ in size of nodules, or multinodular goiter If results of fine needle aspirate are suspicious for malignancy, perform total thyroidectomy. US = ultrasound Individuals with a germline • Developmental support services • Early intervention &/or special education services • Thyroid US to monitor for ↑ in size of nodules, or multinodular goiter • If results of fine needle aspirate are suspicious for malignancy, perform total thyroidectomy. ## Treatment of Manifestations in Individuals with Proteus Syndrome / Proteus-Like Syndrome Individuals with a germline ## Prevention of Primary Manifestations Some women at increased risk for breast cancer consider prophylactic mastectomy, especially if breast tissue is dense or if repeated breast biopsies have been necessary. Prophylactic mastectomy reduces the risk of breast cancer by 90% in women at high risk [ No ## Agents/Circumstances to Avoid Because of the propensity for rapid tissue regrowth and the propensity to form keloid tissue, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms (e.g., pain, deformity) are significant. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the Molecular testing is appropriate for at-risk individuals younger than age 18 years, given the possible early disease presentation in individuals with BRRS and Family members who have not inherited the See ## Therapies Under Investigation Although mTOR inhibitors show promise for treatment of malignancies in individuals who have a germline Search ## Genetic Counseling Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are autosomal dominant disorders caused by either an inherited or a If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. * A parent with somatic and germline mosaicism for a The family history of many individuals diagnosed with If a parent of the proband has the If the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • * A parent with somatic and germline mosaicism for a • The family history of many individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • * A parent with somatic and germline mosaicism for a • If a parent of the proband has the • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are autosomal dominant disorders caused by either an inherited or a ## Risk to Family Members If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. * A parent with somatic and germline mosaicism for a The family history of many individuals diagnosed with If a parent of the proband has the If the If the parents have not been tested for the • If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • * A parent with somatic and germline mosaicism for a • The family history of many individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • * A parent with somatic and germline mosaicism for a • If a parent of the proband has the • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Via San Giuseppe Cottolegno, 36 20143 Milano Italy 3rd Floor, Paternoster House London EC4M 8AB United Kingdom National Breast Cancer Coalition • • • • • • • Via San Giuseppe Cottolegno, 36 • 20143 Milano • Italy • • • 3rd Floor, Paternoster House • London EC4M 8AB • United Kingdom • • • • • • • • • • • National Breast Cancer Coalition • • • ## Molecular Genetics PTEN Hamartoma Tumor Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PTEN Hamartoma Tumor Syndrome ( While much functional research has been accomplished, complete function of PTEN is not yet fully understood. PTEN belongs to a subclass of phosphatases called dual-specificity phosphatases that remove phosphate groups from tyrosine as well as serine and threonine. In addition, PTEN is the major phosphatase for phosphoinositide-3,4,5-triphosphate, and thus downregulates the PI3K/AKT pathway [ The PTEN protein localizes to specific nuclear and cytoplasmic components. The wild type protein is a major lipid phosphatase that downregulates the PI3K/AKT pathway to cause G1 cell cycle arrest and apoptosis. In addition, the protein phosphatase appears to play an important role in inhibition of cell migration and spreading, as well as downregulating several cell cyclins. It appears that nuclear PTEN mediates cell cycle arrest, while cytoplasmic PTEN is required for apoptosis [ Germline pathogenic variants have been found throughout Notable Recurrent pathogenic variants [ Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis While much functional research has been accomplished, complete function of PTEN is not yet fully understood. PTEN belongs to a subclass of phosphatases called dual-specificity phosphatases that remove phosphate groups from tyrosine as well as serine and threonine. In addition, PTEN is the major phosphatase for phosphoinositide-3,4,5-triphosphate, and thus downregulates the PI3K/AKT pathway [ The PTEN protein localizes to specific nuclear and cytoplasmic components. The wild type protein is a major lipid phosphatase that downregulates the PI3K/AKT pathway to cause G1 cell cycle arrest and apoptosis. In addition, the protein phosphatase appears to play an important role in inhibition of cell migration and spreading, as well as downregulating several cell cyclins. It appears that nuclear PTEN mediates cell cycle arrest, while cytoplasmic PTEN is required for apoptosis [ Germline pathogenic variants have been found throughout Notable Recurrent pathogenic variants [ Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors ## Chapter Notes Dr Eng is the chair and coordinator of the International Cowden Syndrome Consortium, founding Chairwoman of the Cleveland Clinic Genomic Medicine Institute, and a primary researcher in the field of We are eternally grateful to the many patients and families who have participated in our research and who continue to educate us in the ever-broadening clinical spectrum of PHTS, without which this review and these management recommendations could not have been written. Our PHTS research has been continuously supported by the American Cancer Society and the Doris Duke Distinguished Clinical Scientist Award, and, recently, by the National Cancer Institute. Dr Charis Eng is the Sondra J and Stephen R Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic. Charis Eng, MD, PhD (2001-present)Heather Hampel, MS; Ohio State University (2001-2006)Robert Pilarski, MS; Ohio State University (2001-2006)Jennifer L Stein, MS, CGC; Cleveland Clinic (2006-2009)Lamis Yehia, PhD (2021-present)Kevin M Zbuk, MD; Cleveland Clinic (2006-2009) 7 August 2025 (lh) Revision: prevalence 11 February 2021 (sw) Comprehensive update posted live 2 June 2016 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 21 July 2011 (me) Comprehensive update posted live 5 May 2009 (me) Comprehensive update posted live 10 January 2006 (me) Comprehensive update posted live 17 December 2003 (me) Comprehensive update posted live 29 November 2001 (me) Review posted live 10 July 2001 (ce) Original submission • 7 August 2025 (lh) Revision: prevalence • 11 February 2021 (sw) Comprehensive update posted live • 2 June 2016 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 21 July 2011 (me) Comprehensive update posted live • 5 May 2009 (me) Comprehensive update posted live • 10 January 2006 (me) Comprehensive update posted live • 17 December 2003 (me) Comprehensive update posted live • 29 November 2001 (me) Review posted live • 10 July 2001 (ce) Original submission ## Author Notes Dr Eng is the chair and coordinator of the International Cowden Syndrome Consortium, founding Chairwoman of the Cleveland Clinic Genomic Medicine Institute, and a primary researcher in the field of ## Acknowledgments We are eternally grateful to the many patients and families who have participated in our research and who continue to educate us in the ever-broadening clinical spectrum of PHTS, without which this review and these management recommendations could not have been written. Our PHTS research has been continuously supported by the American Cancer Society and the Doris Duke Distinguished Clinical Scientist Award, and, recently, by the National Cancer Institute. Dr Charis Eng is the Sondra J and Stephen R Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic. ## Author History Charis Eng, MD, PhD (2001-present)Heather Hampel, MS; Ohio State University (2001-2006)Robert Pilarski, MS; Ohio State University (2001-2006)Jennifer L Stein, MS, CGC; Cleveland Clinic (2006-2009)Lamis Yehia, PhD (2021-present)Kevin M Zbuk, MD; Cleveland Clinic (2006-2009) ## Revision History 7 August 2025 (lh) Revision: prevalence 11 February 2021 (sw) Comprehensive update posted live 2 June 2016 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 21 July 2011 (me) Comprehensive update posted live 5 May 2009 (me) Comprehensive update posted live 10 January 2006 (me) Comprehensive update posted live 17 December 2003 (me) Comprehensive update posted live 29 November 2001 (me) Review posted live 10 July 2001 (ce) Original submission • 7 August 2025 (lh) Revision: prevalence • 11 February 2021 (sw) Comprehensive update posted live • 2 June 2016 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 21 July 2011 (me) Comprehensive update posted live • 5 May 2009 (me) Comprehensive update posted live • 10 January 2006 (me) Comprehensive update posted live • 17 December 2003 (me) Comprehensive update posted live • 29 November 2001 (me) Review posted live • 10 July 2001 (ce) Original submission ## References American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Available • American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available • Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Available ## Published Guidelines / Consensus Statements American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Available • American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available • Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Available ## Literature Cited Trichilemmoma Papillomatous papules in the periocular region (A) and on the dorsum of the hand (B)	[]	29/11/2001	11/2/2021	7/8/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pi4ka	pi4ka	[ "PI4KA-Related Hypomyelinating Leukodystrophy with Pyramidal Features, Developmental Delay, and Intellectual Disability with or without Inflammatory Bowel Disease", "PI4KA-Related Severe Antenatal-Onset Neurologic Disorder with Arthrogryposis and Structural Brain Anomalies", "PI4KA-Related Multiple Intestinal Atresia with or without Immunodeficiency", "Later-Onset Pure Hereditary Spastic Paraplegia (SPG84)", "Phosphatidylinositol 4-kinase alpha", "PI4KA", "PI4KA-Related Disorder" ]		Emma L Baple, Claire Salter, Holm Uhlig, Nicole I Wolf, Andrew H Crosby	Summary The diagnosis of	Hypomyelinating leukodystrophy with pyramidal features, developmental delay, and intellectual disability ± inflammatory bowel disease Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies Multiple intestinal atresia ± immunodeficiency Later-onset pure hereditary spastic paraplegia (SPG84) • Hypomyelinating leukodystrophy with pyramidal features, developmental delay, and intellectual disability ± inflammatory bowel disease • Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies • Multiple intestinal atresia ± immunodeficiency • Later-onset pure hereditary spastic paraplegia (SPG84) ## Diagnosis Peripheral spasticity, often more marked in lower than upper limbs Truncal hypotonia Global developmental delay Intellectual disability (mild to severe) Seizures Ataxia Nystagmus Intention tremor Dysmetria Dystonia Arthrogryposis/contractures Kyphosis or scoliosis Multiple intestinal atresia Very early onset or treatment-refractory inflammatory bowel disease Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) Increased fecal calprotectin Iron-deficient anemia Increased C-reactive protein Hypogammaglobulinemia: variable immunoglobulin defects Leukopenia: cellular defects ranging from severe T-cell lymphopenia (affecting CD8+ T cells more than CD4+ T cells), moderate B- and NK-cell lymphopenia, to normal lymphocyte counts Note: Perisylvian polymicrogyria has to date been reported only in individuals with the The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of Note: Targeted analysis for the known founder variant For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • • Peripheral spasticity, often more marked in lower than upper limbs • Truncal hypotonia • Global developmental delay • Intellectual disability (mild to severe) • Seizures • Ataxia • Nystagmus • Intention tremor • Dysmetria • Dystonia • Arthrogryposis/contractures • Kyphosis or scoliosis • Peripheral spasticity, often more marked in lower than upper limbs • Truncal hypotonia • Global developmental delay • Intellectual disability (mild to severe) • Seizures • Ataxia • Nystagmus • Intention tremor • Dysmetria • Dystonia • Arthrogryposis/contractures • Kyphosis or scoliosis • • Multiple intestinal atresia • Very early onset or treatment-refractory inflammatory bowel disease • Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) • Multiple intestinal atresia • Very early onset or treatment-refractory inflammatory bowel disease • Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) • Peripheral spasticity, often more marked in lower than upper limbs • Truncal hypotonia • Global developmental delay • Intellectual disability (mild to severe) • Seizures • Ataxia • Nystagmus • Intention tremor • Dysmetria • Dystonia • Arthrogryposis/contractures • Kyphosis or scoliosis • Multiple intestinal atresia • Very early onset or treatment-refractory inflammatory bowel disease • Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) • Increased fecal calprotectin • Iron-deficient anemia • Increased C-reactive protein • Hypogammaglobulinemia: variable immunoglobulin defects • Leukopenia: cellular defects ranging from severe T-cell lymphopenia (affecting CD8+ T cells more than CD4+ T cells), moderate B- and NK-cell lymphopenia, to normal lymphocyte counts • Note: Perisylvian polymicrogyria has to date been reported only in individuals with the • Note: Targeted analysis for the known founder variant • For an introduction to multigene panels click ## Suggestive Findings Peripheral spasticity, often more marked in lower than upper limbs Truncal hypotonia Global developmental delay Intellectual disability (mild to severe) Seizures Ataxia Nystagmus Intention tremor Dysmetria Dystonia Arthrogryposis/contractures Kyphosis or scoliosis Multiple intestinal atresia Very early onset or treatment-refractory inflammatory bowel disease Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) Increased fecal calprotectin Iron-deficient anemia Increased C-reactive protein Hypogammaglobulinemia: variable immunoglobulin defects Leukopenia: cellular defects ranging from severe T-cell lymphopenia (affecting CD8+ T cells more than CD4+ T cells), moderate B- and NK-cell lymphopenia, to normal lymphocyte counts Note: Perisylvian polymicrogyria has to date been reported only in individuals with the • • Peripheral spasticity, often more marked in lower than upper limbs • Truncal hypotonia • Global developmental delay • Intellectual disability (mild to severe) • Seizures • Ataxia • Nystagmus • Intention tremor • Dysmetria • Dystonia • Arthrogryposis/contractures • Kyphosis or scoliosis • Peripheral spasticity, often more marked in lower than upper limbs • Truncal hypotonia • Global developmental delay • Intellectual disability (mild to severe) • Seizures • Ataxia • Nystagmus • Intention tremor • Dysmetria • Dystonia • Arthrogryposis/contractures • Kyphosis or scoliosis • • Multiple intestinal atresia • Very early onset or treatment-refractory inflammatory bowel disease • Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) • Multiple intestinal atresia • Very early onset or treatment-refractory inflammatory bowel disease • Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) • Peripheral spasticity, often more marked in lower than upper limbs • Truncal hypotonia • Global developmental delay • Intellectual disability (mild to severe) • Seizures • Ataxia • Nystagmus • Intention tremor • Dysmetria • Dystonia • Arthrogryposis/contractures • Kyphosis or scoliosis • Multiple intestinal atresia • Very early onset or treatment-refractory inflammatory bowel disease • Nonspecific gastrointestinal symptoms (vomiting, diarrhea, constipation, gastroesophageal reflux disease) • Increased fecal calprotectin • Iron-deficient anemia • Increased C-reactive protein • Hypogammaglobulinemia: variable immunoglobulin defects • Leukopenia: cellular defects ranging from severe T-cell lymphopenia (affecting CD8+ T cells more than CD4+ T cells), moderate B- and NK-cell lymphopenia, to normal lymphocyte counts • Note: Perisylvian polymicrogyria has to date been reported only in individuals with the ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of Note: Targeted analysis for the known founder variant For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Note: Targeted analysis for the known founder variant • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of Note: Targeted analysis for the known founder variant For an introduction to multigene panels click • Note: Targeted analysis for the known founder variant • For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Hypomyelinating leukodystrophy with pyramidal features including lower limb spasticity, developmental delay, and intellectual disability, with or without inflammatory bowel disease. The most common presentation; neurologic features typically present in infancy or early childhood. Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies (e.g., perisylvian polymicrogyria, cerebellar hypoplasia) Multiple intestinal atresia presenting shortly after birth, with or without immunodeficiency Rarely, later-onset pure hereditary spastic paraplegia To date, 24 individuals have been identified with Affected persons who died before a specific clinical sign would become apparent are not included in the table. Two individuals with a pure hereditary spastic paraplegia phenotype and later onset of disease (age 2 years and 17 years) have been described [ Musculoskeletal complications include arthrogryposis (reported in 3 severely affected individuals), contractures, and kyphosis or scoliosis, reported in four individuals. One of the most severely affected living individuals with neurologic disease had combined immunodeficiency and at age ten years developed a lymphoma with adult-onset characteristics: grade 3A follicular non-Hodgkin lymphoma with bcl6-translocation and without a Autoimmune neutropenia has been described in one individual [ Genitourinary anomalies (e.g., renal cysts, rectovaginal fistula, cryptorchidism, duplication of the collecting system) Nonspecific mild dysmorphic features Hearing loss described in two individuals; confirmed to be sensorineural in one Reduced visual acuity, optic nerve atrophy, strabismus, and/or ocular motor apraxia Juvenile idiopathic arthritis described in one individual (onset age: 9 years 8 months) [ To date, the limited number of individuals described with Currently, homozygosity for the The To date, 24 individuals with Within the Amish community, founder variant • Hypomyelinating leukodystrophy with pyramidal features including lower limb spasticity, developmental delay, and intellectual disability, with or without inflammatory bowel disease. The most common presentation; neurologic features typically present in infancy or early childhood. • Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies (e.g., perisylvian polymicrogyria, cerebellar hypoplasia) • Multiple intestinal atresia presenting shortly after birth, with or without immunodeficiency • Rarely, later-onset pure hereditary spastic paraplegia • Genitourinary anomalies (e.g., renal cysts, rectovaginal fistula, cryptorchidism, duplication of the collecting system) • Nonspecific mild dysmorphic features • Hearing loss described in two individuals; confirmed to be sensorineural in one • Reduced visual acuity, optic nerve atrophy, strabismus, and/or ocular motor apraxia • Juvenile idiopathic arthritis described in one individual (onset age: 9 years 8 months) [ • Currently, homozygosity for the • The ## Clinical Description Hypomyelinating leukodystrophy with pyramidal features including lower limb spasticity, developmental delay, and intellectual disability, with or without inflammatory bowel disease. The most common presentation; neurologic features typically present in infancy or early childhood. Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies (e.g., perisylvian polymicrogyria, cerebellar hypoplasia) Multiple intestinal atresia presenting shortly after birth, with or without immunodeficiency Rarely, later-onset pure hereditary spastic paraplegia To date, 24 individuals have been identified with Affected persons who died before a specific clinical sign would become apparent are not included in the table. Two individuals with a pure hereditary spastic paraplegia phenotype and later onset of disease (age 2 years and 17 years) have been described [ Musculoskeletal complications include arthrogryposis (reported in 3 severely affected individuals), contractures, and kyphosis or scoliosis, reported in four individuals. One of the most severely affected living individuals with neurologic disease had combined immunodeficiency and at age ten years developed a lymphoma with adult-onset characteristics: grade 3A follicular non-Hodgkin lymphoma with bcl6-translocation and without a Autoimmune neutropenia has been described in one individual [ Genitourinary anomalies (e.g., renal cysts, rectovaginal fistula, cryptorchidism, duplication of the collecting system) Nonspecific mild dysmorphic features Hearing loss described in two individuals; confirmed to be sensorineural in one Reduced visual acuity, optic nerve atrophy, strabismus, and/or ocular motor apraxia Juvenile idiopathic arthritis described in one individual (onset age: 9 years 8 months) [ • Hypomyelinating leukodystrophy with pyramidal features including lower limb spasticity, developmental delay, and intellectual disability, with or without inflammatory bowel disease. The most common presentation; neurologic features typically present in infancy or early childhood. • Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies (e.g., perisylvian polymicrogyria, cerebellar hypoplasia) • Multiple intestinal atresia presenting shortly after birth, with or without immunodeficiency • Rarely, later-onset pure hereditary spastic paraplegia • Genitourinary anomalies (e.g., renal cysts, rectovaginal fistula, cryptorchidism, duplication of the collecting system) • Nonspecific mild dysmorphic features • Hearing loss described in two individuals; confirmed to be sensorineural in one • Reduced visual acuity, optic nerve atrophy, strabismus, and/or ocular motor apraxia • Juvenile idiopathic arthritis described in one individual (onset age: 9 years 8 months) [ ## Neurologic Manifestations Two individuals with a pure hereditary spastic paraplegia phenotype and later onset of disease (age 2 years and 17 years) have been described [ Musculoskeletal complications include arthrogryposis (reported in 3 severely affected individuals), contractures, and kyphosis or scoliosis, reported in four individuals. ## Gastrointestinal Disease One of the most severely affected living individuals with neurologic disease had combined immunodeficiency and at age ten years developed a lymphoma with adult-onset characteristics: grade 3A follicular non-Hodgkin lymphoma with bcl6-translocation and without a Autoimmune neutropenia has been described in one individual [ Genitourinary anomalies (e.g., renal cysts, rectovaginal fistula, cryptorchidism, duplication of the collecting system) Nonspecific mild dysmorphic features Hearing loss described in two individuals; confirmed to be sensorineural in one Reduced visual acuity, optic nerve atrophy, strabismus, and/or ocular motor apraxia Juvenile idiopathic arthritis described in one individual (onset age: 9 years 8 months) [ • Genitourinary anomalies (e.g., renal cysts, rectovaginal fistula, cryptorchidism, duplication of the collecting system) • Nonspecific mild dysmorphic features • Hearing loss described in two individuals; confirmed to be sensorineural in one • Reduced visual acuity, optic nerve atrophy, strabismus, and/or ocular motor apraxia • Juvenile idiopathic arthritis described in one individual (onset age: 9 years 8 months) [ ## Genotype-Phenotype Correlations To date, the limited number of individuals described with Currently, homozygosity for the The • Currently, homozygosity for the • The ## Prevalence To date, 24 individuals with Within the Amish community, founder variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of Genes of Interest in the Differential Diagnosis of AR = autosomal recessive; DiffDx = differential diagnosis; IBD = inflammatory bowel disease; MOI = mode of inheritance; XL = X-linked ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Neurologic eval for spasticity, cerebellar signs, & dystonia Brain MRI EEG (Seizures may be subclinical.) Assessment by developmental pediatrician of developmental milestones, cognitive function, speech (communication) & feeding (swallowing) Assessment by PT of functional disability & equipment needs Pediatric gastroenterology assessment Abdominal radiographs Further abdominal imaging as needed Eval by gastroenterologist CBC ± inflammatory markers (CRP) Fecal calprotectin Endoscopic investigations as indicated by symptomatology Immunology assessment Immunophenotyping incl lymphocyte subsets & immunoglobulins Thymic ultrasound Recommended in all persons w/ Lymphopenia w/disruption of epithelial barrier results in ↑ risk for pathogenic proliferation & sepsis. Community or Social work involvement for parental support; Home nursing referral. CBC = complete blood count; CRP = C-reactive protein; DD = developmental delay; IBD = inflammatory bowel disease; ID = intellectual disability; MOI = mode of inheritance; PT = physical therapist Medical geneticist, certified genetic counselor, certified advanced genetic nurse Individualized care by a multidisciplinary team including a pediatrician, neurologist, gastroenterologist, clinical geneticist, physical therapist, occupational therapist, speech-language therapist, ophthalmologist, audiologist, and primary care physician is recommended. Treatment of Manifestations in Individuals with PT, OT, use of appropriate mobility aids Medical mgmt may incl baclofen (incl intrathecal baclofen), diazepam, & intramuscular botulinum toxin. Speech-language therapy Gastrostomy as needed There is no known treatment for MIA. Parenteral nutrition Intestinal transplant may be considered but is assoc w/high mortality rate. Since there is no established cure, quality of life is an important consideration. In children w/poor prognosis due to MIA, palliative approaches may be considered. Standard anti-inflammatory medications & dietary mgmt established for treatment of IBD incl: immunosuppressants, steroids, & antibody therapies Surgery may be required for treatment-resistant disease & to remove obstructions. Identification of the nature of immune dysfunction should inform clinical mgmt. HSCT may correct immune defects & ↑ survival in persons w/severe immunodeficiency. Note: HSCT does not appear to improve phenotypes related to intestinal epithelial defects in Decision making should also incl burden of treatment in children w/ID. ID = intellectual disability; HSCT = hematopoietic stem cell transplantation; OT = occupational therapy; PT = physical therapy Note: Surgical bowel resections in individuals w/ Due to the phenotypic and mechanistic overlap between To date, no general surveillance guidelines have been developed; monitoring should be individualized. Recommended Surveillance for Individuals with Assessment by gastroenterologist for clinical signs of IBD, which may develop at any age. Consider CBC & inflammatory markers, incl fecal calprotectin, CRP. ± endoscopic investigations if clinical concerns or limited communication due to neurologic manifestations CBC = complete blood count; CRP = C-reactive protein; IBD = inflammatory bowel disease See Recent investigation of anti-apoptotic medications in laboratory and animal models of Search • Neurologic eval for spasticity, cerebellar signs, & dystonia • Brain MRI • EEG (Seizures may be subclinical.) • Assessment by developmental pediatrician of developmental milestones, cognitive function, speech (communication) & feeding (swallowing) • Assessment by PT of functional disability & equipment needs • Pediatric gastroenterology assessment • Abdominal radiographs • Further abdominal imaging as needed • Eval by gastroenterologist • CBC ± inflammatory markers (CRP) • Fecal calprotectin • Endoscopic investigations as indicated by symptomatology • Immunology assessment • Immunophenotyping incl lymphocyte subsets & immunoglobulins • Thymic ultrasound • Recommended in all persons w/ • Lymphopenia w/disruption of epithelial barrier results in ↑ risk for pathogenic proliferation & sepsis. • Community or • Social work involvement for parental support; • Home nursing referral. • PT, OT, use of appropriate mobility aids • Medical mgmt may incl baclofen (incl intrathecal baclofen), diazepam, & intramuscular botulinum toxin. • Speech-language therapy • Gastrostomy as needed • There is no known treatment for MIA. • Parenteral nutrition • Intestinal transplant may be considered but is assoc w/high mortality rate. • Since there is no established cure, quality of life is an important consideration. In children w/poor prognosis due to MIA, palliative approaches may be considered. • Standard anti-inflammatory medications & dietary mgmt established for treatment of IBD incl: immunosuppressants, steroids, & antibody therapies • Surgery may be required for treatment-resistant disease & to remove obstructions. • Identification of the nature of immune dysfunction should inform clinical mgmt. • HSCT may correct immune defects & ↑ survival in persons w/severe immunodeficiency. • Note: HSCT does not appear to improve phenotypes related to intestinal epithelial defects in • Decision making should also incl burden of treatment in children w/ID. • Assessment by gastroenterologist for clinical signs of IBD, which may develop at any age. • Consider CBC & inflammatory markers, incl fecal calprotectin, CRP. • ± endoscopic investigations if clinical concerns or limited communication due to neurologic manifestations ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Neurologic eval for spasticity, cerebellar signs, & dystonia Brain MRI EEG (Seizures may be subclinical.) Assessment by developmental pediatrician of developmental milestones, cognitive function, speech (communication) & feeding (swallowing) Assessment by PT of functional disability & equipment needs Pediatric gastroenterology assessment Abdominal radiographs Further abdominal imaging as needed Eval by gastroenterologist CBC ± inflammatory markers (CRP) Fecal calprotectin Endoscopic investigations as indicated by symptomatology Immunology assessment Immunophenotyping incl lymphocyte subsets & immunoglobulins Thymic ultrasound Recommended in all persons w/ Lymphopenia w/disruption of epithelial barrier results in ↑ risk for pathogenic proliferation & sepsis. Community or Social work involvement for parental support; Home nursing referral. CBC = complete blood count; CRP = C-reactive protein; DD = developmental delay; IBD = inflammatory bowel disease; ID = intellectual disability; MOI = mode of inheritance; PT = physical therapist Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Neurologic eval for spasticity, cerebellar signs, & dystonia • Brain MRI • EEG (Seizures may be subclinical.) • Assessment by developmental pediatrician of developmental milestones, cognitive function, speech (communication) & feeding (swallowing) • Assessment by PT of functional disability & equipment needs • Pediatric gastroenterology assessment • Abdominal radiographs • Further abdominal imaging as needed • Eval by gastroenterologist • CBC ± inflammatory markers (CRP) • Fecal calprotectin • Endoscopic investigations as indicated by symptomatology • Immunology assessment • Immunophenotyping incl lymphocyte subsets & immunoglobulins • Thymic ultrasound • Recommended in all persons w/ • Lymphopenia w/disruption of epithelial barrier results in ↑ risk for pathogenic proliferation & sepsis. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Individualized care by a multidisciplinary team including a pediatrician, neurologist, gastroenterologist, clinical geneticist, physical therapist, occupational therapist, speech-language therapist, ophthalmologist, audiologist, and primary care physician is recommended. Treatment of Manifestations in Individuals with PT, OT, use of appropriate mobility aids Medical mgmt may incl baclofen (incl intrathecal baclofen), diazepam, & intramuscular botulinum toxin. Speech-language therapy Gastrostomy as needed There is no known treatment for MIA. Parenteral nutrition Intestinal transplant may be considered but is assoc w/high mortality rate. Since there is no established cure, quality of life is an important consideration. In children w/poor prognosis due to MIA, palliative approaches may be considered. Standard anti-inflammatory medications & dietary mgmt established for treatment of IBD incl: immunosuppressants, steroids, & antibody therapies Surgery may be required for treatment-resistant disease & to remove obstructions. Identification of the nature of immune dysfunction should inform clinical mgmt. HSCT may correct immune defects & ↑ survival in persons w/severe immunodeficiency. Note: HSCT does not appear to improve phenotypes related to intestinal epithelial defects in Decision making should also incl burden of treatment in children w/ID. ID = intellectual disability; HSCT = hematopoietic stem cell transplantation; OT = occupational therapy; PT = physical therapy Note: Surgical bowel resections in individuals w/ Due to the phenotypic and mechanistic overlap between • PT, OT, use of appropriate mobility aids • Medical mgmt may incl baclofen (incl intrathecal baclofen), diazepam, & intramuscular botulinum toxin. • Speech-language therapy • Gastrostomy as needed • There is no known treatment for MIA. • Parenteral nutrition • Intestinal transplant may be considered but is assoc w/high mortality rate. • Since there is no established cure, quality of life is an important consideration. In children w/poor prognosis due to MIA, palliative approaches may be considered. • Standard anti-inflammatory medications & dietary mgmt established for treatment of IBD incl: immunosuppressants, steroids, & antibody therapies • Surgery may be required for treatment-resistant disease & to remove obstructions. • Identification of the nature of immune dysfunction should inform clinical mgmt. • HSCT may correct immune defects & ↑ survival in persons w/severe immunodeficiency. • Note: HSCT does not appear to improve phenotypes related to intestinal epithelial defects in • Decision making should also incl burden of treatment in children w/ID. ## Surveillance To date, no general surveillance guidelines have been developed; monitoring should be individualized. Recommended Surveillance for Individuals with Assessment by gastroenterologist for clinical signs of IBD, which may develop at any age. Consider CBC & inflammatory markers, incl fecal calprotectin, CRP. ± endoscopic investigations if clinical concerns or limited communication due to neurologic manifestations CBC = complete blood count; CRP = C-reactive protein; IBD = inflammatory bowel disease • Assessment by gastroenterologist for clinical signs of IBD, which may develop at any age. • Consider CBC & inflammatory markers, incl fecal calprotectin, CRP. • ± endoscopic investigations if clinical concerns or limited communication due to neurologic manifestations ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Recent investigation of anti-apoptotic medications in laboratory and animal models of Search ## Genetic Counseling The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics PI4KA-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PI4KA-Related Disorder ( The function of PI4KIIIα depends on a functioning C-terminal catalytic domain and the ability to form a heterotrimeric complex with TTC7A or TTC7B and HYCC1 (FAM126A) to maintain PI4KIIIα stability. The complex is then localized to the cell membrane via another protein, EFR3. The distribution of the TTC7A and TTC7B complexes varies across tissue types; TTC7A-containing complex is more prevalent in gastrointestinal tissues and TTC7B-containing complexes are more prevalent in neurologic tissues. Due to differences in binding sites between PI4KIIIα and TTC7A or TTC7B, The neurologic phenotype associated with the founder variant in the Amish community may be explained by its impact on PI4KIIIα's ability to form a complex with TTC7A and near-normal catalytic activity [ Nonsense-mediated mRNA decay and loss of functional protein Loss of PI4KIIIα catalytic activity due to variants that affect the catalytic domain Loss of protein stability due to inability to form a complex with TTC7A or TTC7B and HYCC1 To date, no affected individuals with biallelic Notable MIA = multiple intestinal atresia Variants listed in the table have been provided by the authors. • Nonsense-mediated mRNA decay and loss of functional protein • Loss of PI4KIIIα catalytic activity due to variants that affect the catalytic domain • Loss of protein stability due to inability to form a complex with TTC7A or TTC7B and HYCC1 ## Molecular Pathogenesis The function of PI4KIIIα depends on a functioning C-terminal catalytic domain and the ability to form a heterotrimeric complex with TTC7A or TTC7B and HYCC1 (FAM126A) to maintain PI4KIIIα stability. The complex is then localized to the cell membrane via another protein, EFR3. The distribution of the TTC7A and TTC7B complexes varies across tissue types; TTC7A-containing complex is more prevalent in gastrointestinal tissues and TTC7B-containing complexes are more prevalent in neurologic tissues. Due to differences in binding sites between PI4KIIIα and TTC7A or TTC7B, The neurologic phenotype associated with the founder variant in the Amish community may be explained by its impact on PI4KIIIα's ability to form a complex with TTC7A and near-normal catalytic activity [ Nonsense-mediated mRNA decay and loss of functional protein Loss of PI4KIIIα catalytic activity due to variants that affect the catalytic domain Loss of protein stability due to inability to form a complex with TTC7A or TTC7B and HYCC1 To date, no affected individuals with biallelic Notable MIA = multiple intestinal atresia Variants listed in the table have been provided by the authors. • Nonsense-mediated mRNA decay and loss of functional protein • Loss of PI4KIIIα catalytic activity due to variants that affect the catalytic domain • Loss of protein stability due to inability to form a complex with TTC7A or TTC7B and HYCC1 ## Chapter Notes Further information on our work with the Amish community can be found at First and foremost, the authors would like to thank the patients and their families as well as the collaborators that have been involved in defining this emerging complex multisystem disorder. We would particularly like to acknowledge Professor Pietro de Camilli and Dr Tamas Balla, without whom we would have been unable to begin to define the pathomechanism of disease. This work was in part supported by the Medical Research Council, Medical Research Foundation, Newlife Foundation for Disabled Children, GW4CAT Wellcome Trust, Australian National Health and Medical Research Council (NHMRC), Victorian Government's Operational Infrastructure Support Program, National Institute for Health Research (NIHR), and National Institutes of Health (NIH). 11 August 2022 (sw) Review posted live 18 April 2022 (eb) Original submission • 11 August 2022 (sw) Review posted live • 18 April 2022 (eb) Original submission ## Author Notes Further information on our work with the Amish community can be found at ## Acknowledgments First and foremost, the authors would like to thank the patients and their families as well as the collaborators that have been involved in defining this emerging complex multisystem disorder. We would particularly like to acknowledge Professor Pietro de Camilli and Dr Tamas Balla, without whom we would have been unable to begin to define the pathomechanism of disease. This work was in part supported by the Medical Research Council, Medical Research Foundation, Newlife Foundation for Disabled Children, GW4CAT Wellcome Trust, Australian National Health and Medical Research Council (NHMRC), Victorian Government's Operational Infrastructure Support Program, National Institute for Health Research (NIHR), and National Institutes of Health (NIH). ## Revision History 11 August 2022 (sw) Review posted live 18 April 2022 (eb) Original submission • 11 August 2022 (sw) Review posted live • 18 April 2022 (eb) Original submission ## References ## Literature Cited	[]	11/8/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pik3ca-overgrowth	pik3ca-overgrowth	[ "PROS", "PROS", "Megalencephaly-Capillary Malformation (MCAP) Syndrome", "Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal (CLOVES) Syndrome", "PIK3CA-Related Fibroadipose Hyperplasia or Overgrowth (FAO)", "Klippel-Trenaunay Syndrome", "Dysplastic Megalencephaly (DMEG), Hemimegalencephaly (HMEG) and Focal Cortical Dysplasia (FCD)", "PIK3CA-Related Isolated Tissue Dysplasia-Overgrowth Phenotypes: Lymphatic Malformations, Vascular Malformations, Venous Malformations, Lipomatosis", "CLAPO Syndrome", "PIK3CA-Related Hemihyperplasia Multiple Lipomatosis (HHML)", "PIK3CA-Related Fibroadipose Infiltrating Lipomatosis / Facial Infiltrative Lipomatosis", "PIK3CA-Related Macrodactyly", "Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform", "PIK3CA", "PIK3CA-Related Overgrowth Spectrum" ]		Ghayda Mirzaa, John M Graham, Kim Keppler-Noreuil	Summary The diagnosis of PROS is established in a proband with suggestive findings and a heterozygous mosaic (or rarely, constitutional) activating pathogenic variant in PROS disorders are not known to be inherited, as most identified pathogenic variants are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date. The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in	Megalencephaly-capillary malformation (MCAP) syndrome Dysplastic megalencephaly (DMEG), hemimegalencephaly (HMEG) and focal cortical dysplasia (FCD) Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome Klippel-Trenaunay syndrome CLAPO syndrome Isolated tissue dysplasia-overgrowth phenotypes: lymphatic malformations, vascular malformations, venous malformations, lipomatosis Fibroadipose hyperplasia or overgrowth (FAO) Hemihyperplasia multiple lipomatosis (HHML) Macrodactyly Fibroadipose infiltrating lipomatosis / facial infiltrative lipomatosis For synonyms and outdated names see For other genetic causes of these phenotypes see • Megalencephaly-capillary malformation (MCAP) syndrome • Dysplastic megalencephaly (DMEG), hemimegalencephaly (HMEG) and focal cortical dysplasia (FCD) • Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome • Klippel-Trenaunay syndrome • CLAPO syndrome • Isolated tissue dysplasia-overgrowth phenotypes: lymphatic malformations, vascular malformations, venous malformations, lipomatosis • Fibroadipose hyperplasia or overgrowth (FAO) • Hemihyperplasia multiple lipomatosis (HHML) • Macrodactyly • Fibroadipose infiltrating lipomatosis / facial infiltrative lipomatosis ## Diagnosis PROS Overgrowth of any of a wide variety of tissues including (but not limited to) brain, adipose, vascular, muscle, skeletal, nerve Vascular malformations including (but not limited to) capillary, venous, arteriovenous, or mixed malformations Lymphatic malformations Cutaneous findings including epidermal nevi and hyperpigmented macules Single or multiple digital anomalies of the hands or feet (e.g., macrodactyly, syndactyly, polydactyly, sandal-toe gap) Kidney malformations Benign tumors, with the exceptions of Wilms tumor and nephroblastomatosis (i.e., diffuse or multifocal clusters of persistent embryonal cells) Hemimegalencephaly (HMEG) Focal cortical dysplasia (FCD) Dysplastic megalencephaly (DMEG) The diagnosis of PROS Experience suggests that sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (e.g., skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing. The level of mosaicism for an activating variant in affected tissues or cultured cells is extremely variable [ Testing of blood or DNA isolated from blood is not recommended based on current technologies, as Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest a diagnosis of PROS, molecular genetic testing approaches can include Note: (1) The pathogenic variants observed in PROS have all been associated with gain of function; thus, gene-targeted deletion/duplication analysis is not recommended. (2) Failure to detect an activating For an introduction to multigene panels click When the diagnosis of PROS has not been considered because an individual has atypical phenotypic features, genomic testing on an appropriate sample (see above) may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The choice of method for somatic Because most affected individuals have a somatic mosaic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The pathogenic variants observed in PROS have all been associated with gain of function; thus, partial or whole • Overgrowth of any of a wide variety of tissues including (but not limited to) brain, adipose, vascular, muscle, skeletal, nerve • Vascular malformations including (but not limited to) capillary, venous, arteriovenous, or mixed malformations • Lymphatic malformations • Cutaneous findings including epidermal nevi and hyperpigmented macules • Single or multiple digital anomalies of the hands or feet (e.g., macrodactyly, syndactyly, polydactyly, sandal-toe gap) • Kidney malformations • Benign tumors, with the exceptions of Wilms tumor and nephroblastomatosis (i.e., diffuse or multifocal clusters of persistent embryonal cells) • Hemimegalencephaly (HMEG) • Focal cortical dysplasia (FCD) • Dysplastic megalencephaly (DMEG) • Experience suggests that sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (e.g., skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing. • The level of mosaicism for an activating variant in affected tissues or cultured cells is extremely variable [ • Testing of blood or DNA isolated from blood is not recommended based on current technologies, as • Note: (1) The pathogenic variants observed in PROS have all been associated with gain of function; thus, gene-targeted deletion/duplication analysis is not recommended. (2) Failure to detect an activating • For an introduction to multigene panels click ## Suggestive Findings PROS Overgrowth of any of a wide variety of tissues including (but not limited to) brain, adipose, vascular, muscle, skeletal, nerve Vascular malformations including (but not limited to) capillary, venous, arteriovenous, or mixed malformations Lymphatic malformations Cutaneous findings including epidermal nevi and hyperpigmented macules Single or multiple digital anomalies of the hands or feet (e.g., macrodactyly, syndactyly, polydactyly, sandal-toe gap) Kidney malformations Benign tumors, with the exceptions of Wilms tumor and nephroblastomatosis (i.e., diffuse or multifocal clusters of persistent embryonal cells) Hemimegalencephaly (HMEG) Focal cortical dysplasia (FCD) Dysplastic megalencephaly (DMEG) • Overgrowth of any of a wide variety of tissues including (but not limited to) brain, adipose, vascular, muscle, skeletal, nerve • Vascular malformations including (but not limited to) capillary, venous, arteriovenous, or mixed malformations • Lymphatic malformations • Cutaneous findings including epidermal nevi and hyperpigmented macules • Single or multiple digital anomalies of the hands or feet (e.g., macrodactyly, syndactyly, polydactyly, sandal-toe gap) • Kidney malformations • Benign tumors, with the exceptions of Wilms tumor and nephroblastomatosis (i.e., diffuse or multifocal clusters of persistent embryonal cells) • Hemimegalencephaly (HMEG) • Focal cortical dysplasia (FCD) • Dysplastic megalencephaly (DMEG) ## Establishing the Diagnosis The diagnosis of PROS Experience suggests that sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (e.g., skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing. The level of mosaicism for an activating variant in affected tissues or cultured cells is extremely variable [ Testing of blood or DNA isolated from blood is not recommended based on current technologies, as Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest a diagnosis of PROS, molecular genetic testing approaches can include Note: (1) The pathogenic variants observed in PROS have all been associated with gain of function; thus, gene-targeted deletion/duplication analysis is not recommended. (2) Failure to detect an activating For an introduction to multigene panels click When the diagnosis of PROS has not been considered because an individual has atypical phenotypic features, genomic testing on an appropriate sample (see above) may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The choice of method for somatic Because most affected individuals have a somatic mosaic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The pathogenic variants observed in PROS have all been associated with gain of function; thus, partial or whole • Experience suggests that sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (e.g., skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing. • The level of mosaicism for an activating variant in affected tissues or cultured cells is extremely variable [ • Testing of blood or DNA isolated from blood is not recommended based on current technologies, as • Note: (1) The pathogenic variants observed in PROS have all been associated with gain of function; thus, gene-targeted deletion/duplication analysis is not recommended. (2) Failure to detect an activating • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest a diagnosis of PROS, molecular genetic testing approaches can include Note: (1) The pathogenic variants observed in PROS have all been associated with gain of function; thus, gene-targeted deletion/duplication analysis is not recommended. (2) Failure to detect an activating For an introduction to multigene panels click • Note: (1) The pathogenic variants observed in PROS have all been associated with gain of function; thus, gene-targeted deletion/duplication analysis is not recommended. (2) Failure to detect an activating • For an introduction to multigene panels click ## Option 2 When the diagnosis of PROS has not been considered because an individual has atypical phenotypic features, genomic testing on an appropriate sample (see above) may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The choice of method for somatic Because most affected individuals have a somatic mosaic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The pathogenic variants observed in PROS have all been associated with gain of function; thus, partial or whole ## Clinical Characteristics In general, PROS can be divided into an Selected Isolated Cognitive & developmental disabilities Seizures are common. Focal neurologic deficits may be present. May result in facial asymmetry Types I, II, III Overgrowth not as exaggerated as in HMEG May → epilepsy, which may be refractory to medications if childhood onset Cognitive impairment Developmental delay Frequently severe epilepsy Focal neurologic deficits may be present. Unilateral hypertrophy of soft tissues of the face (most commonly cheek) w/underlying fat infiltration May incl bony hypertrophy May incl whole limb, part of limb, or only hand or foot (acral overgrowth) May involve soft tissue, muscle, &/or bone May affect ≥1 digits on hand or foot May involve soft tissue, muscle &/or bone Fibrofatty tissue w/dilated veins (phlebectasia) replaces muscle fibers. Low-flow venous or lymphatic malformation May present as painful lump, typically of the gastrocnemius May be assoc w/ankle dorsiflexion & calf contracture Fibroadipose tissue enlargement & bony overgrowth w/in a nerve territory (e.g., upper or lower limbs, hands & feet) w/↑ length & circumference of peripheral nerve Growth can be static (proportionate) or progressive (disproportionate). Benign lichenoid keratosis Epidermal nevi Seborrheic keratosis Overgrowth can affect any part of the body depending on the distribution of the DMEG = dysplastic megalencephaly; HMEG = hemimegalencephaly Often characterized histologically as having dysplastic neurons, balloon cells, and lamination disorganization Type I: isolated focal lesions with architectural abnormalitiesType II: isolated focal lesions with architectural and dysmorphic abnormalitiesType III: cortical disorganization associated with or adjacent to other principal lesions Seizures are typically partial and may include infantile spasms, tonic seizures, or electroclinical features of Ohtahara syndrome. May be associated with precocious dental development, macrodontia, hemimacroglossia, protuberances on the tongue and buccal mucosa, and mucosal neuromas Rare high-flow variants due to excessively muscularized venous channels. Organizing thrombi may be present. Overgrowth of capillary, lymphatic, and venous channels is sometimes referred to as CLVM (capillary lymphatic venous malformations), in which dilated lymphatic channels are combined with venous and capillary components. Selected Syndromic Asymmetric Congenital lipomatous overgrowth of limb or on trunk Hand &/or foot Plantar-palmar overgrowth Typically lymphatic low flow in areas of overgrowth Linear EN Morbid paraspinal high-flow lesions & phlebectasia Scoliosis Spina bifida Pectus deformities Sandal-gap toes Splayed feet & toes Macro-, poly-, & syndactyly Chondromalacia patellae Dislocated knees Renal agenesis/ hypoplasia Splenic lesions Wilms tumor HMEG Seizures Lower-lip capillary malformation w/o progression Lymphatic malformation of face/neck & upper body Segmental & progressive overgrowth of subcutaneous & visceral fibroadipose tissue Occasional skeletal overgrowth Disproportionate linear overgrowth Vascular malformation EN Progressive skeletal overgrowth (preserved architecture) Polydactyly Lipomatous infiltration of muscle Testicular or epididymal cysts & hydrocele Non-spleen/ thymus visceral overgrowth Asymmetric overgrowth of a body part or body segment Overgrowth may be static or mildly progressive. Low-flow venous or lymphatic malformations Port-wine nevus (capillary malformations) Megalencephaly & HMEG Generalized overgrowth (macrosomia) Cutaneous syndactyly & postaxial polydactyly or polysyndactyly Subcutaneous lipomas Hypotonia Seizures Autistic features Mild-to-severe ID Behavioral problems Meningioma-assoc symptoms (rare) Syndactyly Depressed nasal bridge DD ID Hypotonia Seizures Medulloblastoma-assoc clinical features (very rare) CLAPO = capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth; CLOVES = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal; DD = developmental delay; EN = epidermal nevi; FH or FAO = fibroadipose hyperplasia or overgrowth; HHML = hemihyperplasia multiple lipomatosis; HMEG = hemimegalencephaly; ID = intellectual disability; KTS = Klippel-Trenaunay syndrome; MCAP or M-CM = megalencephaly-capillary malformation; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome Most common findings; see May also include cortical dysplasia, polymicrogyria, Arnold-Chiari malformation, and ventriculomegaly Individuals with this phenotype may also display dysmorphic features including prominent forehead, widely spaced eyes, downslanted palpebral fissures, low-set ears, preauricular pits, anteverted nares, and a high and narrow palate. May include megalencephaly, hydrocephalus, and polymicrogyria Features of CLOVES syndrome in a child with (A) a large lipomatous truncal mass that extends into the surrounding tissues and an overlying capillary malformation and (B) macrodactyly of the left foot Features of MCAP syndrome. Photographs of an individual with MCAP syndrome demonstrating the apparent macrocephaly with prominent forehead (D); extensive capillary malformations (A-F1); bilateral 2-3-4 toe syndactyly (G, H); 3-4 finger syndactyly (F1, F2); and postaxial polydactyly of the right hand (F1) From Features of MCAP syndrome. A boy age 40 months with MCAP syndrome (left) and his unaffected twin sister (right). Note left-sided hemihypertrophy, typical facial features, bilateral 2-3 toe syndactyly, and connective tissue dysplasia with loose redundant skin. From The predominant areas of involvement include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Overgrown tissue may have a "ballooning" appearance ‒ that is, the involved body part (usually finger/s, toe/s, and/or dorsum of the hand or foot) resembles an inflated balloon. Unilateral involvement is more common than bilateral involvement. Overgrowth may include some or all of the following tissue types: Fibrous, including dense fibrous tissue encircling the nerves in individuals with the fibroadipose vascular anomaly (See Nervous (See Vascular (See Lymphatic (See Skeletal (See Lipomatous (See Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa [ In children who have undergone neurosurgical shunting for obstructive ventriculomegaly or hydrocephalus, head growth noticeably continues at an accelerated pace, indicating the primary nature of MEG in individuals who have MEG as part of their PROS findings. In most children, OFC SD increased during the first year of life. Although head growth may level off in early childhood, it typically remains at +3 SD or more above the mean. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Low-flow vascular malformations (lymphatic, venous) may be found overlying truncal or limb overgrowth. Vascular malformations may be superficial or deep (visceral). Many of these lesions can only be identified by MRA/MRV imaging (see Cutaneous Affected individuals may be at increased risk for deep venous thrombosis and pulmonary embolism, especially those with The risk increases after surgery or sclerotherapy. Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic High-flow vascular malformations (arteriovenous) can also occur, especially involving the spinal-paraspinal areas. Individuals with the Klippel-Trenaunay phenotype can have hemangiomas and venous and/or lymphatic malformations and are at risk for Kasabach-Merritt syndrome, characterized by thrombocytopenia and coagulopathy. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues including swelling, pain, and occasionally localized bleeding secondary to trauma. Some individuals may have complicated lymphatic anomalies, especially generalized lymphatic anomaly [ Characteristic findings in the hands include broad, spade-like hands with splayed or ulnar deviation of the fingers and overgrowth of one or more fingers. Characteristic findings in the feet include overgrowth with a large "sandal" gap between the great and second toes, large bulbous toes, lipomatous masses on both the dorsal and plantar surfaces, or broad forefoot with wide gaps between the metatarsal heads. Patterning defects may include postaxial, preaxial, or central polydactyly and cutaneous syndactyly, which often involves the toes, but can include the fingers. The cutaneous syndactyly occurs in patterns of 2-3 toes, 2-4 toes, and 2-5 toes with sandal-gap toes. Dislocated knees, leg-length discrepancy, and pattern chondromalacia can occur. Some affected individuals may have scoliosis, vertebral anomalies, spina bifida, and/or pectus anomalies, particularly in the CLOVES phenotype. Progressive skeletal overgrowth has been described in those with the FH or FAO phenotype. Individuals with the MCAP phenotype may have joint hypermobility due to connective tissue dysplasia. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The characteristic truncal lipomatous mass infiltrates surrounding tissues and often requires surgical excision. Severe scoliosis, large truncal mass, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems of the feet and hands, and central phlebectasia/thromboembolism are examples of significant morbidities that need active or prophylactic medical intervention (see Paraspinal and intraspinal extension, more commonly seen in individuals with the CLOVES phenotype, present significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits including myelopathy, warranting prompt diagnosis and multidisciplinary care [ Lipomatosis can be invasive, invading hip joints and intravertebral spaces, which can become quite painful. Infiltration of adipose tissue into muscle with either replacement or compression of muscle, as well as into viscera (liver, spleen, pancreas), intestines, mediastinum, and spine has also been described. Surgery can be difficult because of the vascularity of the lipomatous tissue and the risk of thrombosis. The degree of intellectual disability (ID) appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus (see Most individuals with MCAP syndrome have some intellectual disability; the degree is variable and ranges from mild learning disability to severe disability. Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate. A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in individuals with MCAP syndrome. A subset of children (6/21) with MCAP syndrome have autistic features or a clinical diagnosis of autism [ Attention-deficit/hyperactivity disorder Obsessive-compulsive tendencies Anxiety-related issues Individuals with PROS who have macrocephaly typically undergo brain imaging shortly after birth or within the first year of life, leading to early identification of the following key neuroimaging features (see In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [ While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life. Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [ The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome. In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [ The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities. Cavernous hemangiomas have occurred in brain tissue, necessitating debulking when they enlarge and cause pain. While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. Other benign tumors have included two individuals with MCAP (ages 21 months and 5 years) who had meningioma (which do not tend to enlarge, spread, or metastasize); two individuals with PROS who had spinal and major nerve neurofibromas; and several others with ovarian cystadenoma, uterine fibroids, and lipomas [ The estimated frequency of Wilms tumor ranges from 1.4% to 3.3%. Of 12 individuals reported to have Wilms tumor or nephroblastomatosis, clinical PROS diagnoses included CLOVES (8 individuals), MCAP (2 individuals), and KTS (2 individuals). Mean age at diagnosis was 27.4 months (median 18 months; range 9-119 months). Tumor type included seven individuals (~60%) with Wilms tumor, four (33%) with indeterminate features of Wilms tumor vs nephroblastomatosis, and one (8%) with nephroblastomatosis. Six (50%) had somatic "hot spot" There have been several case reports of individuals with PROS who developed other cancers including the following [ Leukemia (in those with the MCAP phenotype) Vestibular schwannoma Retinoblastoma Systematic data are at present insufficient to determine whether there is a true association between PROS and the development of these types of tumors or whether the case reports represent rare co-occurrences of PROS with these tumors. Dermal melanocytic nevi Café au lait macules Hypopigmented macules Cutis marmorata Pigmented nevi Patchy hyperpigmentation that follows the lines of Blaschko Linear keratinocytic epidermal nevi, which may occur anywhere on the body and may follow a dermatomal distribution Seborrheic keratosis and benign lichenoid dermatosis Skin hyperelasticity, laxity, and thick subcutaneous tissue in those with the MCAP phenotype due to connective tissue dysplasia PROS is a clinical phenocopy of congenital hyperinsulinism (see This profile has been reported both in individuals with MCAP and in those with overlapping forms of PROS that include brain involvement. While hypoglycemia in PROS is most commonly diagnosed in the neonatal period, some individuals may present later in childhood, including at least one male with MCAP who presented with his first episode of hypoglycemia at age six years [Author, personal communication]. Hypoglycemia may be persistent over time, requiring consistent glucose monitoring, evaluation of the hypothalamic-pituitary-adrenal axis, and ongoing treatment (see There are several mutational hot spots in Further, analysis of individuals with PROS suggests that MCAP syndrome in particular is primarily associated with a wide range of Due to the phenotypic variability of the disorders caused by somatic The prevalence of • Cognitive & developmental disabilities • Seizures are common. • Focal neurologic deficits may be present. • May result in facial asymmetry • Types I, II, III • Overgrowth not as exaggerated as in HMEG • May → epilepsy, which may be refractory to medications if childhood onset • Cognitive impairment • Developmental delay • Frequently severe epilepsy • Focal neurologic deficits may be present. • Unilateral hypertrophy of soft tissues of the face (most commonly cheek) w/underlying fat infiltration • May incl bony hypertrophy • May incl whole limb, part of limb, or only hand or foot (acral overgrowth) • May involve soft tissue, muscle, &/or bone • May affect ≥1 digits on hand or foot • May involve soft tissue, muscle &/or bone • Fibrofatty tissue w/dilated veins (phlebectasia) replaces muscle fibers. • Low-flow venous or lymphatic malformation • May present as painful lump, typically of the gastrocnemius • May be assoc w/ankle dorsiflexion & calf contracture • Fibroadipose tissue enlargement & bony overgrowth w/in a nerve territory (e.g., upper or lower limbs, hands & feet) w/↑ length & circumference of peripheral nerve • Growth can be static (proportionate) or progressive (disproportionate). • Benign lichenoid keratosis • Epidermal nevi • Seborrheic keratosis • Asymmetric • Congenital lipomatous overgrowth of limb or on trunk • Hand &/or foot • Plantar-palmar overgrowth • Typically lymphatic low flow in areas of overgrowth • Linear EN • Morbid paraspinal high-flow lesions & phlebectasia • Scoliosis • Spina bifida • Pectus deformities • Sandal-gap toes • Splayed feet & toes • Macro-, poly-, & syndactyly • Chondromalacia patellae • Dislocated knees • Renal agenesis/ hypoplasia • Splenic lesions • Wilms tumor • HMEG • Seizures • Lower-lip capillary malformation w/o progression • Lymphatic malformation of face/neck & upper body • Segmental & progressive overgrowth of subcutaneous & visceral fibroadipose tissue • Occasional skeletal overgrowth • Disproportionate linear overgrowth • Vascular malformation • EN • Progressive skeletal overgrowth (preserved architecture) • Polydactyly • Lipomatous infiltration of muscle • Testicular or epididymal cysts & hydrocele • Non-spleen/ thymus visceral overgrowth • Asymmetric overgrowth of a body part or body segment • Overgrowth may be static or mildly progressive. • Low-flow venous or lymphatic malformations • Port-wine nevus (capillary malformations) • Megalencephaly & HMEG • Generalized overgrowth (macrosomia) • Cutaneous syndactyly & postaxial polydactyly or polysyndactyly • Subcutaneous lipomas • Hypotonia • Seizures • Autistic features • Mild-to-severe ID • Behavioral problems • Meningioma-assoc symptoms (rare) • Syndactyly • Depressed nasal bridge • DD • ID • Hypotonia • Seizures • Medulloblastoma-assoc clinical features (very rare) • Fibrous, including dense fibrous tissue encircling the nerves in individuals with the fibroadipose vascular anomaly (See • Nervous (See • Vascular (See • Lymphatic (See • Skeletal (See • Lipomatous (See • Cutaneous • Affected individuals may be at increased risk for deep venous thrombosis and pulmonary embolism, especially those with • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • High-flow vascular malformations (arteriovenous) can also occur, especially involving the spinal-paraspinal areas. • Individuals with the Klippel-Trenaunay phenotype can have hemangiomas and venous and/or lymphatic malformations and are at risk for Kasabach-Merritt syndrome, characterized by thrombocytopenia and coagulopathy. • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • Paraspinal and intraspinal extension, more commonly seen in individuals with the CLOVES phenotype, present significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits including myelopathy, warranting prompt diagnosis and multidisciplinary care [ • Lipomatosis can be invasive, invading hip joints and intravertebral spaces, which can become quite painful. • Infiltration of adipose tissue into muscle with either replacement or compression of muscle, as well as into viscera (liver, spleen, pancreas), intestines, mediastinum, and spine has also been described. • Surgery can be difficult because of the vascularity of the lipomatous tissue and the risk of thrombosis. • Most individuals with MCAP syndrome have some intellectual disability; the degree is variable and ranges from mild learning disability to severe disability. • Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate. • A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in individuals with MCAP syndrome. • Attention-deficit/hyperactivity disorder • Obsessive-compulsive tendencies • Anxiety-related issues • In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [ • While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life. • Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [ • The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. • Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome. • In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [ • The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. • PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities. • Cavernous hemangiomas have occurred in brain tissue, necessitating debulking when they enlarge and cause pain. • While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. • Mean age at diagnosis was 27.4 months (median 18 months; range 9-119 months). • Tumor type included seven individuals (~60%) with Wilms tumor, four (33%) with indeterminate features of Wilms tumor vs nephroblastomatosis, and one (8%) with nephroblastomatosis. • Six (50%) had somatic "hot spot" • Leukemia (in those with the MCAP phenotype) • Vestibular schwannoma • Retinoblastoma • Dermal melanocytic nevi • Café au lait macules • Hypopigmented macules • Cutis marmorata • Pigmented nevi • Patchy hyperpigmentation that follows the lines of Blaschko • Linear keratinocytic epidermal nevi, which may occur anywhere on the body and may follow a dermatomal distribution • Seborrheic keratosis and benign lichenoid dermatosis • Skin hyperelasticity, laxity, and thick subcutaneous tissue in those with the MCAP phenotype due to connective tissue dysplasia • PROS is a clinical phenocopy of congenital hyperinsulinism (see • This profile has been reported both in individuals with MCAP and in those with overlapping forms of PROS that include brain involvement. • While hypoglycemia in PROS is most commonly diagnosed in the neonatal period, some individuals may present later in childhood, including at least one male with MCAP who presented with his first episode of hypoglycemia at age six years [Author, personal communication]. • Hypoglycemia may be persistent over time, requiring consistent glucose monitoring, evaluation of the hypothalamic-pituitary-adrenal axis, and ongoing treatment (see ## Clinical Description In general, PROS can be divided into an Selected Isolated Cognitive & developmental disabilities Seizures are common. Focal neurologic deficits may be present. May result in facial asymmetry Types I, II, III Overgrowth not as exaggerated as in HMEG May → epilepsy, which may be refractory to medications if childhood onset Cognitive impairment Developmental delay Frequently severe epilepsy Focal neurologic deficits may be present. Unilateral hypertrophy of soft tissues of the face (most commonly cheek) w/underlying fat infiltration May incl bony hypertrophy May incl whole limb, part of limb, or only hand or foot (acral overgrowth) May involve soft tissue, muscle, &/or bone May affect ≥1 digits on hand or foot May involve soft tissue, muscle &/or bone Fibrofatty tissue w/dilated veins (phlebectasia) replaces muscle fibers. Low-flow venous or lymphatic malformation May present as painful lump, typically of the gastrocnemius May be assoc w/ankle dorsiflexion & calf contracture Fibroadipose tissue enlargement & bony overgrowth w/in a nerve territory (e.g., upper or lower limbs, hands & feet) w/↑ length & circumference of peripheral nerve Growth can be static (proportionate) or progressive (disproportionate). Benign lichenoid keratosis Epidermal nevi Seborrheic keratosis Overgrowth can affect any part of the body depending on the distribution of the DMEG = dysplastic megalencephaly; HMEG = hemimegalencephaly Often characterized histologically as having dysplastic neurons, balloon cells, and lamination disorganization Type I: isolated focal lesions with architectural abnormalitiesType II: isolated focal lesions with architectural and dysmorphic abnormalitiesType III: cortical disorganization associated with or adjacent to other principal lesions Seizures are typically partial and may include infantile spasms, tonic seizures, or electroclinical features of Ohtahara syndrome. May be associated with precocious dental development, macrodontia, hemimacroglossia, protuberances on the tongue and buccal mucosa, and mucosal neuromas Rare high-flow variants due to excessively muscularized venous channels. Organizing thrombi may be present. Overgrowth of capillary, lymphatic, and venous channels is sometimes referred to as CLVM (capillary lymphatic venous malformations), in which dilated lymphatic channels are combined with venous and capillary components. Selected Syndromic Asymmetric Congenital lipomatous overgrowth of limb or on trunk Hand &/or foot Plantar-palmar overgrowth Typically lymphatic low flow in areas of overgrowth Linear EN Morbid paraspinal high-flow lesions & phlebectasia Scoliosis Spina bifida Pectus deformities Sandal-gap toes Splayed feet & toes Macro-, poly-, & syndactyly Chondromalacia patellae Dislocated knees Renal agenesis/ hypoplasia Splenic lesions Wilms tumor HMEG Seizures Lower-lip capillary malformation w/o progression Lymphatic malformation of face/neck & upper body Segmental & progressive overgrowth of subcutaneous & visceral fibroadipose tissue Occasional skeletal overgrowth Disproportionate linear overgrowth Vascular malformation EN Progressive skeletal overgrowth (preserved architecture) Polydactyly Lipomatous infiltration of muscle Testicular or epididymal cysts & hydrocele Non-spleen/ thymus visceral overgrowth Asymmetric overgrowth of a body part or body segment Overgrowth may be static or mildly progressive. Low-flow venous or lymphatic malformations Port-wine nevus (capillary malformations) Megalencephaly & HMEG Generalized overgrowth (macrosomia) Cutaneous syndactyly & postaxial polydactyly or polysyndactyly Subcutaneous lipomas Hypotonia Seizures Autistic features Mild-to-severe ID Behavioral problems Meningioma-assoc symptoms (rare) Syndactyly Depressed nasal bridge DD ID Hypotonia Seizures Medulloblastoma-assoc clinical features (very rare) CLAPO = capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth; CLOVES = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal; DD = developmental delay; EN = epidermal nevi; FH or FAO = fibroadipose hyperplasia or overgrowth; HHML = hemihyperplasia multiple lipomatosis; HMEG = hemimegalencephaly; ID = intellectual disability; KTS = Klippel-Trenaunay syndrome; MCAP or M-CM = megalencephaly-capillary malformation; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome Most common findings; see May also include cortical dysplasia, polymicrogyria, Arnold-Chiari malformation, and ventriculomegaly Individuals with this phenotype may also display dysmorphic features including prominent forehead, widely spaced eyes, downslanted palpebral fissures, low-set ears, preauricular pits, anteverted nares, and a high and narrow palate. May include megalencephaly, hydrocephalus, and polymicrogyria Features of CLOVES syndrome in a child with (A) a large lipomatous truncal mass that extends into the surrounding tissues and an overlying capillary malformation and (B) macrodactyly of the left foot Features of MCAP syndrome. Photographs of an individual with MCAP syndrome demonstrating the apparent macrocephaly with prominent forehead (D); extensive capillary malformations (A-F1); bilateral 2-3-4 toe syndactyly (G, H); 3-4 finger syndactyly (F1, F2); and postaxial polydactyly of the right hand (F1) From Features of MCAP syndrome. A boy age 40 months with MCAP syndrome (left) and his unaffected twin sister (right). Note left-sided hemihypertrophy, typical facial features, bilateral 2-3 toe syndactyly, and connective tissue dysplasia with loose redundant skin. From The predominant areas of involvement include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Overgrown tissue may have a "ballooning" appearance ‒ that is, the involved body part (usually finger/s, toe/s, and/or dorsum of the hand or foot) resembles an inflated balloon. Unilateral involvement is more common than bilateral involvement. Overgrowth may include some or all of the following tissue types: Fibrous, including dense fibrous tissue encircling the nerves in individuals with the fibroadipose vascular anomaly (See Nervous (See Vascular (See Lymphatic (See Skeletal (See Lipomatous (See Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa [ In children who have undergone neurosurgical shunting for obstructive ventriculomegaly or hydrocephalus, head growth noticeably continues at an accelerated pace, indicating the primary nature of MEG in individuals who have MEG as part of their PROS findings. In most children, OFC SD increased during the first year of life. Although head growth may level off in early childhood, it typically remains at +3 SD or more above the mean. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Low-flow vascular malformations (lymphatic, venous) may be found overlying truncal or limb overgrowth. Vascular malformations may be superficial or deep (visceral). Many of these lesions can only be identified by MRA/MRV imaging (see Cutaneous Affected individuals may be at increased risk for deep venous thrombosis and pulmonary embolism, especially those with The risk increases after surgery or sclerotherapy. Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic High-flow vascular malformations (arteriovenous) can also occur, especially involving the spinal-paraspinal areas. Individuals with the Klippel-Trenaunay phenotype can have hemangiomas and venous and/or lymphatic malformations and are at risk for Kasabach-Merritt syndrome, characterized by thrombocytopenia and coagulopathy. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues including swelling, pain, and occasionally localized bleeding secondary to trauma. Some individuals may have complicated lymphatic anomalies, especially generalized lymphatic anomaly [ Characteristic findings in the hands include broad, spade-like hands with splayed or ulnar deviation of the fingers and overgrowth of one or more fingers. Characteristic findings in the feet include overgrowth with a large "sandal" gap between the great and second toes, large bulbous toes, lipomatous masses on both the dorsal and plantar surfaces, or broad forefoot with wide gaps between the metatarsal heads. Patterning defects may include postaxial, preaxial, or central polydactyly and cutaneous syndactyly, which often involves the toes, but can include the fingers. The cutaneous syndactyly occurs in patterns of 2-3 toes, 2-4 toes, and 2-5 toes with sandal-gap toes. Dislocated knees, leg-length discrepancy, and pattern chondromalacia can occur. Some affected individuals may have scoliosis, vertebral anomalies, spina bifida, and/or pectus anomalies, particularly in the CLOVES phenotype. Progressive skeletal overgrowth has been described in those with the FH or FAO phenotype. Individuals with the MCAP phenotype may have joint hypermobility due to connective tissue dysplasia. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The characteristic truncal lipomatous mass infiltrates surrounding tissues and often requires surgical excision. Severe scoliosis, large truncal mass, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems of the feet and hands, and central phlebectasia/thromboembolism are examples of significant morbidities that need active or prophylactic medical intervention (see Paraspinal and intraspinal extension, more commonly seen in individuals with the CLOVES phenotype, present significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits including myelopathy, warranting prompt diagnosis and multidisciplinary care [ Lipomatosis can be invasive, invading hip joints and intravertebral spaces, which can become quite painful. Infiltration of adipose tissue into muscle with either replacement or compression of muscle, as well as into viscera (liver, spleen, pancreas), intestines, mediastinum, and spine has also been described. Surgery can be difficult because of the vascularity of the lipomatous tissue and the risk of thrombosis. The degree of intellectual disability (ID) appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus (see Most individuals with MCAP syndrome have some intellectual disability; the degree is variable and ranges from mild learning disability to severe disability. Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate. A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in individuals with MCAP syndrome. A subset of children (6/21) with MCAP syndrome have autistic features or a clinical diagnosis of autism [ Attention-deficit/hyperactivity disorder Obsessive-compulsive tendencies Anxiety-related issues Individuals with PROS who have macrocephaly typically undergo brain imaging shortly after birth or within the first year of life, leading to early identification of the following key neuroimaging features (see In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [ While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life. Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [ The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome. In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [ The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities. Cavernous hemangiomas have occurred in brain tissue, necessitating debulking when they enlarge and cause pain. While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. Other benign tumors have included two individuals with MCAP (ages 21 months and 5 years) who had meningioma (which do not tend to enlarge, spread, or metastasize); two individuals with PROS who had spinal and major nerve neurofibromas; and several others with ovarian cystadenoma, uterine fibroids, and lipomas [ The estimated frequency of Wilms tumor ranges from 1.4% to 3.3%. Of 12 individuals reported to have Wilms tumor or nephroblastomatosis, clinical PROS diagnoses included CLOVES (8 individuals), MCAP (2 individuals), and KTS (2 individuals). Mean age at diagnosis was 27.4 months (median 18 months; range 9-119 months). Tumor type included seven individuals (~60%) with Wilms tumor, four (33%) with indeterminate features of Wilms tumor vs nephroblastomatosis, and one (8%) with nephroblastomatosis. Six (50%) had somatic "hot spot" There have been several case reports of individuals with PROS who developed other cancers including the following [ Leukemia (in those with the MCAP phenotype) Vestibular schwannoma Retinoblastoma Systematic data are at present insufficient to determine whether there is a true association between PROS and the development of these types of tumors or whether the case reports represent rare co-occurrences of PROS with these tumors. Dermal melanocytic nevi Café au lait macules Hypopigmented macules Cutis marmorata Pigmented nevi Patchy hyperpigmentation that follows the lines of Blaschko Linear keratinocytic epidermal nevi, which may occur anywhere on the body and may follow a dermatomal distribution Seborrheic keratosis and benign lichenoid dermatosis Skin hyperelasticity, laxity, and thick subcutaneous tissue in those with the MCAP phenotype due to connective tissue dysplasia PROS is a clinical phenocopy of congenital hyperinsulinism (see This profile has been reported both in individuals with MCAP and in those with overlapping forms of PROS that include brain involvement. While hypoglycemia in PROS is most commonly diagnosed in the neonatal period, some individuals may present later in childhood, including at least one male with MCAP who presented with his first episode of hypoglycemia at age six years [Author, personal communication]. Hypoglycemia may be persistent over time, requiring consistent glucose monitoring, evaluation of the hypothalamic-pituitary-adrenal axis, and ongoing treatment (see • Cognitive & developmental disabilities • Seizures are common. • Focal neurologic deficits may be present. • May result in facial asymmetry • Types I, II, III • Overgrowth not as exaggerated as in HMEG • May → epilepsy, which may be refractory to medications if childhood onset • Cognitive impairment • Developmental delay • Frequently severe epilepsy • Focal neurologic deficits may be present. • Unilateral hypertrophy of soft tissues of the face (most commonly cheek) w/underlying fat infiltration • May incl bony hypertrophy • May incl whole limb, part of limb, or only hand or foot (acral overgrowth) • May involve soft tissue, muscle, &/or bone • May affect ≥1 digits on hand or foot • May involve soft tissue, muscle &/or bone • Fibrofatty tissue w/dilated veins (phlebectasia) replaces muscle fibers. • Low-flow venous or lymphatic malformation • May present as painful lump, typically of the gastrocnemius • May be assoc w/ankle dorsiflexion & calf contracture • Fibroadipose tissue enlargement & bony overgrowth w/in a nerve territory (e.g., upper or lower limbs, hands & feet) w/↑ length & circumference of peripheral nerve • Growth can be static (proportionate) or progressive (disproportionate). • Benign lichenoid keratosis • Epidermal nevi • Seborrheic keratosis • Asymmetric • Congenital lipomatous overgrowth of limb or on trunk • Hand &/or foot • Plantar-palmar overgrowth • Typically lymphatic low flow in areas of overgrowth • Linear EN • Morbid paraspinal high-flow lesions & phlebectasia • Scoliosis • Spina bifida • Pectus deformities • Sandal-gap toes • Splayed feet & toes • Macro-, poly-, & syndactyly • Chondromalacia patellae • Dislocated knees • Renal agenesis/ hypoplasia • Splenic lesions • Wilms tumor • HMEG • Seizures • Lower-lip capillary malformation w/o progression • Lymphatic malformation of face/neck & upper body • Segmental & progressive overgrowth of subcutaneous & visceral fibroadipose tissue • Occasional skeletal overgrowth • Disproportionate linear overgrowth • Vascular malformation • EN • Progressive skeletal overgrowth (preserved architecture) • Polydactyly • Lipomatous infiltration of muscle • Testicular or epididymal cysts & hydrocele • Non-spleen/ thymus visceral overgrowth • Asymmetric overgrowth of a body part or body segment • Overgrowth may be static or mildly progressive. • Low-flow venous or lymphatic malformations • Port-wine nevus (capillary malformations) • Megalencephaly & HMEG • Generalized overgrowth (macrosomia) • Cutaneous syndactyly & postaxial polydactyly or polysyndactyly • Subcutaneous lipomas • Hypotonia • Seizures • Autistic features • Mild-to-severe ID • Behavioral problems • Meningioma-assoc symptoms (rare) • Syndactyly • Depressed nasal bridge • DD • ID • Hypotonia • Seizures • Medulloblastoma-assoc clinical features (very rare) • Fibrous, including dense fibrous tissue encircling the nerves in individuals with the fibroadipose vascular anomaly (See • Nervous (See • Vascular (See • Lymphatic (See • Skeletal (See • Lipomatous (See • Cutaneous • Affected individuals may be at increased risk for deep venous thrombosis and pulmonary embolism, especially those with • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • High-flow vascular malformations (arteriovenous) can also occur, especially involving the spinal-paraspinal areas. • Individuals with the Klippel-Trenaunay phenotype can have hemangiomas and venous and/or lymphatic malformations and are at risk for Kasabach-Merritt syndrome, characterized by thrombocytopenia and coagulopathy. • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • Paraspinal and intraspinal extension, more commonly seen in individuals with the CLOVES phenotype, present significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits including myelopathy, warranting prompt diagnosis and multidisciplinary care [ • Lipomatosis can be invasive, invading hip joints and intravertebral spaces, which can become quite painful. • Infiltration of adipose tissue into muscle with either replacement or compression of muscle, as well as into viscera (liver, spleen, pancreas), intestines, mediastinum, and spine has also been described. • Surgery can be difficult because of the vascularity of the lipomatous tissue and the risk of thrombosis. • Most individuals with MCAP syndrome have some intellectual disability; the degree is variable and ranges from mild learning disability to severe disability. • Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate. • A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in individuals with MCAP syndrome. • Attention-deficit/hyperactivity disorder • Obsessive-compulsive tendencies • Anxiety-related issues • In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [ • While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life. • Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [ • The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. • Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome. • In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [ • The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. • PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities. • Cavernous hemangiomas have occurred in brain tissue, necessitating debulking when they enlarge and cause pain. • While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. • Mean age at diagnosis was 27.4 months (median 18 months; range 9-119 months). • Tumor type included seven individuals (~60%) with Wilms tumor, four (33%) with indeterminate features of Wilms tumor vs nephroblastomatosis, and one (8%) with nephroblastomatosis. • Six (50%) had somatic "hot spot" • Leukemia (in those with the MCAP phenotype) • Vestibular schwannoma • Retinoblastoma • Dermal melanocytic nevi • Café au lait macules • Hypopigmented macules • Cutis marmorata • Pigmented nevi • Patchy hyperpigmentation that follows the lines of Blaschko • Linear keratinocytic epidermal nevi, which may occur anywhere on the body and may follow a dermatomal distribution • Seborrheic keratosis and benign lichenoid dermatosis • Skin hyperelasticity, laxity, and thick subcutaneous tissue in those with the MCAP phenotype due to connective tissue dysplasia • PROS is a clinical phenocopy of congenital hyperinsulinism (see • This profile has been reported both in individuals with MCAP and in those with overlapping forms of PROS that include brain involvement. • While hypoglycemia in PROS is most commonly diagnosed in the neonatal period, some individuals may present later in childhood, including at least one male with MCAP who presented with his first episode of hypoglycemia at age six years [Author, personal communication]. • Hypoglycemia may be persistent over time, requiring consistent glucose monitoring, evaluation of the hypothalamic-pituitary-adrenal axis, and ongoing treatment (see ## Overgrowth The predominant areas of involvement include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Overgrown tissue may have a "ballooning" appearance ‒ that is, the involved body part (usually finger/s, toe/s, and/or dorsum of the hand or foot) resembles an inflated balloon. Unilateral involvement is more common than bilateral involvement. Overgrowth may include some or all of the following tissue types: Fibrous, including dense fibrous tissue encircling the nerves in individuals with the fibroadipose vascular anomaly (See Nervous (See Vascular (See Lymphatic (See Skeletal (See Lipomatous (See • Fibrous, including dense fibrous tissue encircling the nerves in individuals with the fibroadipose vascular anomaly (See • Nervous (See • Vascular (See • Lymphatic (See • Skeletal (See • Lipomatous (See ## Brain Growth Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa [ In children who have undergone neurosurgical shunting for obstructive ventriculomegaly or hydrocephalus, head growth noticeably continues at an accelerated pace, indicating the primary nature of MEG in individuals who have MEG as part of their PROS findings. In most children, OFC SD increased during the first year of life. Although head growth may level off in early childhood, it typically remains at +3 SD or more above the mean. ## Vascular Malformations Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Low-flow vascular malformations (lymphatic, venous) may be found overlying truncal or limb overgrowth. Vascular malformations may be superficial or deep (visceral). Many of these lesions can only be identified by MRA/MRV imaging (see Cutaneous Affected individuals may be at increased risk for deep venous thrombosis and pulmonary embolism, especially those with The risk increases after surgery or sclerotherapy. Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic High-flow vascular malformations (arteriovenous) can also occur, especially involving the spinal-paraspinal areas. Individuals with the Klippel-Trenaunay phenotype can have hemangiomas and venous and/or lymphatic malformations and are at risk for Kasabach-Merritt syndrome, characterized by thrombocytopenia and coagulopathy. • Cutaneous • Affected individuals may be at increased risk for deep venous thrombosis and pulmonary embolism, especially those with • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic • High-flow vascular malformations (arteriovenous) can also occur, especially involving the spinal-paraspinal areas. • Individuals with the Klippel-Trenaunay phenotype can have hemangiomas and venous and/or lymphatic malformations and are at risk for Kasabach-Merritt syndrome, characterized by thrombocytopenia and coagulopathy. • The risk increases after surgery or sclerotherapy. • Thrombotic risk may also be increased due to other causes of chronic stasis including impaired mobility (e.g., dehydration, surgery), decreased anticoagulant proteins, and the effect of the specific pathogenic ## Lymphatic Malformations Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues including swelling, pain, and occasionally localized bleeding secondary to trauma. Some individuals may have complicated lymphatic anomalies, especially generalized lymphatic anomaly [ ## Skeletal Findings Characteristic findings in the hands include broad, spade-like hands with splayed or ulnar deviation of the fingers and overgrowth of one or more fingers. Characteristic findings in the feet include overgrowth with a large "sandal" gap between the great and second toes, large bulbous toes, lipomatous masses on both the dorsal and plantar surfaces, or broad forefoot with wide gaps between the metatarsal heads. Patterning defects may include postaxial, preaxial, or central polydactyly and cutaneous syndactyly, which often involves the toes, but can include the fingers. The cutaneous syndactyly occurs in patterns of 2-3 toes, 2-4 toes, and 2-5 toes with sandal-gap toes. Dislocated knees, leg-length discrepancy, and pattern chondromalacia can occur. Some affected individuals may have scoliosis, vertebral anomalies, spina bifida, and/or pectus anomalies, particularly in the CLOVES phenotype. Progressive skeletal overgrowth has been described in those with the FH or FAO phenotype. Individuals with the MCAP phenotype may have joint hypermobility due to connective tissue dysplasia. ## Lipomatous Overgrowth with or without Regional Reduction of Adipose Tissue Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The characteristic truncal lipomatous mass infiltrates surrounding tissues and often requires surgical excision. Severe scoliosis, large truncal mass, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems of the feet and hands, and central phlebectasia/thromboembolism are examples of significant morbidities that need active or prophylactic medical intervention (see Paraspinal and intraspinal extension, more commonly seen in individuals with the CLOVES phenotype, present significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits including myelopathy, warranting prompt diagnosis and multidisciplinary care [ Lipomatosis can be invasive, invading hip joints and intravertebral spaces, which can become quite painful. Infiltration of adipose tissue into muscle with either replacement or compression of muscle, as well as into viscera (liver, spleen, pancreas), intestines, mediastinum, and spine has also been described. Surgery can be difficult because of the vascularity of the lipomatous tissue and the risk of thrombosis. • Paraspinal and intraspinal extension, more commonly seen in individuals with the CLOVES phenotype, present significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits including myelopathy, warranting prompt diagnosis and multidisciplinary care [ • Lipomatosis can be invasive, invading hip joints and intravertebral spaces, which can become quite painful. • Infiltration of adipose tissue into muscle with either replacement or compression of muscle, as well as into viscera (liver, spleen, pancreas), intestines, mediastinum, and spine has also been described. • Surgery can be difficult because of the vascularity of the lipomatous tissue and the risk of thrombosis. ## Developmental Delay and Intellectual Disability The degree of intellectual disability (ID) appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus (see Most individuals with MCAP syndrome have some intellectual disability; the degree is variable and ranges from mild learning disability to severe disability. Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate. A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in individuals with MCAP syndrome. • Most individuals with MCAP syndrome have some intellectual disability; the degree is variable and ranges from mild learning disability to severe disability. • Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate. • A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in individuals with MCAP syndrome. ## Other Neurodevelopmental Features ## Behavioral Issues and Autistic Features A subset of children (6/21) with MCAP syndrome have autistic features or a clinical diagnosis of autism [ Attention-deficit/hyperactivity disorder Obsessive-compulsive tendencies Anxiety-related issues • Attention-deficit/hyperactivity disorder • Obsessive-compulsive tendencies • Anxiety-related issues ## Neuroimaging Individuals with PROS who have macrocephaly typically undergo brain imaging shortly after birth or within the first year of life, leading to early identification of the following key neuroimaging features (see In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [ While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life. Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [ The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome. In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [ The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities. • In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [ • While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life. • Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [ • The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. • Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome. • In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [ • The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. • PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities. ## Tumors Cavernous hemangiomas have occurred in brain tissue, necessitating debulking when they enlarge and cause pain. While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. Other benign tumors have included two individuals with MCAP (ages 21 months and 5 years) who had meningioma (which do not tend to enlarge, spread, or metastasize); two individuals with PROS who had spinal and major nerve neurofibromas; and several others with ovarian cystadenoma, uterine fibroids, and lipomas [ The estimated frequency of Wilms tumor ranges from 1.4% to 3.3%. Of 12 individuals reported to have Wilms tumor or nephroblastomatosis, clinical PROS diagnoses included CLOVES (8 individuals), MCAP (2 individuals), and KTS (2 individuals). Mean age at diagnosis was 27.4 months (median 18 months; range 9-119 months). Tumor type included seven individuals (~60%) with Wilms tumor, four (33%) with indeterminate features of Wilms tumor vs nephroblastomatosis, and one (8%) with nephroblastomatosis. Six (50%) had somatic "hot spot" There have been several case reports of individuals with PROS who developed other cancers including the following [ Leukemia (in those with the MCAP phenotype) Vestibular schwannoma Retinoblastoma Systematic data are at present insufficient to determine whether there is a true association between PROS and the development of these types of tumors or whether the case reports represent rare co-occurrences of PROS with these tumors. • Cavernous hemangiomas have occurred in brain tissue, necessitating debulking when they enlarge and cause pain. • While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. • Mean age at diagnosis was 27.4 months (median 18 months; range 9-119 months). • Tumor type included seven individuals (~60%) with Wilms tumor, four (33%) with indeterminate features of Wilms tumor vs nephroblastomatosis, and one (8%) with nephroblastomatosis. • Six (50%) had somatic "hot spot" • Leukemia (in those with the MCAP phenotype) • Vestibular schwannoma • Retinoblastoma ## Other Dermal melanocytic nevi Café au lait macules Hypopigmented macules Cutis marmorata Pigmented nevi Patchy hyperpigmentation that follows the lines of Blaschko Linear keratinocytic epidermal nevi, which may occur anywhere on the body and may follow a dermatomal distribution Seborrheic keratosis and benign lichenoid dermatosis Skin hyperelasticity, laxity, and thick subcutaneous tissue in those with the MCAP phenotype due to connective tissue dysplasia PROS is a clinical phenocopy of congenital hyperinsulinism (see This profile has been reported both in individuals with MCAP and in those with overlapping forms of PROS that include brain involvement. While hypoglycemia in PROS is most commonly diagnosed in the neonatal period, some individuals may present later in childhood, including at least one male with MCAP who presented with his first episode of hypoglycemia at age six years [Author, personal communication]. Hypoglycemia may be persistent over time, requiring consistent glucose monitoring, evaluation of the hypothalamic-pituitary-adrenal axis, and ongoing treatment (see • Dermal melanocytic nevi • Café au lait macules • Hypopigmented macules • Cutis marmorata • Pigmented nevi • Patchy hyperpigmentation that follows the lines of Blaschko • Linear keratinocytic epidermal nevi, which may occur anywhere on the body and may follow a dermatomal distribution • Seborrheic keratosis and benign lichenoid dermatosis • Skin hyperelasticity, laxity, and thick subcutaneous tissue in those with the MCAP phenotype due to connective tissue dysplasia • PROS is a clinical phenocopy of congenital hyperinsulinism (see • This profile has been reported both in individuals with MCAP and in those with overlapping forms of PROS that include brain involvement. • While hypoglycemia in PROS is most commonly diagnosed in the neonatal period, some individuals may present later in childhood, including at least one male with MCAP who presented with his first episode of hypoglycemia at age six years [Author, personal communication]. • Hypoglycemia may be persistent over time, requiring consistent glucose monitoring, evaluation of the hypothalamic-pituitary-adrenal axis, and ongoing treatment (see ## Genotype-Phenotype Correlations There are several mutational hot spots in Further, analysis of individuals with PROS suggests that MCAP syndrome in particular is primarily associated with a wide range of ## Nomenclature Due to the phenotypic variability of the disorders caused by somatic ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis A number of overgrowth and megalencephaly disorders overlap with the Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; CLOVES syndrome = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome; DD = developmental delay; DiffDx = differential diagnosis; FCD = focal cortical dysplasia; HMEG = hemimegalencephaly; MEG = megalencephaly; MOI = mode of inheritance; NA = not applicable; PMG = polymicrogyria; XL = X-linked SOLAMEN syndrome is the consequence of a germline pathogenic variant in ## Management Clinical practice guidelines for To establish the extent of disease and needs in an individual with Note: Assessment is complicated by variable findings in individuals with this condition. Accurate and thorough assessment of medical history is necessary to evaluate for vascular malformations as well as other clinical features. Recommended Evaluations Following Initial Diagnosis in Individuals with Brain MRI in those w/megalencephaly to assess for cortical malformations, ventriculomegaly/hydrocephalus, & Chiari malformation (See Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Overgrowth of a limb or portion of a limb, foot abnormalities, splayed toes & spine abnormalities (incl spinal curvature) Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To assess for evidence of ↑ risk of thrombosis (esp in those w/venous malformations) & coagulopathy D-dimer & fibrinogen levels may be a useful screen for thrombosis in those w/vascular malformations. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; EEG = electroencephalogram; GHD = growth hormone deficiency; IGF1 = insulin-like growth factor 1; IGFBP3 = insulin-like growth factor BP3; MOI = mode of inheritance; MRA = MR angiography; MRV = MR venography; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid stimulation hormone The first episode of hypoglycemia can occur later in childhood. Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Targeted Treatment of Initial dose 50 mg taken orally 1x/day In those age ≥6 yrs, dose may be ↑ to 125 mg 1x/day after 24 wks of treatment. PROS = This medication has been approved specifically for the reduction of overgrowth, vascular lesions, and other functional complications. To date, it is unknown whether this drug has any efficacy in treating the neurologic manifestations of PROS (as, e.g., in MCAP syndrome). The tablet should be taken at approximately the same time every day A dose reduction back to 50 gm/day may be considered in those with an adverse reaction on the higher dose. Supportive treatment should ideally by provided through coordinated care from a multidisciplinary team including surgeons, radiologists, geneticists, dermatologists, pathologists, and hematologist/oncologist, the latter of whom are critical for emerging medical management and coordination of the associated long-term follow up [ Supportive Treatment of Manifestations in Individuals with If signs & symptoms of obstructive hydrocephalus or ↑ intracranial pressure Hydrocephalus may be more successfully treated in those w/MCAP via a 3rd ventriculostomy [Author, personal observation]. If signs & symptoms of cerebellar ectopia or syringomyelia Many affected persons have mild cerebellar tonsillar ectopia that may only require monitoring (see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder Education of parents/caregivers See also Capillary malformations seldom require mgmt; may fade w/time. Depending on severity, treatment can range from infusion of IV glucose to administration of sugar-containing drinks or snacks to cornstarch therapy. In some instances of persistent hypoglycemia, glucagon injections may be considered. Primarily affects neonates, though some persons may develop hypoglycemia later in life. In severe, persistent hypoglycemia, eval of the GH axis & HPA axis is indicated. Undertake careful follow up of linear growth & trajectory of overgrowth. Delay of GH therapy until after age 2 yrs has been suggested, avoiding the major period of brain growth. Further evidence is needed to determine relative risks & benefits of GH therapy in GH-deficient persons w/PROS. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GH = growth hormone; HPA = hypothalamic-pituitary-adrenal; OT = occupational therapy; PT = physical therapy Infants may have irritability, excessive drooling, difficulty swallowing, or breathing problems, especially central apnea. Children may have neck pain or headache, motor weakness, sensory changes, vision problems, swallowing difficulties, or behavioral changes. The severity of epilepsy varies depending on the nature and extent of cortical malformations, type of Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Ultrasound or MRI follow up in those w/truncal overgrowth Radiographs of limbs in those w/overgrowth of a limb or portion of a limb Spinal MRI in those w/scoliosis or deformities that affect the spine Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, & other signs/symptoms of Chiari malformation. Physical medicine, OT/PT assessment of mobility, self-help skills Clinical assessment for scoliosis GH = growth hormone; HPA = hypothalamic-pituitary-adrenal; OT = occupational therapy; PT = physical therapy Including leg length discrepancy If rapid growth of a specific body area is identified, consider targeted follow up, which may include other types of monitoring techniques, such as volumetric studies and angiography [ For those with CNS overgrowth or dysplasia: brain MRI every six months until age two years and then annually until age eight years to monitor specifically for progressive hydrocephalus and Chiari malformation [ Infants may have irritability, excessive drooling, difficulty swallowing, or breathing problems, especially central apnea. Children may have neck pain or headache, motor weakness, sensory changes, vision problems, swallowing difficulties, or behavioral changes. Team may include specialists in dermatology, interventional radiology, and hematology/oncology. Tumor screening for Wilms tumor is controversial, given the studies that suggest a frequency of Wilms tumor of between 1.4% and 3.3%. In the US, tumor screening is often undertaken if the tumor risk is 3% or greater. Further longitudinal studies are needed to evaluate the need for Wilms tumor screening in individuals with PROS. See Some studies have demonstrated the efficacy of the mammalian target of rapamycin (mTOR) inhibitor sirolimus for lymphatic diseases [ Search • Brain MRI in those w/megalencephaly to assess for cortical malformations, ventriculomegaly/hydrocephalus, & Chiari malformation (See • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Overgrowth of a limb or portion of a limb, foot abnormalities, splayed toes & spine abnormalities (incl spinal curvature) • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To assess for evidence of ↑ risk of thrombosis (esp in those w/venous malformations) & coagulopathy • D-dimer & fibrinogen levels may be a useful screen for thrombosis in those w/vascular malformations. • Community or • Social work involvement for parental support; • Home nursing referral. • Initial dose 50 mg taken orally 1x/day • In those age ≥6 yrs, dose may be ↑ to 125 mg 1x/day after 24 wks of treatment. • If signs & symptoms of obstructive hydrocephalus or ↑ intracranial pressure • Hydrocephalus may be more successfully treated in those w/MCAP via a 3rd ventriculostomy [Author, personal observation]. • If signs & symptoms of cerebellar ectopia or syringomyelia • Many affected persons have mild cerebellar tonsillar ectopia that may only require monitoring (see • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder • Education of parents/caregivers • See also • Capillary malformations seldom require mgmt; may fade w/time. • Depending on severity, treatment can range from infusion of IV glucose to administration of sugar-containing drinks or snacks to cornstarch therapy. • In some instances of persistent hypoglycemia, glucagon injections may be considered. • Primarily affects neonates, though some persons may develop hypoglycemia later in life. • In severe, persistent hypoglycemia, eval of the GH axis & HPA axis is indicated. • Undertake careful follow up of linear growth & trajectory of overgrowth. • Delay of GH therapy until after age 2 yrs has been suggested, avoiding the major period of brain growth. • Further evidence is needed to determine relative risks & benefits of GH therapy in GH-deficient persons w/PROS. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Ultrasound or MRI follow up in those w/truncal overgrowth • Radiographs of limbs in those w/overgrowth of a limb or portion of a limb • Spinal MRI in those w/scoliosis or deformities that affect the spine • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, & other signs/symptoms of Chiari malformation. • Physical medicine, OT/PT assessment of mobility, self-help skills • Clinical assessment for scoliosis ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual with Note: Assessment is complicated by variable findings in individuals with this condition. Accurate and thorough assessment of medical history is necessary to evaluate for vascular malformations as well as other clinical features. Recommended Evaluations Following Initial Diagnosis in Individuals with Brain MRI in those w/megalencephaly to assess for cortical malformations, ventriculomegaly/hydrocephalus, & Chiari malformation (See Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Overgrowth of a limb or portion of a limb, foot abnormalities, splayed toes & spine abnormalities (incl spinal curvature) Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To assess for evidence of ↑ risk of thrombosis (esp in those w/venous malformations) & coagulopathy D-dimer & fibrinogen levels may be a useful screen for thrombosis in those w/vascular malformations. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; EEG = electroencephalogram; GHD = growth hormone deficiency; IGF1 = insulin-like growth factor 1; IGFBP3 = insulin-like growth factor BP3; MOI = mode of inheritance; MRA = MR angiography; MRV = MR venography; OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid stimulation hormone The first episode of hypoglycemia can occur later in childhood. Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Brain MRI in those w/megalencephaly to assess for cortical malformations, ventriculomegaly/hydrocephalus, & Chiari malformation (See • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Overgrowth of a limb or portion of a limb, foot abnormalities, splayed toes & spine abnormalities (incl spinal curvature) • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To assess for evidence of ↑ risk of thrombosis (esp in those w/venous malformations) & coagulopathy • D-dimer & fibrinogen levels may be a useful screen for thrombosis in those w/vascular malformations. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Targeted Treatment of Initial dose 50 mg taken orally 1x/day In those age ≥6 yrs, dose may be ↑ to 125 mg 1x/day after 24 wks of treatment. PROS = This medication has been approved specifically for the reduction of overgrowth, vascular lesions, and other functional complications. To date, it is unknown whether this drug has any efficacy in treating the neurologic manifestations of PROS (as, e.g., in MCAP syndrome). The tablet should be taken at approximately the same time every day A dose reduction back to 50 gm/day may be considered in those with an adverse reaction on the higher dose. Supportive treatment should ideally by provided through coordinated care from a multidisciplinary team including surgeons, radiologists, geneticists, dermatologists, pathologists, and hematologist/oncologist, the latter of whom are critical for emerging medical management and coordination of the associated long-term follow up [ Supportive Treatment of Manifestations in Individuals with If signs & symptoms of obstructive hydrocephalus or ↑ intracranial pressure Hydrocephalus may be more successfully treated in those w/MCAP via a 3rd ventriculostomy [Author, personal observation]. If signs & symptoms of cerebellar ectopia or syringomyelia Many affected persons have mild cerebellar tonsillar ectopia that may only require monitoring (see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder Education of parents/caregivers See also Capillary malformations seldom require mgmt; may fade w/time. Depending on severity, treatment can range from infusion of IV glucose to administration of sugar-containing drinks or snacks to cornstarch therapy. In some instances of persistent hypoglycemia, glucagon injections may be considered. Primarily affects neonates, though some persons may develop hypoglycemia later in life. In severe, persistent hypoglycemia, eval of the GH axis & HPA axis is indicated. Undertake careful follow up of linear growth & trajectory of overgrowth. Delay of GH therapy until after age 2 yrs has been suggested, avoiding the major period of brain growth. Further evidence is needed to determine relative risks & benefits of GH therapy in GH-deficient persons w/PROS. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GH = growth hormone; HPA = hypothalamic-pituitary-adrenal; OT = occupational therapy; PT = physical therapy Infants may have irritability, excessive drooling, difficulty swallowing, or breathing problems, especially central apnea. Children may have neck pain or headache, motor weakness, sensory changes, vision problems, swallowing difficulties, or behavioral changes. The severity of epilepsy varies depending on the nature and extent of cortical malformations, type of Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Initial dose 50 mg taken orally 1x/day • In those age ≥6 yrs, dose may be ↑ to 125 mg 1x/day after 24 wks of treatment. • If signs & symptoms of obstructive hydrocephalus or ↑ intracranial pressure • Hydrocephalus may be more successfully treated in those w/MCAP via a 3rd ventriculostomy [Author, personal observation]. • If signs & symptoms of cerebellar ectopia or syringomyelia • Many affected persons have mild cerebellar tonsillar ectopia that may only require monitoring (see • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder • Education of parents/caregivers • See also • Capillary malformations seldom require mgmt; may fade w/time. • Depending on severity, treatment can range from infusion of IV glucose to administration of sugar-containing drinks or snacks to cornstarch therapy. • In some instances of persistent hypoglycemia, glucagon injections may be considered. • Primarily affects neonates, though some persons may develop hypoglycemia later in life. • In severe, persistent hypoglycemia, eval of the GH axis & HPA axis is indicated. • Undertake careful follow up of linear growth & trajectory of overgrowth. • Delay of GH therapy until after age 2 yrs has been suggested, avoiding the major period of brain growth. • Further evidence is needed to determine relative risks & benefits of GH therapy in GH-deficient persons w/PROS. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Targeted Therapy There is no cure for Targeted Treatment of Initial dose 50 mg taken orally 1x/day In those age ≥6 yrs, dose may be ↑ to 125 mg 1x/day after 24 wks of treatment. PROS = This medication has been approved specifically for the reduction of overgrowth, vascular lesions, and other functional complications. To date, it is unknown whether this drug has any efficacy in treating the neurologic manifestations of PROS (as, e.g., in MCAP syndrome). The tablet should be taken at approximately the same time every day A dose reduction back to 50 gm/day may be considered in those with an adverse reaction on the higher dose. • Initial dose 50 mg taken orally 1x/day • In those age ≥6 yrs, dose may be ↑ to 125 mg 1x/day after 24 wks of treatment. ## Supportive Care Supportive treatment should ideally by provided through coordinated care from a multidisciplinary team including surgeons, radiologists, geneticists, dermatologists, pathologists, and hematologist/oncologist, the latter of whom are critical for emerging medical management and coordination of the associated long-term follow up [ Supportive Treatment of Manifestations in Individuals with If signs & symptoms of obstructive hydrocephalus or ↑ intracranial pressure Hydrocephalus may be more successfully treated in those w/MCAP via a 3rd ventriculostomy [Author, personal observation]. If signs & symptoms of cerebellar ectopia or syringomyelia Many affected persons have mild cerebellar tonsillar ectopia that may only require monitoring (see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder Education of parents/caregivers See also Capillary malformations seldom require mgmt; may fade w/time. Depending on severity, treatment can range from infusion of IV glucose to administration of sugar-containing drinks or snacks to cornstarch therapy. In some instances of persistent hypoglycemia, glucagon injections may be considered. Primarily affects neonates, though some persons may develop hypoglycemia later in life. In severe, persistent hypoglycemia, eval of the GH axis & HPA axis is indicated. Undertake careful follow up of linear growth & trajectory of overgrowth. Delay of GH therapy until after age 2 yrs has been suggested, avoiding the major period of brain growth. Further evidence is needed to determine relative risks & benefits of GH therapy in GH-deficient persons w/PROS. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; GH = growth hormone; HPA = hypothalamic-pituitary-adrenal; OT = occupational therapy; PT = physical therapy Infants may have irritability, excessive drooling, difficulty swallowing, or breathing problems, especially central apnea. Children may have neck pain or headache, motor weakness, sensory changes, vision problems, swallowing difficulties, or behavioral changes. The severity of epilepsy varies depending on the nature and extent of cortical malformations, type of Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • If signs & symptoms of obstructive hydrocephalus or ↑ intracranial pressure • Hydrocephalus may be more successfully treated in those w/MCAP via a 3rd ventriculostomy [Author, personal observation]. • If signs & symptoms of cerebellar ectopia or syringomyelia • Many affected persons have mild cerebellar tonsillar ectopia that may only require monitoring (see • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder • Education of parents/caregivers • See also • Capillary malformations seldom require mgmt; may fade w/time. • Depending on severity, treatment can range from infusion of IV glucose to administration of sugar-containing drinks or snacks to cornstarch therapy. • In some instances of persistent hypoglycemia, glucagon injections may be considered. • Primarily affects neonates, though some persons may develop hypoglycemia later in life. • In severe, persistent hypoglycemia, eval of the GH axis & HPA axis is indicated. • Undertake careful follow up of linear growth & trajectory of overgrowth. • Delay of GH therapy until after age 2 yrs has been suggested, avoiding the major period of brain growth. • Further evidence is needed to determine relative risks & benefits of GH therapy in GH-deficient persons w/PROS. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one-on-one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Ultrasound or MRI follow up in those w/truncal overgrowth Radiographs of limbs in those w/overgrowth of a limb or portion of a limb Spinal MRI in those w/scoliosis or deformities that affect the spine Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, & other signs/symptoms of Chiari malformation. Physical medicine, OT/PT assessment of mobility, self-help skills Clinical assessment for scoliosis GH = growth hormone; HPA = hypothalamic-pituitary-adrenal; OT = occupational therapy; PT = physical therapy Including leg length discrepancy If rapid growth of a specific body area is identified, consider targeted follow up, which may include other types of monitoring techniques, such as volumetric studies and angiography [ For those with CNS overgrowth or dysplasia: brain MRI every six months until age two years and then annually until age eight years to monitor specifically for progressive hydrocephalus and Chiari malformation [ Infants may have irritability, excessive drooling, difficulty swallowing, or breathing problems, especially central apnea. Children may have neck pain or headache, motor weakness, sensory changes, vision problems, swallowing difficulties, or behavioral changes. Team may include specialists in dermatology, interventional radiology, and hematology/oncology. Tumor screening for Wilms tumor is controversial, given the studies that suggest a frequency of Wilms tumor of between 1.4% and 3.3%. In the US, tumor screening is often undertaken if the tumor risk is 3% or greater. Further longitudinal studies are needed to evaluate the need for Wilms tumor screening in individuals with PROS. • Ultrasound or MRI follow up in those w/truncal overgrowth • Radiographs of limbs in those w/overgrowth of a limb or portion of a limb • Spinal MRI in those w/scoliosis or deformities that affect the spine • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, & other signs/symptoms of Chiari malformation. • Physical medicine, OT/PT assessment of mobility, self-help skills • Clinical assessment for scoliosis ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Some studies have demonstrated the efficacy of the mammalian target of rapamycin (mTOR) inhibitor sirolimus for lymphatic diseases [ Search ## Genetic Counseling Parents of children with somatic mosaicism for a pathogenic variant in Theoretically, a parent of a child with PROS caused by a The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in The risk to sibs of a proband with a Reproductive outcome data on adults with PROS are limited; there are no instances of vertical transmission of these disorders. While adults with PROS have been reported, the developmental outcome of affected individuals is unknown. Individuals with significant neurologic involvement (e.g., DMEG, HMEG) have a poor prognosis. All but a few affected individuals with PROS have had somatic mosaicism for a Several individuals with PROS have had a Counseling for recurrence risk in PROS should emphasize that, while no pregnancy is at zero risk, all empiric evidence suggests that the risk for recurrence in sibs of a proband is not increased over that of the general population, due to the mosaic nature of most of these disorders. The rare families with PROS caused by a The optimal time for determination of genetic risk is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. In addition, molecular genetic prenatal testing may be an option for pregnancies identified by ultrasound examination to be at risk for PROS. Findings on ultrasound examination that suggest MCAP syndrome include marked fetal overgrowth and progressive macrocephaly with no indication of maternal hyperglycemia or fetal hyperinsulinism. Other reported fetal ultrasound findings include ventriculomegaly, pleural effusions, polyhydramnios, hydrops, limb asymmetry, and frontal bossing [ Findings on prenatal ultrasound examination in CLOVES syndrome include prenatal overgrowth, lipomatous truncal masses, and vascular or lymphatic malformations [ • Parents of children with somatic mosaicism for a pathogenic variant in • Theoretically, a parent of a child with PROS caused by a • The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in • The risk to sibs of a proband with a • Reproductive outcome data on adults with PROS are limited; there are no instances of vertical transmission of these disorders. While adults with PROS have been reported, the developmental outcome of affected individuals is unknown. Individuals with significant neurologic involvement (e.g., DMEG, HMEG) have a poor prognosis. • All but a few affected individuals with PROS have had somatic mosaicism for a • Several individuals with PROS have had a • Counseling for recurrence risk in PROS should emphasize that, while no pregnancy is at zero risk, all empiric evidence suggests that the risk for recurrence in sibs of a proband is not increased over that of the general population, due to the mosaic nature of most of these disorders. The rare families with PROS caused by a • The optimal time for determination of genetic risk is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Findings on ultrasound examination that suggest MCAP syndrome include marked fetal overgrowth and progressive macrocephaly with no indication of maternal hyperglycemia or fetal hyperinsulinism. Other reported fetal ultrasound findings include ventriculomegaly, pleural effusions, polyhydramnios, hydrops, limb asymmetry, and frontal bossing [ • Findings on prenatal ultrasound examination in CLOVES syndrome include prenatal overgrowth, lipomatous truncal masses, and vascular or lymphatic malformations [ ## Mode of Inheritance ## Risk to Family Members Parents of children with somatic mosaicism for a pathogenic variant in Theoretically, a parent of a child with PROS caused by a The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in The risk to sibs of a proband with a Reproductive outcome data on adults with PROS are limited; there are no instances of vertical transmission of these disorders. While adults with PROS have been reported, the developmental outcome of affected individuals is unknown. Individuals with significant neurologic involvement (e.g., DMEG, HMEG) have a poor prognosis. All but a few affected individuals with PROS have had somatic mosaicism for a Several individuals with PROS have had a • Parents of children with somatic mosaicism for a pathogenic variant in • Theoretically, a parent of a child with PROS caused by a • The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in • The risk to sibs of a proband with a • Reproductive outcome data on adults with PROS are limited; there are no instances of vertical transmission of these disorders. While adults with PROS have been reported, the developmental outcome of affected individuals is unknown. Individuals with significant neurologic involvement (e.g., DMEG, HMEG) have a poor prognosis. • All but a few affected individuals with PROS have had somatic mosaicism for a • Several individuals with PROS have had a ## Related Genetic Counseling Issues Counseling for recurrence risk in PROS should emphasize that, while no pregnancy is at zero risk, all empiric evidence suggests that the risk for recurrence in sibs of a proband is not increased over that of the general population, due to the mosaic nature of most of these disorders. The rare families with PROS caused by a The optimal time for determination of genetic risk is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Counseling for recurrence risk in PROS should emphasize that, while no pregnancy is at zero risk, all empiric evidence suggests that the risk for recurrence in sibs of a proband is not increased over that of the general population, due to the mosaic nature of most of these disorders. The rare families with PROS caused by a • The optimal time for determination of genetic risk is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Prenatal Testing and Preimplantation Genetic Testing In addition, molecular genetic prenatal testing may be an option for pregnancies identified by ultrasound examination to be at risk for PROS. Findings on ultrasound examination that suggest MCAP syndrome include marked fetal overgrowth and progressive macrocephaly with no indication of maternal hyperglycemia or fetal hyperinsulinism. Other reported fetal ultrasound findings include ventriculomegaly, pleural effusions, polyhydramnios, hydrops, limb asymmetry, and frontal bossing [ Findings on prenatal ultrasound examination in CLOVES syndrome include prenatal overgrowth, lipomatous truncal masses, and vascular or lymphatic malformations [ • Findings on ultrasound examination that suggest MCAP syndrome include marked fetal overgrowth and progressive macrocephaly with no indication of maternal hyperglycemia or fetal hyperinsulinism. Other reported fetal ultrasound findings include ventriculomegaly, pleural effusions, polyhydramnios, hydrops, limb asymmetry, and frontal bossing [ • Findings on prenatal ultrasound examination in CLOVES syndrome include prenatal overgrowth, lipomatous truncal masses, and vascular or lymphatic malformations [ ## Resources PO BOX 406 West Kennebunk 04094 PO Box 97 Chatham NY 12037 • • PO BOX 406 • West Kennebunk 04094 • • • PO Box 97 • Chatham NY 12037 • • • • ## Molecular Genetics PIK3CA-Related Overgrowth Spectrum: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PIK3CA-Related Overgrowth Spectrum ( The PIK3CA protein is critical for the action of insulin to lower blood glucose, and for the action of insulin-like growth factor 1 (IGF1), which promotes tissue growth through a receptor closely similar to the insulin receptor, and which mediates many actions of growth hormone. Pathologically activated PIK3CA may mimic the action of insulin and/or IGF1 in cells. For such a mechanism to translate into a clinically important endocrinopathy, target tissues need to have a high variant burden. This mechanism may explain why some affected infants have clinical features similar to hyperinsulinism. In order to detect new or very rare variants, sequencing of entire exons is typically necessary. Sanger sequencing can be used only if the pathogenic variant allele fraction is relatively high (~20%). Targeted capture of the entire In MCAP syndrome, sequence analysis of DNA derived from saliva or skin fibroblasts (whether visibly affected or not) has a higher detection rate than peripheral blood-derived DNA [ In focal brain overgrowth disorders (HMEG, FCD, DMEG), analysis of DNA derived from affected brain tissues (for example, removed at the time of epilepsy surgery) has a higher detection rate than peripheral tissues (blood or saliva) [ Notable Variants listed in the table have been provided by the authors. CLOVES syndrome, fibroadipose hyperplasia, lymphatic/vascular malformations, hemimegalencephaly, and focal cortical dysplasia (See Most (>80%) activating Among the approximately 160 Common Cancer-Related • In order to detect new or very rare variants, sequencing of entire exons is typically necessary. • Sanger sequencing can be used only if the pathogenic variant allele fraction is relatively high (~20%). • Targeted capture of the entire • In MCAP syndrome, sequence analysis of DNA derived from saliva or skin fibroblasts (whether visibly affected or not) has a higher detection rate than peripheral blood-derived DNA [ • In focal brain overgrowth disorders (HMEG, FCD, DMEG), analysis of DNA derived from affected brain tissues (for example, removed at the time of epilepsy surgery) has a higher detection rate than peripheral tissues (blood or saliva) [ ## Molecular Pathogenesis The PIK3CA protein is critical for the action of insulin to lower blood glucose, and for the action of insulin-like growth factor 1 (IGF1), which promotes tissue growth through a receptor closely similar to the insulin receptor, and which mediates many actions of growth hormone. Pathologically activated PIK3CA may mimic the action of insulin and/or IGF1 in cells. For such a mechanism to translate into a clinically important endocrinopathy, target tissues need to have a high variant burden. This mechanism may explain why some affected infants have clinical features similar to hyperinsulinism. In order to detect new or very rare variants, sequencing of entire exons is typically necessary. Sanger sequencing can be used only if the pathogenic variant allele fraction is relatively high (~20%). Targeted capture of the entire In MCAP syndrome, sequence analysis of DNA derived from saliva or skin fibroblasts (whether visibly affected or not) has a higher detection rate than peripheral blood-derived DNA [ In focal brain overgrowth disorders (HMEG, FCD, DMEG), analysis of DNA derived from affected brain tissues (for example, removed at the time of epilepsy surgery) has a higher detection rate than peripheral tissues (blood or saliva) [ Notable Variants listed in the table have been provided by the authors. CLOVES syndrome, fibroadipose hyperplasia, lymphatic/vascular malformations, hemimegalencephaly, and focal cortical dysplasia (See • In order to detect new or very rare variants, sequencing of entire exons is typically necessary. • Sanger sequencing can be used only if the pathogenic variant allele fraction is relatively high (~20%). • Targeted capture of the entire • In MCAP syndrome, sequence analysis of DNA derived from saliva or skin fibroblasts (whether visibly affected or not) has a higher detection rate than peripheral blood-derived DNA [ • In focal brain overgrowth disorders (HMEG, FCD, DMEG), analysis of DNA derived from affected brain tissues (for example, removed at the time of epilepsy surgery) has a higher detection rate than peripheral tissues (blood or saliva) [ ## Cancer and Benign Tumors Most (>80%) activating Among the approximately 160 Common Cancer-Related ## Chapter Notes Dr Ghayda Mirzaa is an Associate Professor of Medical Genetics and Pediatrics at the University of Washington School of Medicine. Her research is focused on developmental brain disorders including megalencephaly with multiple publications related to Dr John M Graham Jr is a Professor Emeritus of Pediatrics at David Geffen School of Medicine at UCLA and Consulting Clinical Geneticist at Cedars-Sinai Medical Center and Harbor UCLA Medical Center. He has had a long-term clinical interest in PROS with many publications on this topic. Dr Kim Keppler-Noreuil is a clinical geneticist and Division Chief of Genetics & Metabolism at the University of Wisconsin School of Medicine and Public Health; she has multiple publications related to PROS, including invited review articles and original research focused particularly on the clinical and molecular diagnosis, and potential therapies for PROS. We would like to thank the patients, their families, and our collaborators for their valuable contribution to our knowledge about these disorders. Robert Conway, MD; Wayne State University (2013-2021)Willliam B Dobyns, MD; Seattle Childfren's Hospital (2013-2021)John H Graham Jr, MD, ScD (2013-present)Kim Keppler-Noreuil, MD, FAAP, FACMG (2021-present)Ghayda Mirzaa, MD, FAAP, FACMG (2013-present) 6 April 2023 (ma/aa) Revision: expanded information on 25 August 2022 (aa) Revision: FDA approval of alpelisib for treatment of PROS ( 23 December 2021 (ma) Comprehensive update posted live 15 August 2013 (me) Review posted live 11 March 2013 (gm) Original submission • 6 April 2023 (ma/aa) Revision: expanded information on • 25 August 2022 (aa) Revision: FDA approval of alpelisib for treatment of PROS ( • 23 December 2021 (ma) Comprehensive update posted live • 15 August 2013 (me) Review posted live • 11 March 2013 (gm) Original submission ## Author Notes Dr Ghayda Mirzaa is an Associate Professor of Medical Genetics and Pediatrics at the University of Washington School of Medicine. Her research is focused on developmental brain disorders including megalencephaly with multiple publications related to Dr John M Graham Jr is a Professor Emeritus of Pediatrics at David Geffen School of Medicine at UCLA and Consulting Clinical Geneticist at Cedars-Sinai Medical Center and Harbor UCLA Medical Center. He has had a long-term clinical interest in PROS with many publications on this topic. Dr Kim Keppler-Noreuil is a clinical geneticist and Division Chief of Genetics & Metabolism at the University of Wisconsin School of Medicine and Public Health; she has multiple publications related to PROS, including invited review articles and original research focused particularly on the clinical and molecular diagnosis, and potential therapies for PROS. ## Acknowledgments We would like to thank the patients, their families, and our collaborators for their valuable contribution to our knowledge about these disorders. ## Author History Robert Conway, MD; Wayne State University (2013-2021)Willliam B Dobyns, MD; Seattle Childfren's Hospital (2013-2021)John H Graham Jr, MD, ScD (2013-present)Kim Keppler-Noreuil, MD, FAAP, FACMG (2021-present)Ghayda Mirzaa, MD, FAAP, FACMG (2013-present) ## Revision History 6 April 2023 (ma/aa) Revision: expanded information on 25 August 2022 (aa) Revision: FDA approval of alpelisib for treatment of PROS ( 23 December 2021 (ma) Comprehensive update posted live 15 August 2013 (me) Review posted live 11 March 2013 (gm) Original submission • 6 April 2023 (ma/aa) Revision: expanded information on • 25 August 2022 (aa) Revision: FDA approval of alpelisib for treatment of PROS ( • 23 December 2021 (ma) Comprehensive update posted live • 15 August 2013 (me) Review posted live • 11 March 2013 (gm) Original submission ## Key Sections in this ## References ## Literature Cited Characteristic brain MRI of MCAP syndrome in three individuals (A-D, E-H, and I-L). Note: Megalencephaly with a prominent forehead (A, E, I); cerebellar tonsillar ectopia with a large cerebellum and crowded posterior fossa (A, E, I); ventriculomegaly (G) and hydrocephalus (J, K, L); and bilateral perisylvian polymicrogyria (B, D, F, G, H, K, and L). From	[]	15/8/2013	23/12/2021	6/4/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pink1-pd	pink1-pd	[ "PARK-PINK1", "PARK-PINK1", "Serine/threonine-protein kinase PINK1, mitochondrial", "PINK1", "PINK1 Type of Young-Onset Parkinson Disease" ]		Lara M Lange, Christine Klein	Summary The diagnosis of	## Diagnosis Updated guidelines on the molecular diagnosis of Parkinson disease were provided in a joint effort by the European Federation of Neurological Societies (EFNS), the European Section of the International Parkinson and Movement Disorders Society (MDS-ES), and the European Neurological Society (ENS) [ In addition, new diagnostic criteria using a biological classification referred to as SynNeurGe have been published [ Early onset. Onset is age <40 years in 57%; late onset (27%) and juvenile onset (16%) can also occur. Parkinsonism (bradykinesia, resting tremor, rigidity) Dyskinesia Motor fluctuations Dystonia Cognitive decline Psychiatric manifestations Good response to levodopa (L-dopa) treatment (in 98% of individuals with a reported L-dopa response) The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making [ Because the phenotype of Note: (1) For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in the interpretation of sequence analysis results, click Data derived from the subscription-based professional view of the Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Early onset. Onset is age <40 years in 57%; late onset (27%) and juvenile onset (16%) can also occur. • Parkinsonism (bradykinesia, resting tremor, rigidity) • Dyskinesia • Motor fluctuations • Dystonia • Cognitive decline • Psychiatric manifestations • Good response to levodopa (L-dopa) treatment (in 98% of individuals with a reported L-dopa response) ## Suggestive Findings Early onset. Onset is age <40 years in 57%; late onset (27%) and juvenile onset (16%) can also occur. Parkinsonism (bradykinesia, resting tremor, rigidity) Dyskinesia Motor fluctuations Dystonia Cognitive decline Psychiatric manifestations Good response to levodopa (L-dopa) treatment (in 98% of individuals with a reported L-dopa response) • Early onset. Onset is age <40 years in 57%; late onset (27%) and juvenile onset (16%) can also occur. • Parkinsonism (bradykinesia, resting tremor, rigidity) • Dyskinesia • Motor fluctuations • Dystonia • Cognitive decline • Psychiatric manifestations • Good response to levodopa (L-dopa) treatment (in 98% of individuals with a reported L-dopa response) ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making [ Because the phenotype of Note: (1) For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in the interpretation of sequence analysis results, click Data derived from the subscription-based professional view of the Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in the interpretation of sequence analysis results, click Data derived from the subscription-based professional view of the Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics Data is based on 205 reported individuals identified through the MDSGene Information on the occurrence of The evidence of heterozygous Several individuals with Parkinson disease and a heterozygous No correlation between the type of variant and age at onset, clinical presentation, or disease progression has yet been observed. Further, one individual with biallelic Biallelic Based on the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by The prevalence is not known. The proportion of women among individuals with ## Clinical Description Data is based on 205 reported individuals identified through the MDSGene Information on the occurrence of The evidence of heterozygous Several individuals with Parkinson disease and a heterozygous ## Heterozygotes The evidence of heterozygous Several individuals with Parkinson disease and a heterozygous ## Genotype-Phenotype Correlations No correlation between the type of variant and age at onset, clinical presentation, or disease progression has yet been observed. Further, one individual with biallelic ## Penetrance Biallelic ## Nomenclature Based on the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by ## Prevalence The prevalence is not known. The proportion of women among individuals with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Clinically, Genes Associated with Early-Onset Autosomal Recessive Parkinson Disease in the Differential Diagnosis of Most common cause of EOPD PARK- Phenotype similar to PARK- IDD &/or seizures occasionally Pyramidal signs IDD / early cognitive impairment Early & vivid hallucinations on intake of dopamine agonists Early falls Saccadic abnormalities Pyramidal signs IDD / early cognitive impairment Early & vivid hallucinations & behavioral abnormalities on intake of dopamine agonists Early falls Saccadic abnormalities Gaze palsy Oculogyric spasms Pyramidal signs Autonomic dysfunction Early cognitive impairment Early falls Saccadic abnormalities Gaze palsy Pyramidal signs Ataxia Autonomic dysfunction Early cognitive impairment Early falls Pyramidal signs Autonomic dysfunction EOPD = early-onset Parkinson disease; IDD = intellectual developmental disorder Nomenclature based on Data based on Tyrosine hydroxylase-deficient dopa-responsive dystonia (see Sepiapterin reductase-deficient dopa-responsive dystonia (see In general, the phenotype of tyrosine hydroxylase-deficient dopa-responsive dystonia and sepiapterin reductase-deficient dopa-responsive dystonia is much more severe. • Most common cause of EOPD • PARK- • Phenotype similar to PARK- • IDD &/or seizures occasionally • Pyramidal signs • IDD / early cognitive impairment • Early & vivid hallucinations on intake of dopamine agonists • Early falls • Saccadic abnormalities • Pyramidal signs • IDD / early cognitive impairment • Early & vivid hallucinations & behavioral abnormalities on intake of dopamine agonists • Early falls • Saccadic abnormalities • Gaze palsy • Oculogyric spasms • Pyramidal signs • Autonomic dysfunction • Early cognitive impairment • Early falls • Saccadic abnormalities • Gaze palsy • Pyramidal signs • Ataxia • Autonomic dysfunction • Early cognitive impairment • Early falls • Pyramidal signs • Autonomic dysfunction • Tyrosine hydroxylase-deficient dopa-responsive dystonia (see • Sepiapterin reductase-deficient dopa-responsive dystonia (see ## Management No clinical practice guidelines specifically for To establish the extent of disease and needs in an individual diagnosed with Nutritional eval by dietician to monitor & ensure adequate caloric intake SLP assessment of safety of feeding Community or Social work referral Home nursing referral MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SLP = speech-language therapist Goetz et al2008] Medical geneticist, certified genetic counselor, certified advanced genetic nurse To date, the treatment of To date, no therapy can slow or stop the progression of Parkinson disease; available treatment options are purely symptomatic. In general, optimal management should begin at diagnosis and involve a multidisciplinary team approach, including pharmacologic and non-pharmacologic interventions [ Immediate-release (IR) tablets Disintegrating tablets Controlled-release (CR) tablets Extended-release (ER) capsules Inhalation powder IR & CR tablets Subcutaneous injections (apomorphine) Transdermal patch (rotigotine) Response to L-dopa is usually significant & sustained for low doses even after long disease duration in persons w/ The major problem is the early occurrence of severe L-dopa-induced dyskinesias (abnormal involuntary movements) & fluctuations. Fluctuations can be ↓ by a combination of dopamine therapies (e.g., dopamine agonists), adding COMT inhibitors, & keeping the doses of L-dopa as low as possible. PT &/or OT to improve &/or maintain gross motor & fine motor skills. Speech therapy Intrajejunal L-dopa-carbidopa pump Subcutaneous apomorphine pump DBS (preferably STN-DBS) Can be considered for advanced stages w/fluctuations not satisfactorily controlled w/oral medications. STN-DBS improves motor symptoms & quality of life. The use of DBS was reported to be successful in 4/5 persons w/ Reduction of L-dopa dose Dopamine receptor agonists DBS Continuous application of L-dopa or apomorphine (pump therapies) Atypical neuroleptic agents such as low-dose clozapine, quetiapine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations. Standard treatments for depression COMT = catechol-O-methyltransferase; DBS = deep brain stimulation; MAO-B = monoamine oxidase-B; OT = occupational therapy; PT = physical therapy; STN = subthalamic nucleus Treatment recommendations on invasive therapies based on the recent EAS/MDS-ES guidelines [ According to the most recent review [ Assessment of presence/severity of atypical manifestations Assessment of need for PT, OT, & speech therapy Nutritional eval by dietician to monitor & ensure adequate caloric intake SLP assessment of safety of feeding Assess for symptoms of orthostasis. Measure supine & standing blood pressure & pulse. Assess for constipation, urinary urgency, or urge incontinence. Community or online resources Social work support; Home nursing referral. OT = occupational therapy; PT = physical therapy Neuroleptic treatment may exacerbate parkinsonism. See There is only a single case report of a woman with biallelic In general, data on pregnancy in individuals with Parkinson disease is rare, since age of onset is often after the childbearing years. Historically, it was reported that parkinsonian symptoms may exacerbate during pregnancy, but this may be because antiparkinsonian medications were not recommended or were underdosed [ See Search • Nutritional eval by dietician to monitor & ensure adequate caloric intake • SLP assessment of safety of feeding • Community or • Social work referral • Home nursing referral • Immediate-release (IR) tablets • Disintegrating tablets • Controlled-release (CR) tablets • Extended-release (ER) capsules • Inhalation powder • IR & CR tablets • Subcutaneous injections (apomorphine) • Transdermal patch (rotigotine) • Response to L-dopa is usually significant & sustained for low doses even after long disease duration in persons w/ • The major problem is the early occurrence of severe L-dopa-induced dyskinesias (abnormal involuntary movements) & fluctuations. Fluctuations can be ↓ by a combination of dopamine therapies (e.g., dopamine agonists), adding COMT inhibitors, & keeping the doses of L-dopa as low as possible. • PT &/or OT to improve &/or maintain gross motor & fine motor skills. • Speech therapy • Intrajejunal L-dopa-carbidopa pump • Subcutaneous apomorphine pump • DBS (preferably STN-DBS) • Can be considered for advanced stages w/fluctuations not satisfactorily controlled w/oral medications. • STN-DBS improves motor symptoms & quality of life. • The use of DBS was reported to be successful in 4/5 persons w/ • Reduction of L-dopa dose • Dopamine receptor agonists • DBS • Continuous application of L-dopa or apomorphine (pump therapies) • Atypical neuroleptic agents such as low-dose clozapine, quetiapine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations. • Standard treatments for depression • Assessment of presence/severity of atypical manifestations • Assessment of need for PT, OT, & speech therapy • Nutritional eval by dietician to monitor & ensure adequate caloric intake • SLP assessment of safety of feeding • Assess for symptoms of orthostasis. • Measure supine & standing blood pressure & pulse. • Assess for constipation, urinary urgency, or urge incontinence. • Community or online resources • Social work support; • Home nursing referral. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Nutritional eval by dietician to monitor & ensure adequate caloric intake SLP assessment of safety of feeding Community or Social work referral Home nursing referral MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SLP = speech-language therapist Goetz et al2008] Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Nutritional eval by dietician to monitor & ensure adequate caloric intake • SLP assessment of safety of feeding • Community or • Social work referral • Home nursing referral ## Treatment of Manifestations To date, the treatment of To date, no therapy can slow or stop the progression of Parkinson disease; available treatment options are purely symptomatic. In general, optimal management should begin at diagnosis and involve a multidisciplinary team approach, including pharmacologic and non-pharmacologic interventions [ Immediate-release (IR) tablets Disintegrating tablets Controlled-release (CR) tablets Extended-release (ER) capsules Inhalation powder IR & CR tablets Subcutaneous injections (apomorphine) Transdermal patch (rotigotine) Response to L-dopa is usually significant & sustained for low doses even after long disease duration in persons w/ The major problem is the early occurrence of severe L-dopa-induced dyskinesias (abnormal involuntary movements) & fluctuations. Fluctuations can be ↓ by a combination of dopamine therapies (e.g., dopamine agonists), adding COMT inhibitors, & keeping the doses of L-dopa as low as possible. PT &/or OT to improve &/or maintain gross motor & fine motor skills. Speech therapy Intrajejunal L-dopa-carbidopa pump Subcutaneous apomorphine pump DBS (preferably STN-DBS) Can be considered for advanced stages w/fluctuations not satisfactorily controlled w/oral medications. STN-DBS improves motor symptoms & quality of life. The use of DBS was reported to be successful in 4/5 persons w/ Reduction of L-dopa dose Dopamine receptor agonists DBS Continuous application of L-dopa or apomorphine (pump therapies) Atypical neuroleptic agents such as low-dose clozapine, quetiapine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations. Standard treatments for depression COMT = catechol-O-methyltransferase; DBS = deep brain stimulation; MAO-B = monoamine oxidase-B; OT = occupational therapy; PT = physical therapy; STN = subthalamic nucleus Treatment recommendations on invasive therapies based on the recent EAS/MDS-ES guidelines [ According to the most recent review [ • Immediate-release (IR) tablets • Disintegrating tablets • Controlled-release (CR) tablets • Extended-release (ER) capsules • Inhalation powder • IR & CR tablets • Subcutaneous injections (apomorphine) • Transdermal patch (rotigotine) • Response to L-dopa is usually significant & sustained for low doses even after long disease duration in persons w/ • The major problem is the early occurrence of severe L-dopa-induced dyskinesias (abnormal involuntary movements) & fluctuations. Fluctuations can be ↓ by a combination of dopamine therapies (e.g., dopamine agonists), adding COMT inhibitors, & keeping the doses of L-dopa as low as possible. • PT &/or OT to improve &/or maintain gross motor & fine motor skills. • Speech therapy • Intrajejunal L-dopa-carbidopa pump • Subcutaneous apomorphine pump • DBS (preferably STN-DBS) • Can be considered for advanced stages w/fluctuations not satisfactorily controlled w/oral medications. • STN-DBS improves motor symptoms & quality of life. • The use of DBS was reported to be successful in 4/5 persons w/ • Reduction of L-dopa dose • Dopamine receptor agonists • DBS • Continuous application of L-dopa or apomorphine (pump therapies) • Atypical neuroleptic agents such as low-dose clozapine, quetiapine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations. • Standard treatments for depression ## Surveillance Assessment of presence/severity of atypical manifestations Assessment of need for PT, OT, & speech therapy Nutritional eval by dietician to monitor & ensure adequate caloric intake SLP assessment of safety of feeding Assess for symptoms of orthostasis. Measure supine & standing blood pressure & pulse. Assess for constipation, urinary urgency, or urge incontinence. Community or online resources Social work support; Home nursing referral. OT = occupational therapy; PT = physical therapy • Assessment of presence/severity of atypical manifestations • Assessment of need for PT, OT, & speech therapy • Nutritional eval by dietician to monitor & ensure adequate caloric intake • SLP assessment of safety of feeding • Assess for symptoms of orthostasis. • Measure supine & standing blood pressure & pulse. • Assess for constipation, urinary urgency, or urge incontinence. • Community or online resources • Social work support; • Home nursing referral. ## Agents/Circumstances to Avoid Neuroleptic treatment may exacerbate parkinsonism. ## Evaluation of Relatives at Risk See ## Pregnancy Management There is only a single case report of a woman with biallelic In general, data on pregnancy in individuals with Parkinson disease is rare, since age of onset is often after the childbearing years. Historically, it was reported that parkinsonian symptoms may exacerbate during pregnancy, but this may be because antiparkinsonian medications were not recommended or were underdosed [ See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single If both parents are known to be heterozygous for a The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single Heterozygote testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single If both parents are known to be heterozygous for a The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • The risk to heterozygotes of developing symptoms is not yet determined; however, several individuals with parkinsonism who have a single ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics PINK1 Type of Young-Onset Parkinson Disease : Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PINK1 Type of Young-Onset Parkinson Disease ( Most of the known pathogenic variants are localized within the serine/threonine kinase domain of Overexpression of parkin can rescue the effects of a ## Molecular Pathogenesis Most of the known pathogenic variants are localized within the serine/threonine kinase domain of Overexpression of parkin can rescue the effects of a ## Chapter Notes Lara M Lange, MD ( Lara M Lange and Christine Klein are also interested in hearing from clinicians treating families affected by Parkinson disease in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Lara M Lange or Prof Christine Klein to inquire about the review of Lara M Lange and Christine Klein would like to thank Susanne Schneider for her previous engagement in the Lara M Lange acknowledges support from the Bachmann-Strauss Dystonia and Parkinson Foundation. Christine Klein acknowledges support from the Aligning Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2), The Michael J Fox Foundation (MJFF), and the German Research Foundation (FOR2488). Christine Klein, MD (2010-present)Lara M Lange, MD (2024-present)Susanne A Schneider, MD, PhD; Ludwig Maximilian University Munich (2010-2024) 25 April 2024 (sw) Comprehensive update posted live 24 May 2018 (sw) Comprehensive update posted live 18 September 2014 (me) Comprehensive update posted live 6 September 2012 (me) Comprehensive update posted live 16 March 2010 (me) Review posted live 1 December 2009 (ck) Original submission • 25 April 2024 (sw) Comprehensive update posted live • 24 May 2018 (sw) Comprehensive update posted live • 18 September 2014 (me) Comprehensive update posted live • 6 September 2012 (me) Comprehensive update posted live • 16 March 2010 (me) Review posted live • 1 December 2009 (ck) Original submission ## Author Notes Lara M Lange, MD ( Lara M Lange and Christine Klein are also interested in hearing from clinicians treating families affected by Parkinson disease in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Contact Dr Lara M Lange or Prof Christine Klein to inquire about the review of ## Acknowledgments Lara M Lange and Christine Klein would like to thank Susanne Schneider for her previous engagement in the Lara M Lange acknowledges support from the Bachmann-Strauss Dystonia and Parkinson Foundation. Christine Klein acknowledges support from the Aligning Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2), The Michael J Fox Foundation (MJFF), and the German Research Foundation (FOR2488). ## Author History Christine Klein, MD (2010-present)Lara M Lange, MD (2024-present)Susanne A Schneider, MD, PhD; Ludwig Maximilian University Munich (2010-2024) ## Revision History 25 April 2024 (sw) Comprehensive update posted live 24 May 2018 (sw) Comprehensive update posted live 18 September 2014 (me) Comprehensive update posted live 6 September 2012 (me) Comprehensive update posted live 16 March 2010 (me) Review posted live 1 December 2009 (ck) Original submission • 25 April 2024 (sw) Comprehensive update posted live • 24 May 2018 (sw) Comprehensive update posted live • 18 September 2014 (me) Comprehensive update posted live • 6 September 2012 (me) Comprehensive update posted live • 16 March 2010 (me) Review posted live • 1 December 2009 (ck) Original submission ## References ## Literature Cited	[]	16/3/2010	25/4/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pitt-hopkins	pitt-hopkins	[ "TCF4-Related Pitt-Hopkins Syndrome", "TCF4-Related Pitt-Hopkins Syndrome", "Transcription factor 4", "TCF4", "Pitt-Hopkins Syndrome" ]	Pitt-Hopkins Syndrome	David A Sweetser, Kevin S Gipson, Claire Zar-Kessler	Summary Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia. The diagnosis of PTHS is established in a proband with suggestive findings and one of the following identified by molecular genetic testing: (1) a heterozygous PTHS is an autosomal dominant disorder typically caused by a	## Diagnosis Clinical and molecular diagnostic criteria for Pitt-Hopkins syndrome (PTHS) have been established [ PTHS Delayed motor milestones, often associated with hypotonia Severely limited-to-absent speech, with regression in verbal abilities in some individuals Intellectual disability, typically moderate to severe Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. Anxiety Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism Narrow forehead (bitemporal narrowing) Thin lateral eyebrows Wide nasal bridge/ridge/tip Flared nasal alae Full cheeks and prominent midface Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow Thickened/overfolded helices Respiratory dysregulation Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. Hyperventilation triggered by excitement or anxiety is common. Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. Other Intestinal dysmotility with constipation High pain tolerance to external stimuli, with visceral hyperalgesia Cool extremities Decreased sweating with heat intolerance The diagnosis of PTHS A heterozygous A heterozygous deletion of chromosome 18q21.2 involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pitt-Hopkins Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Pathogenic variants include whole- or partial-gene deletions, varying in size from a single exon to ~12 Mb [ • • Delayed motor milestones, often associated with hypotonia • Severely limited-to-absent speech, with regression in verbal abilities in some individuals • Intellectual disability, typically moderate to severe • Delayed motor milestones, often associated with hypotonia • Severely limited-to-absent speech, with regression in verbal abilities in some individuals • Intellectual disability, typically moderate to severe • • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. • Anxiety • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. • Anxiety • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism • Narrow forehead (bitemporal narrowing) • Thin lateral eyebrows • Wide nasal bridge/ridge/tip • Flared nasal alae • Full cheeks and prominent midface • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow • Thickened/overfolded helices • Narrow forehead (bitemporal narrowing) • Thin lateral eyebrows • Wide nasal bridge/ridge/tip • Flared nasal alae • Full cheeks and prominent midface • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow • Thickened/overfolded helices • • Respiratory dysregulation • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Other • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Respiratory dysregulation • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Other • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Delayed motor milestones, often associated with hypotonia • Severely limited-to-absent speech, with regression in verbal abilities in some individuals • Intellectual disability, typically moderate to severe • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. • Anxiety • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism • Narrow forehead (bitemporal narrowing) • Thin lateral eyebrows • Wide nasal bridge/ridge/tip • Flared nasal alae • Full cheeks and prominent midface • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow • Thickened/overfolded helices • Respiratory dysregulation • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Other • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • A heterozygous • A heterozygous deletion of chromosome 18q21.2 involving • For an introduction to multigene panels click ## Suggestive Findings PTHS Delayed motor milestones, often associated with hypotonia Severely limited-to-absent speech, with regression in verbal abilities in some individuals Intellectual disability, typically moderate to severe Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. Anxiety Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism Narrow forehead (bitemporal narrowing) Thin lateral eyebrows Wide nasal bridge/ridge/tip Flared nasal alae Full cheeks and prominent midface Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow Thickened/overfolded helices Respiratory dysregulation Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. Hyperventilation triggered by excitement or anxiety is common. Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. Other Intestinal dysmotility with constipation High pain tolerance to external stimuli, with visceral hyperalgesia Cool extremities Decreased sweating with heat intolerance • • Delayed motor milestones, often associated with hypotonia • Severely limited-to-absent speech, with regression in verbal abilities in some individuals • Intellectual disability, typically moderate to severe • Delayed motor milestones, often associated with hypotonia • Severely limited-to-absent speech, with regression in verbal abilities in some individuals • Intellectual disability, typically moderate to severe • • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. • Anxiety • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. • Anxiety • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism • Narrow forehead (bitemporal narrowing) • Thin lateral eyebrows • Wide nasal bridge/ridge/tip • Flared nasal alae • Full cheeks and prominent midface • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow • Thickened/overfolded helices • Narrow forehead (bitemporal narrowing) • Thin lateral eyebrows • Wide nasal bridge/ridge/tip • Flared nasal alae • Full cheeks and prominent midface • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow • Thickened/overfolded helices • • Respiratory dysregulation • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Other • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Respiratory dysregulation • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Other • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Delayed motor milestones, often associated with hypotonia • Severely limited-to-absent speech, with regression in verbal abilities in some individuals • Intellectual disability, typically moderate to severe • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present. • Anxiety • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism • Narrow forehead (bitemporal narrowing) • Thin lateral eyebrows • Wide nasal bridge/ridge/tip • Flared nasal alae • Full cheeks and prominent midface • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow • Thickened/overfolded helices • Respiratory dysregulation • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Other • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur. • Hyperventilation triggered by excitement or anxiety is common. • Breathing abnormalities may begin sometime in the second half of the first decade, later, or not at all [ • Note: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS. • Intestinal dysmotility with constipation • High pain tolerance to external stimuli, with visceral hyperalgesia • Cool extremities • Decreased sweating with heat intolerance ## Establishing the Diagnosis The diagnosis of PTHS A heterozygous A heterozygous deletion of chromosome 18q21.2 involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pitt-Hopkins Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Pathogenic variants include whole- or partial-gene deletions, varying in size from a single exon to ~12 Mb [ • A heterozygous • A heterozygous deletion of chromosome 18q21.2 involving • For an introduction to multigene panels click ## Clinical Characteristics Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia (see Pitt-Hopkins Syndrome: Frequency of Select Features Based on Receptive language is generally stronger than expressive language; many individuals understand and follow simple commands. The use of augmentative communication devices and alternate forms of communication including signs often improve communication, thus helping to reduce frustrations and behaviors and to improve learning (see Self-care skills are also delayed; few individuals develop consistent dressing or toileting skills. Some individuals meet diagnostic criteria for ASD. Eight of ten participants scored at or above the social, behavioral, and communication criteria for ASD using the Autism Diagnostic Interview Revised (ADI-R) [ By contrast, most individuals with PTHS often seek attention and enjoy being with people. Most individuals generally have an easygoing, happy temperament [ Individuals may be shy or anxious in new situations (such as disruptions of routines) and can show self-aggression such as hand biting and head banging, pinching, or hitting themselves [ Many individuals have outbursts of aggression or bouts of shouting associated with frustration or unanticipated changes in routine [ Stereotypic head movements (e.g., head rotation) and hand movements (e.g., flapping, clapping, washing movements, hand to mouth, finger crossing) are common [ Individuals with PTHS invariably have a profound affinity for music. Families report that during episodes of anxiety or frustration, music is often soothing. Apnea from birth to age three months, not associated with prematurity or seizures, is seen in about 6% of infants [D Sweetser, personal observation]. Subtle breathing pauses are common. Overt breath-holding with hypoxia and cyanosis can be seen, and in rare cases syncope may occur [ In some children, hyperventilation and/or breath-holding episodes are observed for only a few months or years; however, in most individuals breathing abnormalities persist to some degree. It is difficult to make conclusive statements about frequency or severity of such episodes in adults, as to date too few adults with PTHS have been described. Disorders of sleep-related breathing, such as obstructive apnea, hypoxemia, and hypoventilation, can have significant long-term effects on health, behavior, and development. Children with developmental disorders may be more susceptible to the deleterious effects of these disorders than neurotypical children [ Dilated pupils with sluggish response to light Decreased distal circulation Urinary retention High external pain tolerance with visceral hyperesthesia Dysregulation of body temperature Constipation, which is common (75%), often starts in infancy, may be severe, and generally is lifelong. Dysmotility of the gastrointestinal tract and autonomic dysfunction resulting in gastroparesis and chronic intestinal pseudo-obstruction are thought to contribute to frequent and significant abdominal pain. Constipation or intestinal dysmotility is a common source of pain. Effective control of constipation and improving gastrointestinal motility may lessen such spells [ Visceral hyperalgesia can be a cause of abdominal pain [ Aerophagia (i.e., excessive air swallowing) can be caused by dysregulated breathing, leading to abdominal bloating. While aerophagia is generally benign, it can cause abdominal pain; rarely, it has been associated with colonic volvulus and/or bowel perforation [ Malrotation, reported in up to 16% of individuals [ Gastroesophageal reflux disease (GERD), reported in fewer than half of individuals with PTHS [ Bruxism is also common [ Myopia can be severe (>6 diopters) and evident before age two years [ Cerebral visual impairment has been diagnosed in about 14% of individuals [D Sweetser, personal observation]. In an internet-based questionnaire involving 101 families, 37.6% reported epilepsy [ In a study of 38 individuals with PTHS, Although seizures are usually well controlled with standard anti-seizure medications, presumed sudden unexplained death in epilepsy has been observed [D Sweetser, personal observation]. EEG findings in four individuals reported no specific patterns other than occipital and central delta waves in the two younger individuals. Pseudo-/quasiperiodic complexes present during wakefulness over the central and occipital regions were at times admixed with slow spike and wave in the two older individuals [ Of 11 EEGs in individuals with PTHS with seizures, the most common EEG findings were generalized background slowing in six individuals, focal spikes and discharges in three, and focal slowing in two [D Sweetser, personal observation]. Some infants with PTHS have been described as quiet and "unusually good," with excessive sleeping [ Mild-to-moderate scoliosis has been noted in about 20% [ Minor hand and foot anomalies such as slender or small hands and feet, broad fingertips, clinodactyly, tapered fingers, transverse palmar crease, prominent heels, overriding toes, and short metatarsals have been reported [ Many affected individuals have prominent pads (i.e., persistent fetal pads) on fingertips and/or toes [ Growth is typically in the normal range for size at birth; slower postnatal growth with short stature has been noted in 26%-38% of individuals [ Head growth slowed postnatally in 26% of individuals [ Hearing loss (type not specified) was reported in 10% of individuals [ Hands and feet are reported to be cold and cyanosed in some individuals. Supernumerary nipples have been observed in at least 10 individuals [ In addition to the craniofacial features (see The initiation and progression of secondary sexual characteristics appear to be unaffected [D Sweetser, personal observation]. PTHS is associated with Milder nonsyndromic intellectual disability (see Milder intellectual disability in association with preserved language but with typical facial features has been observed with certain presumably leaky splice site variants or in-frame deletions [D Sweetser, personal observation]. The phenotypes of individuals with an 18q21.2 contiguous gene deletion up to 12 Mb involving The phenotypes of individuals with deletions larger than 12 Mb involving Overall prevalence of PTHS is unknown. However, based on a lower relative detection rate as compared to • Dilated pupils with sluggish response to light • Decreased distal circulation • Urinary retention • High external pain tolerance with visceral hyperesthesia • Dysregulation of body temperature • Growth is typically in the normal range for size at birth; slower postnatal growth with short stature has been noted in 26%-38% of individuals [ • Head growth slowed postnatally in 26% of individuals [ • Hearing loss (type not specified) was reported in 10% of individuals [ • Hands and feet are reported to be cold and cyanosed in some individuals. • Supernumerary nipples have been observed in at least 10 individuals [ • In addition to the craniofacial features (see • The initiation and progression of secondary sexual characteristics appear to be unaffected [D Sweetser, personal observation]. • PTHS is associated with • Milder nonsyndromic intellectual disability (see • Milder intellectual disability in association with preserved language but with typical facial features has been observed with certain presumably leaky splice site variants or in-frame deletions [D Sweetser, personal observation]. • The phenotypes of individuals with an 18q21.2 contiguous gene deletion up to 12 Mb involving • The phenotypes of individuals with deletions larger than 12 Mb involving ## Clinical Description Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia (see Pitt-Hopkins Syndrome: Frequency of Select Features Based on Receptive language is generally stronger than expressive language; many individuals understand and follow simple commands. The use of augmentative communication devices and alternate forms of communication including signs often improve communication, thus helping to reduce frustrations and behaviors and to improve learning (see Self-care skills are also delayed; few individuals develop consistent dressing or toileting skills. Some individuals meet diagnostic criteria for ASD. Eight of ten participants scored at or above the social, behavioral, and communication criteria for ASD using the Autism Diagnostic Interview Revised (ADI-R) [ By contrast, most individuals with PTHS often seek attention and enjoy being with people. Most individuals generally have an easygoing, happy temperament [ Individuals may be shy or anxious in new situations (such as disruptions of routines) and can show self-aggression such as hand biting and head banging, pinching, or hitting themselves [ Many individuals have outbursts of aggression or bouts of shouting associated with frustration or unanticipated changes in routine [ Stereotypic head movements (e.g., head rotation) and hand movements (e.g., flapping, clapping, washing movements, hand to mouth, finger crossing) are common [ Individuals with PTHS invariably have a profound affinity for music. Families report that during episodes of anxiety or frustration, music is often soothing. Apnea from birth to age three months, not associated with prematurity or seizures, is seen in about 6% of infants [D Sweetser, personal observation]. Subtle breathing pauses are common. Overt breath-holding with hypoxia and cyanosis can be seen, and in rare cases syncope may occur [ In some children, hyperventilation and/or breath-holding episodes are observed for only a few months or years; however, in most individuals breathing abnormalities persist to some degree. It is difficult to make conclusive statements about frequency or severity of such episodes in adults, as to date too few adults with PTHS have been described. Disorders of sleep-related breathing, such as obstructive apnea, hypoxemia, and hypoventilation, can have significant long-term effects on health, behavior, and development. Children with developmental disorders may be more susceptible to the deleterious effects of these disorders than neurotypical children [ Dilated pupils with sluggish response to light Decreased distal circulation Urinary retention High external pain tolerance with visceral hyperesthesia Dysregulation of body temperature Constipation, which is common (75%), often starts in infancy, may be severe, and generally is lifelong. Dysmotility of the gastrointestinal tract and autonomic dysfunction resulting in gastroparesis and chronic intestinal pseudo-obstruction are thought to contribute to frequent and significant abdominal pain. Constipation or intestinal dysmotility is a common source of pain. Effective control of constipation and improving gastrointestinal motility may lessen such spells [ Visceral hyperalgesia can be a cause of abdominal pain [ Aerophagia (i.e., excessive air swallowing) can be caused by dysregulated breathing, leading to abdominal bloating. While aerophagia is generally benign, it can cause abdominal pain; rarely, it has been associated with colonic volvulus and/or bowel perforation [ Malrotation, reported in up to 16% of individuals [ Gastroesophageal reflux disease (GERD), reported in fewer than half of individuals with PTHS [ Bruxism is also common [ Myopia can be severe (>6 diopters) and evident before age two years [ Cerebral visual impairment has been diagnosed in about 14% of individuals [D Sweetser, personal observation]. In an internet-based questionnaire involving 101 families, 37.6% reported epilepsy [ In a study of 38 individuals with PTHS, Although seizures are usually well controlled with standard anti-seizure medications, presumed sudden unexplained death in epilepsy has been observed [D Sweetser, personal observation]. EEG findings in four individuals reported no specific patterns other than occipital and central delta waves in the two younger individuals. Pseudo-/quasiperiodic complexes present during wakefulness over the central and occipital regions were at times admixed with slow spike and wave in the two older individuals [ Of 11 EEGs in individuals with PTHS with seizures, the most common EEG findings were generalized background slowing in six individuals, focal spikes and discharges in three, and focal slowing in two [D Sweetser, personal observation]. Some infants with PTHS have been described as quiet and "unusually good," with excessive sleeping [ Mild-to-moderate scoliosis has been noted in about 20% [ Minor hand and foot anomalies such as slender or small hands and feet, broad fingertips, clinodactyly, tapered fingers, transverse palmar crease, prominent heels, overriding toes, and short metatarsals have been reported [ Many affected individuals have prominent pads (i.e., persistent fetal pads) on fingertips and/or toes [ Growth is typically in the normal range for size at birth; slower postnatal growth with short stature has been noted in 26%-38% of individuals [ Head growth slowed postnatally in 26% of individuals [ Hearing loss (type not specified) was reported in 10% of individuals [ Hands and feet are reported to be cold and cyanosed in some individuals. Supernumerary nipples have been observed in at least 10 individuals [ In addition to the craniofacial features (see The initiation and progression of secondary sexual characteristics appear to be unaffected [D Sweetser, personal observation]. • Dilated pupils with sluggish response to light • Decreased distal circulation • Urinary retention • High external pain tolerance with visceral hyperesthesia • Dysregulation of body temperature • Growth is typically in the normal range for size at birth; slower postnatal growth with short stature has been noted in 26%-38% of individuals [ • Head growth slowed postnatally in 26% of individuals [ • Hearing loss (type not specified) was reported in 10% of individuals [ • Hands and feet are reported to be cold and cyanosed in some individuals. • Supernumerary nipples have been observed in at least 10 individuals [ • In addition to the craniofacial features (see • The initiation and progression of secondary sexual characteristics appear to be unaffected [D Sweetser, personal observation]. ## Genotype-Phenotype Correlations PTHS is associated with Milder nonsyndromic intellectual disability (see Milder intellectual disability in association with preserved language but with typical facial features has been observed with certain presumably leaky splice site variants or in-frame deletions [D Sweetser, personal observation]. The phenotypes of individuals with an 18q21.2 contiguous gene deletion up to 12 Mb involving The phenotypes of individuals with deletions larger than 12 Mb involving • PTHS is associated with • Milder nonsyndromic intellectual disability (see • Milder intellectual disability in association with preserved language but with typical facial features has been observed with certain presumably leaky splice site variants or in-frame deletions [D Sweetser, personal observation]. • The phenotypes of individuals with an 18q21.2 contiguous gene deletion up to 12 Mb involving • The phenotypes of individuals with deletions larger than 12 Mb involving ## Prevalence Overall prevalence of PTHS is unknown. However, based on a lower relative detection rate as compared to ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders with features that overlap those of Pitt-Hopkins syndrome (PTHS) are listed in Disorders to Consider in the Differential Diagnosis of Pitt-Hopkins Syndrome DD, severe speech disorder, seizures Recurrent hyperventilation episodes reported in 1 persons w/an Hand & lower-limb dystonia Absence of characteristic PTHS facial features Severe DD, impaired speech & language development, constipation, reflux Adult phenotype may incl some PTHS facial features & hyperventilation. Seizures are typically more severe w/early-onset intractable epilepsy. Persistent feeding problems are more common. Movement disorders: chorea, dystonia Absence of characteristic PTHS facial gestalt in childhood Severe global delays, lack of speech, stereotypies, seizures Episodic hyperventilation episodes reported in 3 persons. Congenital abnormalities: cardiac, renal, urologic Facial features distinct from PTHS Postnatal growth deficiency, progressive microcephaly, hyperkinetic/dyskinetic movement disorder Absence of characteristic PTHS facial features Normal early development followed by stagnation, then regression of language & motor skills Progressive Primarily affects females Absence of PTHS facial features Seizures, ID w/poor or absent speech, hypotonia, poor motor development, episodic hyperventilation MRI findings: enlarged ventricles, thin corpus callosum Severe global delays, lack of speech, stereotypies Episodic breathing abnormalities in 3 persons (2 w/hyperventilation episodes; 1 w/breath-holding episodes) Abnormal sleep-wake cycles (not commonly reported in PTHS) Absence of characteristic PTHS facial features Severe ID w/absent speech, wide nasal bridge, full cheeks, prominent midface Overall PTHS phenotype in 22% of reported person. DD w/absent speech, seizures, microcephaly, wide-based gait, happy disposition 2% of 86 individuals suspected of having AS actually had PTHS. EEG almost universally abnormal w/slow background & rhythmic delta waves & "posterior spike" patterns Seizures in 90% of persons Sleep problems common Tremor & ataxia almost universal Absence of PTHS facial features Neonatal feeding problems ID less severe Breathing abnormalities not typically hyperventilation/apnea DD, absent speech, hypotonia Some facial features overlap. Unusual uplifted earlobe configuration & hypertelorism in MWS MWS more likely to be assoc w/variety of malformations (Hirschsprung disease, genitourinary anomalies, heart defects, structural eye anomalies) Absence of PTHS facial gestalt Distinctive cerebellar vermis hypoplasia assoc w/molar tooth sign on brain MRI, oculomotor apraxia, & truncal ataxia Irregular breathing patterns w/hyperventilation & apnea noted in early infancy but improve w/age. Absence of PTHS facial features AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; DEE = developmental and epileptic encephalopathy; ID = intellectual disability; MOI = mode of inheritance; NDD = neurodevelopmental disorder; PHTS = Pitt-Hopkins syndrome; PV = pathogenic variant (including likely pathogenic variants); XL = X-linked Joubert syndrome is inherited predominantly in an autosomal recessive manner. Joubert syndrome caused by pathogenic variants in • DD, severe speech disorder, seizures • Recurrent hyperventilation episodes reported in 1 persons w/an • Hand & lower-limb dystonia • Absence of characteristic PTHS facial features • Severe DD, impaired speech & language development, constipation, reflux • Adult phenotype may incl some PTHS facial features & hyperventilation. • Seizures are typically more severe w/early-onset intractable epilepsy. • Persistent feeding problems are more common. • Movement disorders: chorea, dystonia • Absence of characteristic PTHS facial gestalt in childhood • Severe global delays, lack of speech, stereotypies, seizures • Episodic hyperventilation episodes reported in 3 persons. • Congenital abnormalities: cardiac, renal, urologic • Facial features distinct from PTHS • Postnatal growth deficiency, progressive microcephaly, hyperkinetic/dyskinetic movement disorder • Absence of characteristic PTHS facial features • Normal early development followed by stagnation, then regression of language & motor skills • Progressive • Primarily affects females • Absence of PTHS facial features • Seizures, ID w/poor or absent speech, hypotonia, poor motor development, episodic hyperventilation • MRI findings: enlarged ventricles, thin corpus callosum • Severe global delays, lack of speech, stereotypies • Episodic breathing abnormalities in 3 persons (2 w/hyperventilation episodes; 1 w/breath-holding episodes) • Abnormal sleep-wake cycles (not commonly reported in PTHS) • Absence of characteristic PTHS facial features • Severe ID w/absent speech, wide nasal bridge, full cheeks, prominent midface • Overall PTHS phenotype in 22% of reported person. • DD w/absent speech, seizures, microcephaly, wide-based gait, happy disposition • 2% of 86 individuals suspected of having AS actually had PTHS. • EEG almost universally abnormal w/slow background & rhythmic delta waves & "posterior spike" patterns • Seizures in 90% of persons • Sleep problems common • Tremor & ataxia almost universal • Absence of PTHS facial features • Neonatal feeding problems • ID less severe • Breathing abnormalities not typically hyperventilation/apnea • DD, absent speech, hypotonia • Some facial features overlap. • Unusual uplifted earlobe configuration & hypertelorism in MWS • MWS more likely to be assoc w/variety of malformations (Hirschsprung disease, genitourinary anomalies, heart defects, structural eye anomalies) • Absence of PTHS facial gestalt • Distinctive cerebellar vermis hypoplasia assoc w/molar tooth sign on brain MRI, oculomotor apraxia, & truncal ataxia • Irregular breathing patterns w/hyperventilation & apnea noted in early infancy but improve w/age. • Absence of PTHS facial features ## Management Clinical practice guidelines for management of individuals with Pitt-Hopkins syndrome (PTHS) have been published [ To establish the extent of disease and needs in an individual diagnosed with PTHS, the evaluations summarized in Pitt-Hopkins Syndrome: Recommended Evaluations Following Initial Diagnosis To establish a neurologic baseline & evaluate for other neurologic issues such as sleep dysfunction or seizures To incl brain MRI if not previously performed Consider EEG if seizures are a concern. To assess cognitive baseline & determine the types of services & educational strategies needed For infants & young children: evaluate for early intervention. For school-age children: determine need for IEP or 504 plan. By speech-language pathologist By therapist trained in accessory & augmentative communication Assess for respiratory dysregulation, signs of chronic hypoxemia, and aspiration Infants with prolonged neonatal apnea should be evaluated for seizures Exclude sleep-related breathing disorders Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility & need for special mobility equipment &/or orthotics to aid in foot position Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral GERD = gastroesophageal reflux disease; IEP = individualized education plan; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; PTHS = Pitt-Hopkins syndrome Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for PTHS. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Pitt-Hopkins Syndrome: Treatment of Manifestations In most persons, seizures are well controlled by ASMs w/valproic acid, levetiracetam, lamotrigine, & carbamazepine being the most common. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Intensive PT & OT to build core strength Orthotics for abnormal foot position to aid ambulation Orthopedic treatment of scoliosis as needed Consider need for positioning & mobility devices, disability parking placard. Routine mgmt of GERD w/H2 blockers & proton pump inhibitors Assess aspiration risk when swallowing problems are present. Mgmt of constipation w/high fiber diet &/or stool softeners, prokinetics, osmotic agents, or laxatives as needed When constipation cannot be managed w/medication, surgical intervention can inclue cecostomy tube placement or colectomy. Acute onset of severe abdominal pain & distention w/bilious vomiting may represent a life-threatening volvulus & should be treated as a medical emergency. For disruptive or refractory drooling, salivary botulinum neurotoxin injections can be a temporary option. Surgery w/selective salivary gland excision &/or duct ligation can be a very effective, satisfactory, & permanent solution. Adenotonsillectomy is first-line therapy for children w/adenotonsillar hypertrophy contributing to OSA. Positive airway pressure therapy (e.g., CPAP, BiPAP) can be considered for persistent OSA after surgery or when surgery is contraindicated or not feasible. Behavioral preparation may be necessary to ensure adherence in children w/developmental disorders. Iron supplementation for serum ferritin less than 50 ug/L Gamma-aminobutyric acid analogs (e.g., gabapentin) To ↓ symptoms & improve sleep quality GABA analogs modulate neurotransmission to ↓ excessive motor activity during sleep. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy Alternative means of communication (e.g., Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see D Sweetser & H Winters, personal communication Acetazolamide can reduce the frequency and duration of episodic hyperventilation and apnea and improve oxygen saturation; some reports suggest significant improvement in overall respiratory function [ Typically restless sleep disorder or periodic limb movement disorder Treatment with iron for serum ferritin of less than 50 ug/L has been associated with improvement in restless leg syndrome that can result in sleep disruption [ The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Pitt-Hopkins Syndrome: Recommended Surveillance Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures per treating neurologist. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Monitor for frequent hyperventilation or breath-holding, & for the development of clubbing or other signs of chronic hypoxemia. Assess for symptoms of progressive exercise intolerance or dyspnea, which might indicate development of pulmonary hypertension. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapist; PT = physical therapist Chronic hypoxia, if untreated, may contribute to development of pulmonary hypertension and other systemic complications. If progressive exercise intolerance or dyspnea is noted, consider screening tests including oximetry, six-minute walk test, ambulatory end-tidal CO See Search • To establish a neurologic baseline & evaluate for other neurologic issues such as sleep dysfunction or seizures • To incl brain MRI if not previously performed • Consider EEG if seizures are a concern. • To assess cognitive baseline & determine the types of services & educational strategies needed • For infants & young children: evaluate for early intervention. • For school-age children: determine need for IEP or 504 plan. • By speech-language pathologist • By therapist trained in accessory & augmentative communication • Assess for respiratory dysregulation, signs of chronic hypoxemia, and aspiration • Infants with prolonged neonatal apnea should be evaluated for seizures • Exclude sleep-related breathing disorders • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility & need for special mobility equipment &/or orthotics to aid in foot position • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral • In most persons, seizures are well controlled by ASMs w/valproic acid, levetiracetam, lamotrigine, & carbamazepine being the most common. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Intensive PT & OT to build core strength • Orthotics for abnormal foot position to aid ambulation • Orthopedic treatment of scoliosis as needed • Consider need for positioning & mobility devices, disability parking placard. • Routine mgmt of GERD w/H2 blockers & proton pump inhibitors • Assess aspiration risk when swallowing problems are present. • Mgmt of constipation w/high fiber diet &/or stool softeners, prokinetics, osmotic agents, or laxatives as needed • When constipation cannot be managed w/medication, surgical intervention can inclue cecostomy tube placement or colectomy. • Acute onset of severe abdominal pain & distention w/bilious vomiting may represent a life-threatening volvulus & should be treated as a medical emergency. • For disruptive or refractory drooling, salivary botulinum neurotoxin injections can be a temporary option. • Surgery w/selective salivary gland excision &/or duct ligation can be a very effective, satisfactory, & permanent solution. • Adenotonsillectomy is first-line therapy for children w/adenotonsillar hypertrophy contributing to OSA. • Positive airway pressure therapy (e.g., CPAP, BiPAP) can be considered for persistent OSA after surgery or when surgery is contraindicated or not feasible. • Behavioral preparation may be necessary to ensure adherence in children w/developmental disorders. • Iron supplementation for serum ferritin less than 50 ug/L • Gamma-aminobutyric acid analogs (e.g., gabapentin) • To ↓ symptoms & improve sleep quality • GABA analogs modulate neurotransmission to ↓ excessive motor activity during sleep. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures per treating neurologist. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • Monitor for frequent hyperventilation or breath-holding, & for the development of clubbing or other signs of chronic hypoxemia. • Assess for symptoms of progressive exercise intolerance or dyspnea, which might indicate development of pulmonary hypertension. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PTHS, the evaluations summarized in Pitt-Hopkins Syndrome: Recommended Evaluations Following Initial Diagnosis To establish a neurologic baseline & evaluate for other neurologic issues such as sleep dysfunction or seizures To incl brain MRI if not previously performed Consider EEG if seizures are a concern. To assess cognitive baseline & determine the types of services & educational strategies needed For infants & young children: evaluate for early intervention. For school-age children: determine need for IEP or 504 plan. By speech-language pathologist By therapist trained in accessory & augmentative communication Assess for respiratory dysregulation, signs of chronic hypoxemia, and aspiration Infants with prolonged neonatal apnea should be evaluated for seizures Exclude sleep-related breathing disorders Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility & need for special mobility equipment &/or orthotics to aid in foot position Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral GERD = gastroesophageal reflux disease; IEP = individualized education plan; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; PTHS = Pitt-Hopkins syndrome Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To establish a neurologic baseline & evaluate for other neurologic issues such as sleep dysfunction or seizures • To incl brain MRI if not previously performed • Consider EEG if seizures are a concern. • To assess cognitive baseline & determine the types of services & educational strategies needed • For infants & young children: evaluate for early intervention. • For school-age children: determine need for IEP or 504 plan. • By speech-language pathologist • By therapist trained in accessory & augmentative communication • Assess for respiratory dysregulation, signs of chronic hypoxemia, and aspiration • Infants with prolonged neonatal apnea should be evaluated for seizures • Exclude sleep-related breathing disorders • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility & need for special mobility equipment &/or orthotics to aid in foot position • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for PTHS. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Pitt-Hopkins Syndrome: Treatment of Manifestations In most persons, seizures are well controlled by ASMs w/valproic acid, levetiracetam, lamotrigine, & carbamazepine being the most common. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Intensive PT & OT to build core strength Orthotics for abnormal foot position to aid ambulation Orthopedic treatment of scoliosis as needed Consider need for positioning & mobility devices, disability parking placard. Routine mgmt of GERD w/H2 blockers & proton pump inhibitors Assess aspiration risk when swallowing problems are present. Mgmt of constipation w/high fiber diet &/or stool softeners, prokinetics, osmotic agents, or laxatives as needed When constipation cannot be managed w/medication, surgical intervention can inclue cecostomy tube placement or colectomy. Acute onset of severe abdominal pain & distention w/bilious vomiting may represent a life-threatening volvulus & should be treated as a medical emergency. For disruptive or refractory drooling, salivary botulinum neurotoxin injections can be a temporary option. Surgery w/selective salivary gland excision &/or duct ligation can be a very effective, satisfactory, & permanent solution. Adenotonsillectomy is first-line therapy for children w/adenotonsillar hypertrophy contributing to OSA. Positive airway pressure therapy (e.g., CPAP, BiPAP) can be considered for persistent OSA after surgery or when surgery is contraindicated or not feasible. Behavioral preparation may be necessary to ensure adherence in children w/developmental disorders. Iron supplementation for serum ferritin less than 50 ug/L Gamma-aminobutyric acid analogs (e.g., gabapentin) To ↓ symptoms & improve sleep quality GABA analogs modulate neurotransmission to ↓ excessive motor activity during sleep. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy Alternative means of communication (e.g., Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see D Sweetser & H Winters, personal communication Acetazolamide can reduce the frequency and duration of episodic hyperventilation and apnea and improve oxygen saturation; some reports suggest significant improvement in overall respiratory function [ Typically restless sleep disorder or periodic limb movement disorder Treatment with iron for serum ferritin of less than 50 ug/L has been associated with improvement in restless leg syndrome that can result in sleep disruption [ The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In most persons, seizures are well controlled by ASMs w/valproic acid, levetiracetam, lamotrigine, & carbamazepine being the most common. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Intensive PT & OT to build core strength • Orthotics for abnormal foot position to aid ambulation • Orthopedic treatment of scoliosis as needed • Consider need for positioning & mobility devices, disability parking placard. • Routine mgmt of GERD w/H2 blockers & proton pump inhibitors • Assess aspiration risk when swallowing problems are present. • Mgmt of constipation w/high fiber diet &/or stool softeners, prokinetics, osmotic agents, or laxatives as needed • When constipation cannot be managed w/medication, surgical intervention can inclue cecostomy tube placement or colectomy. • Acute onset of severe abdominal pain & distention w/bilious vomiting may represent a life-threatening volvulus & should be treated as a medical emergency. • For disruptive or refractory drooling, salivary botulinum neurotoxin injections can be a temporary option. • Surgery w/selective salivary gland excision &/or duct ligation can be a very effective, satisfactory, & permanent solution. • Adenotonsillectomy is first-line therapy for children w/adenotonsillar hypertrophy contributing to OSA. • Positive airway pressure therapy (e.g., CPAP, BiPAP) can be considered for persistent OSA after surgery or when surgery is contraindicated or not feasible. • Behavioral preparation may be necessary to ensure adherence in children w/developmental disorders. • Iron supplementation for serum ferritin less than 50 ug/L • Gamma-aminobutyric acid analogs (e.g., gabapentin) • To ↓ symptoms & improve sleep quality • GABA analogs modulate neurotransmission to ↓ excessive motor activity during sleep. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Pitt-Hopkins Syndrome: Recommended Surveillance Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures per treating neurologist. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Monitor for frequent hyperventilation or breath-holding, & for the development of clubbing or other signs of chronic hypoxemia. Assess for symptoms of progressive exercise intolerance or dyspnea, which might indicate development of pulmonary hypertension. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapist; PT = physical therapist Chronic hypoxia, if untreated, may contribute to development of pulmonary hypertension and other systemic complications. If progressive exercise intolerance or dyspnea is noted, consider screening tests including oximetry, six-minute walk test, ambulatory end-tidal CO • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures per treating neurologist. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • Monitor for frequent hyperventilation or breath-holding, & for the development of clubbing or other signs of chronic hypoxemia. • Assess for symptoms of progressive exercise intolerance or dyspnea, which might indicate development of pulmonary hypertension. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Pitt-Hopkins syndrome (PTHS) is an autosomal dominant disorder typically caused by a Most individuals diagnosed with PTHS whose parents have undergone molecular genetic/cytogenetic testing have the disorder as the result of a Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a parent. Sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism has been reported [ Genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. If the If a parent of the proband has the genetic alteration (even in a mosaic state), the risk to the sibs of inheriting the genetic alteration may be as high as 50%. Sibs who inherit a genetic alteration will be affected; phenotypic variability among affected sibs (born to a presumably mosaic parent) has been reported [ If the parents have not been tested for the genetic alteration but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for PTHS because of the possibility of parental gonadal mosaicism. Each child of an individual with PTHS has a 50% chance of inheriting the PTHS-related genetic alteration; however, individuals with PTHS typically do not reproduce. Transmission of a PTHS-related genetic alteration from an affected non-mosaic mother to her affected child has been reported in one family to date [ The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with PTHS whose parents have undergone molecular genetic/cytogenetic testing have the disorder as the result of a • Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a parent. Sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism has been reported [ • Genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ • * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ • * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ • * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. • If the • If a parent of the proband has the genetic alteration (even in a mosaic state), the risk to the sibs of inheriting the genetic alteration may be as high as 50%. • Sibs who inherit a genetic alteration will be affected; phenotypic variability among affected sibs (born to a presumably mosaic parent) has been reported [ • If the parents have not been tested for the genetic alteration but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for PTHS because of the possibility of parental gonadal mosaicism. • Each child of an individual with PTHS has a 50% chance of inheriting the PTHS-related genetic alteration; however, individuals with PTHS typically do not reproduce. • Transmission of a PTHS-related genetic alteration from an affected non-mosaic mother to her affected child has been reported in one family to date [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance Pitt-Hopkins syndrome (PTHS) is an autosomal dominant disorder typically caused by a ## Risk to Family Members Most individuals diagnosed with PTHS whose parents have undergone molecular genetic/cytogenetic testing have the disorder as the result of a Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a parent. Sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism has been reported [ Genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. If the If a parent of the proband has the genetic alteration (even in a mosaic state), the risk to the sibs of inheriting the genetic alteration may be as high as 50%. Sibs who inherit a genetic alteration will be affected; phenotypic variability among affected sibs (born to a presumably mosaic parent) has been reported [ If the parents have not been tested for the genetic alteration but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for PTHS because of the possibility of parental gonadal mosaicism. Each child of an individual with PTHS has a 50% chance of inheriting the PTHS-related genetic alteration; however, individuals with PTHS typically do not reproduce. Transmission of a PTHS-related genetic alteration from an affected non-mosaic mother to her affected child has been reported in one family to date [ • Most individuals diagnosed with PTHS whose parents have undergone molecular genetic/cytogenetic testing have the disorder as the result of a • Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a parent. Sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism has been reported [ • Genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ • * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ • * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [ • * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only. • If the • If a parent of the proband has the genetic alteration (even in a mosaic state), the risk to the sibs of inheriting the genetic alteration may be as high as 50%. • Sibs who inherit a genetic alteration will be affected; phenotypic variability among affected sibs (born to a presumably mosaic parent) has been reported [ • If the parents have not been tested for the genetic alteration but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for PTHS because of the possibility of parental gonadal mosaicism. • Each child of an individual with PTHS has a 50% chance of inheriting the PTHS-related genetic alteration; however, individuals with PTHS typically do not reproduce. • Transmission of a PTHS-related genetic alteration from an affected non-mosaic mother to her affected child has been reported in one family to date [ ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Pitt Hopkins UK • • • • • • Pitt Hopkins UK • • • • • • • • ## Molecular Genetics Pitt-Hopkins Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pitt-Hopkins Syndrome ( ## Molecular Pathogenesis ## Chapter Notes The authors are all providers in the Massachusetts General Hospital Pitt Hopkins Clinic. Chief of Medical Genetics and MetabolismMGH Site Director Undiagnosed Diseases NetworkCo-Director Harvard Affiliated Hospitals NORD Rare Disease Center of ExcellenceAssociate Professor of Pediatrics Harvard Medical SchoolDepartment of Pediatrics and Center for Genomic MedicineMassachusetts General HospitalBoston, Massachusetts Dr Sweetser is a biochemical and medical genetics clinician-researcher with a focus on understanding and diagnosing rare and undiagnosed diseases. He has a clinical and research focus on rare neurodevelopmental disorders. Dr Sweetser is actively involved in clinical and basic science research regarding individuals with Pitt-Hopkins syndrome (PTHS). He would be happy to communicate with persons who have any questions regarding diagnosis of PTHS or other considerations. Contact Dr Sweetser to inquire about review of Web pages: Division of Pediatric Pulmonology and Sleep MedicineMassGeneral for ChildrenBoston, Massachusetts Dr Gipson is a pediatric pulmonologist and sleep medicine physician who specializes in the care of infants, children, and adolescents with complex respiratory and sleep disorders. Web page: Medical Director, Pediatric Neurogastroenterology ProgramInstructor, Harvard Medical SchoolDivision of Pediatric Gastroenterology and NutritionMassGeneral for ChildrenBoston, Massachusetts Dr Zar-Kessler is a pediatric gastroenterologist who specializes in the care of difficult-to-manage gastrointestinal problems and is involved in research studying the evaluation and management of gastrointestinal motility diseases and the overlap with psychiatric disorders. Web page: The Massachusetts General Hospital Pitt Hopkins Clinic would like to acknowledge the generous support of Walter Herlihy and Nancy LeGendre and the many families we have seen in our multidisciplinary clinic that have broadened our understanding of PTHS. Holly H Ardinger, MD; University of Missouri-Kansas City (2012-2018)Ibrahim Elsharkawi, MD; Washington University (2018-2025)Kevin S Gipson, MD, MS (2025-present)Kimberly Parkin; Massachusetts General Hospital (2018-2025)Carol J Saunders, PhD; University of Missouri-Kansas City (2012-2018)Marci Steeves, MS, CGC; MassGeneral Hospital for Children (2018-2025)David A Sweetser, MD, PhD (2018-present)Ronald Thibert, DO, MsPH; Massachusetts General Hospital (2018-2025)Holly I Welsh, MS; University of Missouri-Kansas City (2012-2018)Lael Yonker, MD; MassGeneral Hospital for Children (2018-2025)Claire Zar-Kessler, MD, MPH (2025-present) 22 May 2025 (bp) Comprehensive update posted live 12 April 2018 (ha) Comprehensive update posted live 30 August 2012 (me) Review posted live 4 May 2012 (hha) Original submission • • • 22 May 2025 (bp) Comprehensive update posted live • 12 April 2018 (ha) Comprehensive update posted live • 30 August 2012 (me) Review posted live • 4 May 2012 (hha) Original submission ## Author Notes The authors are all providers in the Massachusetts General Hospital Pitt Hopkins Clinic. Chief of Medical Genetics and MetabolismMGH Site Director Undiagnosed Diseases NetworkCo-Director Harvard Affiliated Hospitals NORD Rare Disease Center of ExcellenceAssociate Professor of Pediatrics Harvard Medical SchoolDepartment of Pediatrics and Center for Genomic MedicineMassachusetts General HospitalBoston, Massachusetts Dr Sweetser is a biochemical and medical genetics clinician-researcher with a focus on understanding and diagnosing rare and undiagnosed diseases. He has a clinical and research focus on rare neurodevelopmental disorders. Dr Sweetser is actively involved in clinical and basic science research regarding individuals with Pitt-Hopkins syndrome (PTHS). He would be happy to communicate with persons who have any questions regarding diagnosis of PTHS or other considerations. Contact Dr Sweetser to inquire about review of Web pages: Division of Pediatric Pulmonology and Sleep MedicineMassGeneral for ChildrenBoston, Massachusetts Dr Gipson is a pediatric pulmonologist and sleep medicine physician who specializes in the care of infants, children, and adolescents with complex respiratory and sleep disorders. Web page: Medical Director, Pediatric Neurogastroenterology ProgramInstructor, Harvard Medical SchoolDivision of Pediatric Gastroenterology and NutritionMassGeneral for ChildrenBoston, Massachusetts Dr Zar-Kessler is a pediatric gastroenterologist who specializes in the care of difficult-to-manage gastrointestinal problems and is involved in research studying the evaluation and management of gastrointestinal motility diseases and the overlap with psychiatric disorders. Web page: • • ## Acknowledgments The Massachusetts General Hospital Pitt Hopkins Clinic would like to acknowledge the generous support of Walter Herlihy and Nancy LeGendre and the many families we have seen in our multidisciplinary clinic that have broadened our understanding of PTHS. ## Author History Holly H Ardinger, MD; University of Missouri-Kansas City (2012-2018)Ibrahim Elsharkawi, MD; Washington University (2018-2025)Kevin S Gipson, MD, MS (2025-present)Kimberly Parkin; Massachusetts General Hospital (2018-2025)Carol J Saunders, PhD; University of Missouri-Kansas City (2012-2018)Marci Steeves, MS, CGC; MassGeneral Hospital for Children (2018-2025)David A Sweetser, MD, PhD (2018-present)Ronald Thibert, DO, MsPH; Massachusetts General Hospital (2018-2025)Holly I Welsh, MS; University of Missouri-Kansas City (2012-2018)Lael Yonker, MD; MassGeneral Hospital for Children (2018-2025)Claire Zar-Kessler, MD, MPH (2025-present) ## Revision History 22 May 2025 (bp) Comprehensive update posted live 12 April 2018 (ha) Comprehensive update posted live 30 August 2012 (me) Review posted live 4 May 2012 (hha) Original submission • 22 May 2025 (bp) Comprehensive update posted live • 12 April 2018 (ha) Comprehensive update posted live • 30 August 2012 (me) Review posted live • 4 May 2012 (hha) Original submission ## References ## Literature Cited Newborn male with Pitt-Hopkins syndrome. Note wide nasal root with prominent nasal bridge, flared nasal alae, depressed nasal tip, ears with overfolded helix, and full everted vermilion of the lower lip. Boy age seven years with Pitt-Hopkins syndrome (same individual as in Boy age 13 years with Pitt-Hopkins syndrome (same individual as in Girl age ten years with Pitt-Hopkins syndrome. Note deeply set eyes, thin lateral eyebrows, wide nasal ridge, depressed nasal tip, thick and everted vermilion of the lower lip, widely spaced teeth, and prominent chin. Woman age 24 years with Pitt-Hopkins syndrome (same individual as in	[]	30/8/2012	22/5/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pjs	pjs	[ "PJS", "PJS", "Serine/threonine-protein kinase STK11", "STK11", "Peutz-Jeghers Syndrome" ]	Peutz-Jeghers Syndrome	Thomas J McGarrity, Christopher I Amos, Maria J Baker	Summary Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis, mucocutaneous pigmentation, and cancer predisposition. PJS-type hamartomatous polyps are most common in the small intestine (in order of prevalence: jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and extraintestinal sites including the renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, and ureters. GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection. Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Recognition of the distinctive skin manifestations is important especially in individuals who have PJS as the result of a The diagnosis of PJS is based on clinical findings. Identification of a heterozygous pathogenic variant in In adults: Colonoscopy, upper endoscopy, and small-bowel examination by MRE or VCE every two to three years beginning at age 18 years; clinical breast examination in women every six months beginning at age 30 years; mammogram and breast MRI in women annually beginning at age 30 years; pelvic examination and pap smear in women annually beginning at age 18 to 20 years. Pancreatic imaging with endoscopic ultrasound or MRI/MRCP annually beginning at age 30 to 35 years. PJS is inherited in an autosomal dominant manner. The majority of individuals diagnosed with PJS have an affected parent; however, many individuals with PJS represent apparently simplex cases. The exact proportion of individuals who have PJS as the result of a	## Diagnosis Peutz-Jeghers syndrome (PJS) Two or more PJS-type hamartomatous polyps of the gastrointestinal (GI) tract. Characteristic mucocutaneous pigmentation and hyperpigmented macules (periorbital, lips, fingers, nose, toes, and anus) Gynecomastia in males as a result of estrogen-producing Sertoli cell testicular tumors History of intussusception, especially in a child or young adult Note: Individuals with PJS also develop many other polyps; polyps showing adenomatous changes frequently arise in the colon and may cause confusion with The clinical diagnosis of PJS Two or more histologically confirmed PJS-type hamartomatous polyps Any number of PJS-type polyps detected in an individual who has a family history of PJS in at least one close relative Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in at least one close relative Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation The molecular diagnosis of PJS Note: Identification of a heterozygous Molecular genetic testing approaches can include Note: If no For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Peutz-Jeghers Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals without a pathogenic identified, sequence analysis and deletion/duplication testing of an alternate DNA source (e.g., buccal cells) for somatic mosaicism should be considered. To date, seven individuals have been identified with somatic mosaic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Includes larger deletions, such as whole-gene deletions of Of 25 individuals who had PJS but did not have a detectable • Two or more PJS-type hamartomatous polyps of the gastrointestinal (GI) tract. • Characteristic mucocutaneous pigmentation and hyperpigmented macules (periorbital, lips, fingers, nose, toes, and anus) • Gynecomastia in males as a result of estrogen-producing Sertoli cell testicular tumors • History of intussusception, especially in a child or young adult • Two or more histologically confirmed PJS-type hamartomatous polyps • Any number of PJS-type polyps detected in an individual who has a family history of PJS in at least one close relative • Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in at least one close relative • Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation ## Suggestive Findings Peutz-Jeghers syndrome (PJS) Two or more PJS-type hamartomatous polyps of the gastrointestinal (GI) tract. Characteristic mucocutaneous pigmentation and hyperpigmented macules (periorbital, lips, fingers, nose, toes, and anus) Gynecomastia in males as a result of estrogen-producing Sertoli cell testicular tumors History of intussusception, especially in a child or young adult Note: Individuals with PJS also develop many other polyps; polyps showing adenomatous changes frequently arise in the colon and may cause confusion with • Two or more PJS-type hamartomatous polyps of the gastrointestinal (GI) tract. • Characteristic mucocutaneous pigmentation and hyperpigmented macules (periorbital, lips, fingers, nose, toes, and anus) • Gynecomastia in males as a result of estrogen-producing Sertoli cell testicular tumors • History of intussusception, especially in a child or young adult ## Establishing the Diagnosis The clinical diagnosis of PJS Two or more histologically confirmed PJS-type hamartomatous polyps Any number of PJS-type polyps detected in an individual who has a family history of PJS in at least one close relative Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in at least one close relative Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation The molecular diagnosis of PJS Note: Identification of a heterozygous Molecular genetic testing approaches can include Note: If no For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Peutz-Jeghers Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In individuals without a pathogenic identified, sequence analysis and deletion/duplication testing of an alternate DNA source (e.g., buccal cells) for somatic mosaicism should be considered. To date, seven individuals have been identified with somatic mosaic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Includes larger deletions, such as whole-gene deletions of Of 25 individuals who had PJS but did not have a detectable • Two or more histologically confirmed PJS-type hamartomatous polyps • Any number of PJS-type polyps detected in an individual who has a family history of PJS in at least one close relative • Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in at least one close relative • Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation ## Clinical Characteristics Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis and mucocutaneous pigmentation. The risk for GI and extraintestinal malignancies is significantly increased. Distinct benign and malignant gonadal and gynecologic tumors can also be seen. Variable expressivity is common; for example, some affected individuals in families with PJS may have only polyps or perioral pigmentation. Adenomas also appear with increased prevalence throughout the GI tract. The malignant potential of PJS-type hamartomatous polyps is unknown; however, the polyps can cause significant complications including bowel obstruction, rectal prolapse, and/or severe GI bleeding with secondary anemia requiring multiple emergency laparotomies and bowel resections. The age of onset of symptoms from polyps is variable, with some children developing symptoms within the first few years of life. The risk of intussusception was estimated to be 44% by age ten years and 50% by age 20 years [ Significant interfamilial variability in the age at which polyps first appear is observed, suggesting that the natural history of polyps in a family may be a predictor of severity for offspring. Increasingly, case series have demonstrated a younger onset of GI pathology either through diagnostic testing or evaluation based on a positive family history. These data have prompted recommendations to begin surveillance at a younger age to detect and remove GI polyps, decrease risk of malignancy, and reduce complications of bowel obstruction [ Histologically, increased melanocytes are observed at the epidermal-dermal junction, with increased melanin in the basal cells. No malignancy risk is associated with MM. In sporadic cases, MM is often the first diagnostic clue to PJS. Males occasionally develop large cell calcifying Sertoli cell tumors of the testes derived from sperm cord cells. These tumors may secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated. Multifocal calcifications are typically seen on testicular ultrasound. Aromatase inhibitors help reverse the hormonal effects of Sertoli cell tumors including reduction of gynecomastia and slowing of linear bone growth and bone age [ Cumulative Risk of Cancers in Peutz-Jeghers Syndrome Adapted from SCTAT = sex cord tumor with annular tubules The current risk for gynecologic cancer in females with PJS is estimated to range from 18% to 50% by age 50 years [ Data on genotype-phenotype correlation related to In a study of 297 individuals with PJS, the type or site of the To date all reported individuals with pathogenic variants in The following terms have also been used for PJS: Polyp and spots syndrome Inherited hamartomatous polyps in association with mucocutaneous melanocyte macules Hutchinson Weber-Peutz syndrome Perioral lentiginosis (sometimes used inappropriately as a synonym for PJS) Birth prevalence has not been reliably established; estimates range widely, from 1:25,000 to 1:280,000 [ PJS can occur in any racial or ethnic group. • Polyp and spots syndrome • Inherited hamartomatous polyps in association with mucocutaneous melanocyte macules • Hutchinson Weber-Peutz syndrome • Perioral lentiginosis (sometimes used inappropriately as a synonym for PJS) ## Clinical Description Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis and mucocutaneous pigmentation. The risk for GI and extraintestinal malignancies is significantly increased. Distinct benign and malignant gonadal and gynecologic tumors can also be seen. Variable expressivity is common; for example, some affected individuals in families with PJS may have only polyps or perioral pigmentation. Adenomas also appear with increased prevalence throughout the GI tract. The malignant potential of PJS-type hamartomatous polyps is unknown; however, the polyps can cause significant complications including bowel obstruction, rectal prolapse, and/or severe GI bleeding with secondary anemia requiring multiple emergency laparotomies and bowel resections. The age of onset of symptoms from polyps is variable, with some children developing symptoms within the first few years of life. The risk of intussusception was estimated to be 44% by age ten years and 50% by age 20 years [ Significant interfamilial variability in the age at which polyps first appear is observed, suggesting that the natural history of polyps in a family may be a predictor of severity for offspring. Increasingly, case series have demonstrated a younger onset of GI pathology either through diagnostic testing or evaluation based on a positive family history. These data have prompted recommendations to begin surveillance at a younger age to detect and remove GI polyps, decrease risk of malignancy, and reduce complications of bowel obstruction [ Histologically, increased melanocytes are observed at the epidermal-dermal junction, with increased melanin in the basal cells. No malignancy risk is associated with MM. In sporadic cases, MM is often the first diagnostic clue to PJS. Males occasionally develop large cell calcifying Sertoli cell tumors of the testes derived from sperm cord cells. These tumors may secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated. Multifocal calcifications are typically seen on testicular ultrasound. Aromatase inhibitors help reverse the hormonal effects of Sertoli cell tumors including reduction of gynecomastia and slowing of linear bone growth and bone age [ Cumulative Risk of Cancers in Peutz-Jeghers Syndrome Adapted from SCTAT = sex cord tumor with annular tubules The current risk for gynecologic cancer in females with PJS is estimated to range from 18% to 50% by age 50 years [ ## Genotype-Phenotype Correlations Data on genotype-phenotype correlation related to In a study of 297 individuals with PJS, the type or site of the ## Penetrance To date all reported individuals with pathogenic variants in ## Nomenclature The following terms have also been used for PJS: Polyp and spots syndrome Inherited hamartomatous polyps in association with mucocutaneous melanocyte macules Hutchinson Weber-Peutz syndrome Perioral lentiginosis (sometimes used inappropriately as a synonym for PJS) • Polyp and spots syndrome • Inherited hamartomatous polyps in association with mucocutaneous melanocyte macules • Hutchinson Weber-Peutz syndrome • Perioral lentiginosis (sometimes used inappropriately as a synonym for PJS) ## Prevalence Birth prevalence has not been reliably established; estimates range widely, from 1:25,000 to 1:280,000 [ PJS can occur in any racial or ethnic group. ## Genetically Related (Allelic) Disorders One individual with a pathogenic nonsense variant of ## Differential Diagnosis Autosomal Dominant Genetic Cancer Syndromes Showing Signs and Symptoms that Overlap with Peutz-Jeghers Syndrome CC = Carney complex; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; JPS = juvenile polyposis syndrome; MM = melanocytic macules; PJS = Peutz-Jeghers syndrome The term "juvenile" refers to the type of polyp, not the age of onset of polyps. HMPS can be caused by either a JPS may occur with hereditary hemorrhagic telangiectasia (HHT); or the combined entity of JPS-HHT. The JPS-HHT overlap syndrome has been reported in 22% of individuals with JPS due to a Of 14 individuals with juvenile-type polyposis: two had pathogenic variants in Of 23 individuals with hyperplastic/mixed polyposis, two had Of nine individuals with an unknown hamartomatous polyposis, pathogenic variants were seen in Laugier-Hunziker syndrome (LHS), characterized by the presence of perioral, digit, and nailbed lentiginosis (small, well-demarcated; dark-brown to blue-black in color). This condition usually develops in adults and the hyperpigmentation is progressive. LHS has not been associated with any known exposure and has not been reported to occur in families. LHS is diagnosed by the absence of diseases associated with mucocutaneous pigmentation such as underlying PJS and Addison's disease [ A fixed drug reaction A normal feature, especially in African Americans [ Sex cord tumors with annular tubules (SCTAT); 50% are associated with PJS; the remainder may occur as an isolated finding. Calcifying Sertoli tumors of the testes and adenoma malignum of the cervix in women; these may also occur as an isolated finding or in other disorders. • Of 14 individuals with juvenile-type polyposis: two had pathogenic variants in • Of 23 individuals with hyperplastic/mixed polyposis, two had • Of nine individuals with an unknown hamartomatous polyposis, pathogenic variants were seen in • Laugier-Hunziker syndrome (LHS), characterized by the presence of perioral, digit, and nailbed lentiginosis (small, well-demarcated; dark-brown to blue-black in color). This condition usually develops in adults and the hyperpigmentation is progressive. LHS has not been associated with any known exposure and has not been reported to occur in families. LHS is diagnosed by the absence of diseases associated with mucocutaneous pigmentation such as underlying PJS and Addison's disease [ • A fixed drug reaction • A normal feature, especially in African Americans [ • Sex cord tumors with annular tubules (SCTAT); 50% are associated with PJS; the remainder may occur as an isolated finding. • Calcifying Sertoli tumors of the testes and adenoma malignum of the cervix in women; these may also occur as an isolated finding or in other disorders. ## Management To establish the extent of disease and need for clinical follow up in an individual diagnosed with Peutz-Jeghers syndrome (PJS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Peutz-Jeghers Syndrome Colonoscopy Upper endoscopy Small-bowel exam by MRE or VCE Pelvic exam for uterine & ovarian cancer (typically SCTAT) Pap smear for cervical cancer (typically adenoma malignum) Testicular exam Exam for feminizing changes in males Testicular ultrasound exam if clinically indicated MOI= mode of inheritance; MRCP = magnetic resonance cholangiopancreatography; MRE = magnetic resonance enterography; PJS = Peutz-Jeghers syndrome; SCTAT = sex cord tumors with annular tubules; VCE = video capsule endoscopy Medical geneticist, certified genetic counselor, certified advanced genetic nurse To decrease the sequelae of large polyps including bleeding, anemia, obstruction, and intussusception To reduce the risk for cancer by the malignant transformation of PJS-type polyps The luminal polyp-related complications arise in childhood whereas cancer in PJS is typically seen in adulthood. Some evidence indicates that routine endoscopy and intraoperative enteroscopy with polypectomy decreases the frequency of emergency laparotomy and bowel loss. From St Mark's PJS registry of 51 affected individuals who underwent surveillance endoscopies, none had emergency surgical interventions and no GI luminal cancers were diagnosed [ Until recently, distal small-bowel polyps that are beyond the reach of conventional endoscopy have been difficult to manage. In the past, barium contrast upper-GI series with a small-bowel follow through has been recommended. However, recent advances allow better diagnosis and eradication of small-bowel polyps, often without laparotomy and with a decrease in the radiation burden related to prior dependence on CT scan imaging [ Video capsule endoscopy (VCE) allows for better visualization of the small-bowel polyps than barium x-rays and is recommended as a first-line surveillance procedure. In children, the capsule can be deployed in the duodenum after upper endoscopy. The results of the small-bowel imaging studies direct the endoscopic removal of polyps. See Note. Magnetic resonance enterography (MRE) is a reliable procedure for the detection of larger small-bowel polyps with similar sensitivity to VCE, and avoids the radiation exposure of CT enterography. CT and MR enteroclysis are alternative procedures but are less well tolerated. See Note. Balloon-assisted enteroscopy (BAE) can remove distal small-bowel polyps with or without laparotomy [ Note: (1) VCE was preferred by individuals and detected more large polyps than MRE [ Although not specifically studied in females with PJS, prophylactic mastectomy may be considered to manage the increased risk for breast cancer based on the family history or other clinical factors. Prophylactic hysterectomy and bilateral salpingo-oophorectomy to prevent gynecologic malignancy in women may be considered. In some disorders with a high risk for malignancy (e.g., Surveillance guidelines for PJS have evolved. With accumulation of clinical data demonstrating a high incidence of polyp-associated complications in young individuals with PJS and the greater availability of endoscopic expertise and pediatric-sized endoscopes, the trend is to begin endoscopic surveillance at age eight years. Some recommend beginning surveillance at age five years [ Recommended Surveillance Guidelines for Children and Adolescents with Peutz-Jeghers Syndrome If the baseline endoscopy at age 8 yrs is negative, rpt at age 18 yrs. If polyps are detected at baseline, endoscopy every 1-3 yrs based on size, number, & histopathology Every 1-3 yrs beginning at age 8 yrs Or frequency based on findings; repeat at least by age 18 yrs. Testicular exam Exam for feminizing changes in males Testicular ultrasound exam if clinically indicated MRE = magnetic resonance enterography; VCE = video capsule endoscopy Recommended Surveillance Guidelines for Adults with Peutz-Jeghers Syndrome Colonoscopy Upper endoscopy Small-bowel exam by MRE or VCE Pelvic exam for uterine & ovarian cancer (typically SCTAT) Pap smear for cervical cancer (typically adenoma malignum) Modified from MRCP = magnetic resonance cholangiopancreatography; MRE = magnetic resonance enterography; SCTAT = sex cord tumors with annular tubules; VCE = video capsule endoscopy Shorter intervals may be indicated depending on polyp size, number, and pathology. No agents that increase the risk for polyps or malignancy in individuals with PJS have been described. Due to the increased risk for cervical, lung, and pancreatic cancer in individuals with PJS, smoking should be avoided. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Morbidity and mortality can be reduced in those individuals identified to have the family-specific pathogenic variant by means of early diagnosis, treatment, and surveillance (see Relatives in whom the familial pathogenic variant is not identified (and who do not meet clinical diagnostic criteria for PJS) should not be considered as requiring PJS surveillance [ Clinical diagnostic evaluations to identify those family members who will benefit from early treatment; Surveillance as outlined in See Search Several animal models of PJS have been generated using Selective COX-2 inhibitors have been used to inhibit premalignant adenoma formation. To date, however, no clinical trials in the US are studying efficacy of COX-2 inhibitors in reducing polyp formation in individuals with PJS. Increased cardiovascular and cerebrovascular adverse events with selective COX-2 inhibitors limit their use. Observation of hyperactivation of mTOR in hereditary hamartoma syndrome and a variety of cancers suggests that mTOR inhibitors may be useful in the management of PJS [ In addition, in two small trials in persons with • Colonoscopy • Upper endoscopy • Small-bowel exam by MRE or VCE • Pelvic exam for uterine & ovarian cancer (typically SCTAT) • Pap smear for cervical cancer (typically adenoma malignum) • Testicular exam • Exam for feminizing changes in males • Testicular ultrasound exam if clinically indicated • To decrease the sequelae of large polyps including bleeding, anemia, obstruction, and intussusception • To reduce the risk for cancer by the malignant transformation of PJS-type polyps • Video capsule endoscopy (VCE) allows for better visualization of the small-bowel polyps than barium x-rays and is recommended as a first-line surveillance procedure. In children, the capsule can be deployed in the duodenum after upper endoscopy. The results of the small-bowel imaging studies direct the endoscopic removal of polyps. See Note. • Magnetic resonance enterography (MRE) is a reliable procedure for the detection of larger small-bowel polyps with similar sensitivity to VCE, and avoids the radiation exposure of CT enterography. CT and MR enteroclysis are alternative procedures but are less well tolerated. See Note. • Balloon-assisted enteroscopy (BAE) can remove distal small-bowel polyps with or without laparotomy [ • If the baseline endoscopy at age 8 yrs is negative, rpt at age 18 yrs. • If polyps are detected at baseline, endoscopy every 1-3 yrs based on size, number, & histopathology • Every 1-3 yrs beginning at age 8 yrs • Or frequency based on findings; repeat at least by age 18 yrs. • Testicular exam • Exam for feminizing changes in males • Testicular ultrasound exam if clinically indicated • Colonoscopy • Upper endoscopy • Small-bowel exam by MRE or VCE • Pelvic exam for uterine & ovarian cancer (typically SCTAT) • Pap smear for cervical cancer (typically adenoma malignum) • Morbidity and mortality can be reduced in those individuals identified to have the family-specific pathogenic variant by means of early diagnosis, treatment, and surveillance (see • Relatives in whom the familial pathogenic variant is not identified (and who do not meet clinical diagnostic criteria for PJS) should not be considered as requiring PJS surveillance [ • Clinical diagnostic evaluations to identify those family members who will benefit from early treatment; • Surveillance as outlined in ## Evaluations Following Initial Diagnosis To establish the extent of disease and need for clinical follow up in an individual diagnosed with Peutz-Jeghers syndrome (PJS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Peutz-Jeghers Syndrome Colonoscopy Upper endoscopy Small-bowel exam by MRE or VCE Pelvic exam for uterine & ovarian cancer (typically SCTAT) Pap smear for cervical cancer (typically adenoma malignum) Testicular exam Exam for feminizing changes in males Testicular ultrasound exam if clinically indicated MOI= mode of inheritance; MRCP = magnetic resonance cholangiopancreatography; MRE = magnetic resonance enterography; PJS = Peutz-Jeghers syndrome; SCTAT = sex cord tumors with annular tubules; VCE = video capsule endoscopy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Colonoscopy • Upper endoscopy • Small-bowel exam by MRE or VCE • Pelvic exam for uterine & ovarian cancer (typically SCTAT) • Pap smear for cervical cancer (typically adenoma malignum) • Testicular exam • Exam for feminizing changes in males • Testicular ultrasound exam if clinically indicated ## Treatment of Manifestations To decrease the sequelae of large polyps including bleeding, anemia, obstruction, and intussusception To reduce the risk for cancer by the malignant transformation of PJS-type polyps The luminal polyp-related complications arise in childhood whereas cancer in PJS is typically seen in adulthood. Some evidence indicates that routine endoscopy and intraoperative enteroscopy with polypectomy decreases the frequency of emergency laparotomy and bowel loss. From St Mark's PJS registry of 51 affected individuals who underwent surveillance endoscopies, none had emergency surgical interventions and no GI luminal cancers were diagnosed [ Until recently, distal small-bowel polyps that are beyond the reach of conventional endoscopy have been difficult to manage. In the past, barium contrast upper-GI series with a small-bowel follow through has been recommended. However, recent advances allow better diagnosis and eradication of small-bowel polyps, often without laparotomy and with a decrease in the radiation burden related to prior dependence on CT scan imaging [ Video capsule endoscopy (VCE) allows for better visualization of the small-bowel polyps than barium x-rays and is recommended as a first-line surveillance procedure. In children, the capsule can be deployed in the duodenum after upper endoscopy. The results of the small-bowel imaging studies direct the endoscopic removal of polyps. See Note. Magnetic resonance enterography (MRE) is a reliable procedure for the detection of larger small-bowel polyps with similar sensitivity to VCE, and avoids the radiation exposure of CT enterography. CT and MR enteroclysis are alternative procedures but are less well tolerated. See Note. Balloon-assisted enteroscopy (BAE) can remove distal small-bowel polyps with or without laparotomy [ Note: (1) VCE was preferred by individuals and detected more large polyps than MRE [ • To decrease the sequelae of large polyps including bleeding, anemia, obstruction, and intussusception • To reduce the risk for cancer by the malignant transformation of PJS-type polyps • Video capsule endoscopy (VCE) allows for better visualization of the small-bowel polyps than barium x-rays and is recommended as a first-line surveillance procedure. In children, the capsule can be deployed in the duodenum after upper endoscopy. The results of the small-bowel imaging studies direct the endoscopic removal of polyps. See Note. • Magnetic resonance enterography (MRE) is a reliable procedure for the detection of larger small-bowel polyps with similar sensitivity to VCE, and avoids the radiation exposure of CT enterography. CT and MR enteroclysis are alternative procedures but are less well tolerated. See Note. • Balloon-assisted enteroscopy (BAE) can remove distal small-bowel polyps with or without laparotomy [ ## Prevention of Primary Manifestations Although not specifically studied in females with PJS, prophylactic mastectomy may be considered to manage the increased risk for breast cancer based on the family history or other clinical factors. Prophylactic hysterectomy and bilateral salpingo-oophorectomy to prevent gynecologic malignancy in women may be considered. In some disorders with a high risk for malignancy (e.g., ## Surveillance Surveillance guidelines for PJS have evolved. With accumulation of clinical data demonstrating a high incidence of polyp-associated complications in young individuals with PJS and the greater availability of endoscopic expertise and pediatric-sized endoscopes, the trend is to begin endoscopic surveillance at age eight years. Some recommend beginning surveillance at age five years [ Recommended Surveillance Guidelines for Children and Adolescents with Peutz-Jeghers Syndrome If the baseline endoscopy at age 8 yrs is negative, rpt at age 18 yrs. If polyps are detected at baseline, endoscopy every 1-3 yrs based on size, number, & histopathology Every 1-3 yrs beginning at age 8 yrs Or frequency based on findings; repeat at least by age 18 yrs. Testicular exam Exam for feminizing changes in males Testicular ultrasound exam if clinically indicated MRE = magnetic resonance enterography; VCE = video capsule endoscopy Recommended Surveillance Guidelines for Adults with Peutz-Jeghers Syndrome Colonoscopy Upper endoscopy Small-bowel exam by MRE or VCE Pelvic exam for uterine & ovarian cancer (typically SCTAT) Pap smear for cervical cancer (typically adenoma malignum) Modified from MRCP = magnetic resonance cholangiopancreatography; MRE = magnetic resonance enterography; SCTAT = sex cord tumors with annular tubules; VCE = video capsule endoscopy Shorter intervals may be indicated depending on polyp size, number, and pathology. • If the baseline endoscopy at age 8 yrs is negative, rpt at age 18 yrs. • If polyps are detected at baseline, endoscopy every 1-3 yrs based on size, number, & histopathology • Every 1-3 yrs beginning at age 8 yrs • Or frequency based on findings; repeat at least by age 18 yrs. • Testicular exam • Exam for feminizing changes in males • Testicular ultrasound exam if clinically indicated • Colonoscopy • Upper endoscopy • Small-bowel exam by MRE or VCE • Pelvic exam for uterine & ovarian cancer (typically SCTAT) • Pap smear for cervical cancer (typically adenoma malignum) ## Agents/Circumstances to Avoid No agents that increase the risk for polyps or malignancy in individuals with PJS have been described. Due to the increased risk for cervical, lung, and pancreatic cancer in individuals with PJS, smoking should be avoided. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Morbidity and mortality can be reduced in those individuals identified to have the family-specific pathogenic variant by means of early diagnosis, treatment, and surveillance (see Relatives in whom the familial pathogenic variant is not identified (and who do not meet clinical diagnostic criteria for PJS) should not be considered as requiring PJS surveillance [ Clinical diagnostic evaluations to identify those family members who will benefit from early treatment; Surveillance as outlined in See • Morbidity and mortality can be reduced in those individuals identified to have the family-specific pathogenic variant by means of early diagnosis, treatment, and surveillance (see • Relatives in whom the familial pathogenic variant is not identified (and who do not meet clinical diagnostic criteria for PJS) should not be considered as requiring PJS surveillance [ • Clinical diagnostic evaluations to identify those family members who will benefit from early treatment; • Surveillance as outlined in ## Therapies Under Investigation Search ## Other Several animal models of PJS have been generated using Selective COX-2 inhibitors have been used to inhibit premalignant adenoma formation. To date, however, no clinical trials in the US are studying efficacy of COX-2 inhibitors in reducing polyp formation in individuals with PJS. Increased cardiovascular and cerebrovascular adverse events with selective COX-2 inhibitors limit their use. Observation of hyperactivation of mTOR in hereditary hamartoma syndrome and a variety of cancers suggests that mTOR inhibitors may be useful in the management of PJS [ In addition, in two small trials in persons with ## Genetic Counseling Peutz-Jeghers syndrome (PJS) is inherited in an autosomal dominant manner. The majority of individuals diagnosed with PJS have an affected parent. In large series, 60%-78% of individuals with PJS had affected relatives [ Many individuals diagnosed with PJS represent apparently simplex cases (i.e., a single affected family member). In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a If the proband appears to be the only affected family member, recommendations for the evaluation of parents of a proband include: Molecular genetic testing if an Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). If the pathogenic variant identified in the proband is not identified in either parent, neither parent has clinical findings consistent with PJS, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the The family history of some individuals diagnosed with PJS may appear to be negative because of failure to recognize the disorder in family members or early death of the parent (and other relatives) before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband and/or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. PJS is marked by a wide range of phenotypic expression in family members with the same If the proband has a known If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PJS because of the possibility of parental mosaicism. Each child of an individual with PJS and an identified The risk to the offspring of a proband with a clinical diagnosis of PJS, a negative family history, and no identified See Management, Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The majority of individuals diagnosed with PJS have an affected parent. In large series, 60%-78% of individuals with PJS had affected relatives [ • Many individuals diagnosed with PJS represent apparently simplex cases (i.e., a single affected family member). • In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ • In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a • In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ • In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a • If the proband appears to be the only affected family member, recommendations for the evaluation of parents of a proband include: • Molecular genetic testing if an • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). • Molecular genetic testing if an • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). • If the pathogenic variant identified in the proband is not identified in either parent, neither parent has clinical findings consistent with PJS, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the • The family history of some individuals diagnosed with PJS may appear to be negative because of failure to recognize the disorder in family members or early death of the parent (and other relatives) before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband and/or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ • In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a • Molecular genetic testing if an • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. PJS is marked by a wide range of phenotypic expression in family members with the same • If the proband has a known • If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PJS because of the possibility of parental mosaicism. • Each child of an individual with PJS and an identified • The risk to the offspring of a proband with a clinical diagnosis of PJS, a negative family history, and no identified • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Peutz-Jeghers syndrome (PJS) is inherited in an autosomal dominant manner. ## Risk to Family Members The majority of individuals diagnosed with PJS have an affected parent. In large series, 60%-78% of individuals with PJS had affected relatives [ Many individuals diagnosed with PJS represent apparently simplex cases (i.e., a single affected family member). In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a If the proband appears to be the only affected family member, recommendations for the evaluation of parents of a proband include: Molecular genetic testing if an Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). If the pathogenic variant identified in the proband is not identified in either parent, neither parent has clinical findings consistent with PJS, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the The family history of some individuals diagnosed with PJS may appear to be negative because of failure to recognize the disorder in family members or early death of the parent (and other relatives) before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband and/or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. PJS is marked by a wide range of phenotypic expression in family members with the same If the proband has a known If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PJS because of the possibility of parental mosaicism. Each child of an individual with PJS and an identified The risk to the offspring of a proband with a clinical diagnosis of PJS, a negative family history, and no identified • The majority of individuals diagnosed with PJS have an affected parent. In large series, 60%-78% of individuals with PJS had affected relatives [ • Many individuals diagnosed with PJS represent apparently simplex cases (i.e., a single affected family member). • In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ • In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a • In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ • In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a • If the proband appears to be the only affected family member, recommendations for the evaluation of parents of a proband include: • Molecular genetic testing if an • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). • Molecular genetic testing if an • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). • If the pathogenic variant identified in the proband is not identified in either parent, neither parent has clinical findings consistent with PJS, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the • The family history of some individuals diagnosed with PJS may appear to be negative because of failure to recognize the disorder in family members or early death of the parent (and other relatives) before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband and/or molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • In the series noted above, 17%-40% of probands represent apparently simplex cases. In a separate study, between 30% and 45% of probands represent simplex cases [ • In a study of 38 individuals with PJS, 11 of 26 probands had the disorder as the result of a • Molecular genetic testing if an • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in PJS. Somatic mosaicism can have variable effects on severity of the phenotype depending on which tissues have the • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. PJS is marked by a wide range of phenotypic expression in family members with the same • If the proband has a known • If the genetic status of the parents is unknown but they are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PJS because of the possibility of parental mosaicism. • Each child of an individual with PJS and an identified • The risk to the offspring of a proband with a clinical diagnosis of PJS, a negative family history, and no identified ## Related Genetic Counseling Issues See Management, Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • ## Molecular Genetics Peutz-Jeghers Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Peutz-Jeghers Syndrome ( STK11 activates STK11 expression was shown to cause apoptosis in epithelial cells [ STK11 was reported to phosphorylate AMPK and several other members of the AMPK-related subfamily of kinases including the microtubule affinity-regulating kinases (MARKs) to regulate cell polarity [ Through activation of AMPK by phosphorylation, STK11 plays a role in energy metabolism [ Loss of STK11 increased tumor-promoting cytokines with reduced expression of PD-1 ligand in mouse and human tumors [ More than 300 • STK11 activates • STK11 expression was shown to cause apoptosis in epithelial cells [ • STK11 was reported to phosphorylate AMPK and several other members of the AMPK-related subfamily of kinases including the microtubule affinity-regulating kinases (MARKs) to regulate cell polarity [ • Through activation of AMPK by phosphorylation, STK11 plays a role in energy metabolism [ • Loss of STK11 increased tumor-promoting cytokines with reduced expression of PD-1 ligand in mouse and human tumors [ ## Molecular Pathogenesis STK11 activates STK11 expression was shown to cause apoptosis in epithelial cells [ STK11 was reported to phosphorylate AMPK and several other members of the AMPK-related subfamily of kinases including the microtubule affinity-regulating kinases (MARKs) to regulate cell polarity [ Through activation of AMPK by phosphorylation, STK11 plays a role in energy metabolism [ Loss of STK11 increased tumor-promoting cytokines with reduced expression of PD-1 ligand in mouse and human tumors [ More than 300 • STK11 activates • STK11 expression was shown to cause apoptosis in epithelial cells [ • STK11 was reported to phosphorylate AMPK and several other members of the AMPK-related subfamily of kinases including the microtubule affinity-regulating kinases (MARKs) to regulate cell polarity [ • Through activation of AMPK by phosphorylation, STK11 plays a role in energy metabolism [ • Loss of STK11 increased tumor-promoting cytokines with reduced expression of PD-1 ligand in mouse and human tumors [ ## Cancer and Benign Tumors ## Chapter Notes Dr Amos is a research scholar in the Cancer Prevention Research Institute of Texas supported by RR170048. Dr McGarrity is a gastroenterologist who partially specializes in the diagnosis and treatment of PJS. Dr Baker is a genetic counselor and medical geneticist who specializes in the recognition of hereditary cancer predisposition syndromes. Christopher I Amos, PhD (2001-present)Maria J Baker, PhD (2016-present)Marsha L Frazier, PhD; University of Texas MD Anderson Cancer Center (2001-2016)Thomas J McGarrity, MD (2001-present)Chongjuan Wei, PhD; University of Texas MD Anderson Cancer Center (2001-2016) 2 September 2021 (sw) Comprehensive update posted live 14 July 2016 (sw) Comprehensive update posted live 25 July 2013 (me) Comprehensive update posted live 22 February 2011 (me) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 15 May 2007 (me) Comprehensive update posted live 19 May 2004 (ca) Revision: Genetic Counseling 26 November 2003 (me) Comprehensive update posted live 23 February 2001 (me) Review posted live 11 July 2000 (ca) Original submission • 2 September 2021 (sw) Comprehensive update posted live • 14 July 2016 (sw) Comprehensive update posted live • 25 July 2013 (me) Comprehensive update posted live • 22 February 2011 (me) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 15 May 2007 (me) Comprehensive update posted live • 19 May 2004 (ca) Revision: Genetic Counseling • 26 November 2003 (me) Comprehensive update posted live • 23 February 2001 (me) Review posted live • 11 July 2000 (ca) Original submission ## Author Notes Dr Amos is a research scholar in the Cancer Prevention Research Institute of Texas supported by RR170048. Dr McGarrity is a gastroenterologist who partially specializes in the diagnosis and treatment of PJS. Dr Baker is a genetic counselor and medical geneticist who specializes in the recognition of hereditary cancer predisposition syndromes. ## Author History Christopher I Amos, PhD (2001-present)Maria J Baker, PhD (2016-present)Marsha L Frazier, PhD; University of Texas MD Anderson Cancer Center (2001-2016)Thomas J McGarrity, MD (2001-present)Chongjuan Wei, PhD; University of Texas MD Anderson Cancer Center (2001-2016) ## Revision History 2 September 2021 (sw) Comprehensive update posted live 14 July 2016 (sw) Comprehensive update posted live 25 July 2013 (me) Comprehensive update posted live 22 February 2011 (me) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 15 May 2007 (me) Comprehensive update posted live 19 May 2004 (ca) Revision: Genetic Counseling 26 November 2003 (me) Comprehensive update posted live 23 February 2001 (me) Review posted live 11 July 2000 (ca) Original submission • 2 September 2021 (sw) Comprehensive update posted live • 14 July 2016 (sw) Comprehensive update posted live • 25 July 2013 (me) Comprehensive update posted live • 22 February 2011 (me) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 15 May 2007 (me) Comprehensive update posted live • 19 May 2004 (ca) Revision: Genetic Counseling • 26 November 2003 (me) Comprehensive update posted live • 23 February 2001 (me) Review posted live • 11 July 2000 (ca) Original submission ## References ## Published Guidelines / Consensus Statements ## Literature Cited	[]	23/2/2001	2/9/2021	19/5/2004	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pkan	pkan	[ "PKAN", "PKAN", "HARP Syndrome", "Atypical PKAN", "Pantothenate kinase 2, mitochondrial", "PANK2", "Pantothenate Kinase-Associated Neurodegeneration" ]	Pantothenate Kinase-Associated Neurodegeneration	Allison Gregory, Susan J Hayflick	Summary Pantothenate kinase-associated neurodegeneration (PKAN) is a type of neurodegeneration with brain iron accumulation (NBIA). The phenotypic spectrum of PKAN includes classic PKAN and atypical PKAN. Classic PKAN is characterized by early-childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. The diagnosis of PKAN is established in a proband with the characteristic clinical features and the "eye of the tiger" sign identified on brain MRI (a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T PKAN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at risk, and preimplantation genetic testing are possible if both pathogenic variants have been identified in an affected family member.	Classic PKAN Atypical PKAN For synonyms and outdated names see For other genetic causes of these phenotypes see • Classic PKAN • Atypical PKAN ## Diagnosis Pantothenate kinase-associated neurodegeneration (PKAN) Dystonia Dysarthria Spasticity Choreoathetosis Parkinsonism Hyperreflexia Extensor toe signs Onset in first to third decade of life Gait change / loss of ambulation Pigmentary retinopathy Intellectual and developmental disabilities, mainly in children with very young onset Abnormalities of plasma ceruloplasmin concentration or copper metabolism (See Evidence of neuronal ceroid-lipofuscinosis by electron microscopy, enzymatic assay, or the presence of a pathogenic variant in any of the genes associated with this condition Pathologic evidence of spheroid bodies in the peripheral nervous system, indicative of The diagnosis of PKAN Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Dystonia Spasticity Choreoathetosis Note: (1) The sign may be absent in the early stages of disease [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PKAN and NBIA See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click NBIA International Mutation Database, Oregon Health & Science University, unpublished data Sequence analysis of the coding region and splice sites of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exon and multiexon deletions in • Dystonia • Dysarthria • Spasticity • Choreoathetosis • Parkinsonism • Hyperreflexia • Extensor toe signs • Onset in first to third decade of life • Gait change / loss of ambulation • Pigmentary retinopathy • Intellectual and developmental disabilities, mainly in children with very young onset • Abnormalities of plasma ceruloplasmin concentration or copper metabolism (See • Evidence of neuronal ceroid-lipofuscinosis by electron microscopy, enzymatic assay, or the presence of a pathogenic variant in any of the genes associated with this condition • Pathologic evidence of spheroid bodies in the peripheral nervous system, indicative of • Dystonia • Spasticity • Choreoathetosis • Dystonia • Spasticity • Choreoathetosis • • • Dystonia • Spasticity • Choreoathetosis • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Pantothenate kinase-associated neurodegeneration (PKAN) Dystonia Dysarthria Spasticity Choreoathetosis Parkinsonism Hyperreflexia Extensor toe signs Onset in first to third decade of life Gait change / loss of ambulation Pigmentary retinopathy Intellectual and developmental disabilities, mainly in children with very young onset Abnormalities of plasma ceruloplasmin concentration or copper metabolism (See Evidence of neuronal ceroid-lipofuscinosis by electron microscopy, enzymatic assay, or the presence of a pathogenic variant in any of the genes associated with this condition Pathologic evidence of spheroid bodies in the peripheral nervous system, indicative of • Dystonia • Dysarthria • Spasticity • Choreoathetosis • Parkinsonism • Hyperreflexia • Extensor toe signs • Onset in first to third decade of life • Gait change / loss of ambulation • Pigmentary retinopathy • Intellectual and developmental disabilities, mainly in children with very young onset • Abnormalities of plasma ceruloplasmin concentration or copper metabolism (See • Evidence of neuronal ceroid-lipofuscinosis by electron microscopy, enzymatic assay, or the presence of a pathogenic variant in any of the genes associated with this condition • Pathologic evidence of spheroid bodies in the peripheral nervous system, indicative of ## Establishing the Diagnosis The diagnosis of PKAN Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Dystonia Spasticity Choreoathetosis Note: (1) The sign may be absent in the early stages of disease [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PKAN and NBIA See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click NBIA International Mutation Database, Oregon Health & Science University, unpublished data Sequence analysis of the coding region and splice sites of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exon and multiexon deletions in • Dystonia • Spasticity • Choreoathetosis • Dystonia • Spasticity • Choreoathetosis • • • Dystonia • Spasticity • Choreoathetosis • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The clinical features of classic PKAN are remarkably homogeneous. It presents in early childhood, usually before age six years (mean age: 3.4 years). The most common presenting symptom is impaired gait resulting from a combination of lower-extremity dystonia and spasticity, as well as restricted visual fields in those children with retinopathy. Some children have developmental delay, which is primarily motor but occasionally global. Early histories of ADHD or toe-walking are also common. Visual symptoms may bring children with PKAN to medical attention. Corticospinal tract involvement is common and includes spasticity, hyperreflexia, and extensor toe signs. Seizures are rare. Abnormal eye movements, including vertical saccades and saccadic pursuits, are common. In one study, eight of ten individuals with PKAN had sectoral iris paralysis and partial loss of the pupillary ruff consistent with bilateral Adie's pupil [ Premature death does occur. However, with improvements in medical care, a greater number of affected individuals are living into adulthood. Orofacial dystonia can result in the secondary effects of swallowing difficulty and poor nutrition. Premature death is more likely related to these secondary effects (e.g., nutrition-related immunodeficiency, aspiration pneumonia) than to the primary neurodegenerative process. In rare cases death occurs during status dystonicus. The clinical features of atypical PKAN are more varied than those of classic PKAN. Onset is in the first three decades (mean age: 13.6 years). Progression of the atypical form is slower, and presenting features are distinct, usually involving speech as either the sole presenting feature or part of the constellation of findings. The speech defects include palilalia (repetition of words or phrases), tachylalia/tachylogia (rapid speech of words and/or phrases), and dysarthria (poor articulation, slurring). Psychiatric symptoms including personality changes with impulsivity and violent outbursts, depression, and emotional lability are common in atypical PKAN. Affected individuals may also exhibit motor and verbal tics, obsessive-compulsive behavior, and, rarely, psychotic symptoms [ As with classic PKAN, cognitive impairment may occur in individuals with atypical PKAN, but additional investigations are needed. Motor involvement is usually a later feature, although individuals with motor involvement often have been described as clumsy in childhood and adolescence. Spasticity, hyperreflexia, and other signs of corticospinal tract involvement are common and eventually limit ambulation. Conspicuously reminiscent of An essential tremor-like syndrome has also been reported [ Retinopathy is rare in atypical PKAN, and optic atrophy has not been associated with atypical PKAN. A clear genotype-phenotype correlation for PKAN has not been observed. However, individuals with two null variants (which predict no protein production) consistently have classic PKAN. Other combinations of pathogenic variants (i.e., null/missense, homozygous missense, or compound heterozygous missense) yield either classic or atypical phenotypes in no predictable pattern. Homozygosity for the pathogenic missense variant Within families, the phenotype is fairly consistent among affected individuals. Greater variance in age at onset, presenting features, and rate of progression is seen in families with atypical PKAN. The eponym Hallervorden-Spatz syndrome (HSS) is no longer favored in view of the unethical activities of these two German neuropathologists before and during World War II [ No reliable prevalence data on this rare disorder have been collected. An estimate of one to three in 1,000,000 has been suggested. This figure would imply a general population carrier frequency of 1:275-1:500. A founder effect has been described in the Netherlands [ ## Clinical Description The clinical features of classic PKAN are remarkably homogeneous. It presents in early childhood, usually before age six years (mean age: 3.4 years). The most common presenting symptom is impaired gait resulting from a combination of lower-extremity dystonia and spasticity, as well as restricted visual fields in those children with retinopathy. Some children have developmental delay, which is primarily motor but occasionally global. Early histories of ADHD or toe-walking are also common. Visual symptoms may bring children with PKAN to medical attention. Corticospinal tract involvement is common and includes spasticity, hyperreflexia, and extensor toe signs. Seizures are rare. Abnormal eye movements, including vertical saccades and saccadic pursuits, are common. In one study, eight of ten individuals with PKAN had sectoral iris paralysis and partial loss of the pupillary ruff consistent with bilateral Adie's pupil [ Premature death does occur. However, with improvements in medical care, a greater number of affected individuals are living into adulthood. Orofacial dystonia can result in the secondary effects of swallowing difficulty and poor nutrition. Premature death is more likely related to these secondary effects (e.g., nutrition-related immunodeficiency, aspiration pneumonia) than to the primary neurodegenerative process. In rare cases death occurs during status dystonicus. The clinical features of atypical PKAN are more varied than those of classic PKAN. Onset is in the first three decades (mean age: 13.6 years). Progression of the atypical form is slower, and presenting features are distinct, usually involving speech as either the sole presenting feature or part of the constellation of findings. The speech defects include palilalia (repetition of words or phrases), tachylalia/tachylogia (rapid speech of words and/or phrases), and dysarthria (poor articulation, slurring). Psychiatric symptoms including personality changes with impulsivity and violent outbursts, depression, and emotional lability are common in atypical PKAN. Affected individuals may also exhibit motor and verbal tics, obsessive-compulsive behavior, and, rarely, psychotic symptoms [ As with classic PKAN, cognitive impairment may occur in individuals with atypical PKAN, but additional investigations are needed. Motor involvement is usually a later feature, although individuals with motor involvement often have been described as clumsy in childhood and adolescence. Spasticity, hyperreflexia, and other signs of corticospinal tract involvement are common and eventually limit ambulation. Conspicuously reminiscent of An essential tremor-like syndrome has also been reported [ Retinopathy is rare in atypical PKAN, and optic atrophy has not been associated with atypical PKAN. ## Classic Pantothenate Kinase-Associated Neurodegeneration (PKAN) The clinical features of classic PKAN are remarkably homogeneous. It presents in early childhood, usually before age six years (mean age: 3.4 years). The most common presenting symptom is impaired gait resulting from a combination of lower-extremity dystonia and spasticity, as well as restricted visual fields in those children with retinopathy. Some children have developmental delay, which is primarily motor but occasionally global. Early histories of ADHD or toe-walking are also common. Visual symptoms may bring children with PKAN to medical attention. Corticospinal tract involvement is common and includes spasticity, hyperreflexia, and extensor toe signs. Seizures are rare. Abnormal eye movements, including vertical saccades and saccadic pursuits, are common. In one study, eight of ten individuals with PKAN had sectoral iris paralysis and partial loss of the pupillary ruff consistent with bilateral Adie's pupil [ Premature death does occur. However, with improvements in medical care, a greater number of affected individuals are living into adulthood. Orofacial dystonia can result in the secondary effects of swallowing difficulty and poor nutrition. Premature death is more likely related to these secondary effects (e.g., nutrition-related immunodeficiency, aspiration pneumonia) than to the primary neurodegenerative process. In rare cases death occurs during status dystonicus. ## Atypical PKAN The clinical features of atypical PKAN are more varied than those of classic PKAN. Onset is in the first three decades (mean age: 13.6 years). Progression of the atypical form is slower, and presenting features are distinct, usually involving speech as either the sole presenting feature or part of the constellation of findings. The speech defects include palilalia (repetition of words or phrases), tachylalia/tachylogia (rapid speech of words and/or phrases), and dysarthria (poor articulation, slurring). Psychiatric symptoms including personality changes with impulsivity and violent outbursts, depression, and emotional lability are common in atypical PKAN. Affected individuals may also exhibit motor and verbal tics, obsessive-compulsive behavior, and, rarely, psychotic symptoms [ As with classic PKAN, cognitive impairment may occur in individuals with atypical PKAN, but additional investigations are needed. Motor involvement is usually a later feature, although individuals with motor involvement often have been described as clumsy in childhood and adolescence. Spasticity, hyperreflexia, and other signs of corticospinal tract involvement are common and eventually limit ambulation. Conspicuously reminiscent of An essential tremor-like syndrome has also been reported [ Retinopathy is rare in atypical PKAN, and optic atrophy has not been associated with atypical PKAN. ## Genotype-Phenotype Correlations A clear genotype-phenotype correlation for PKAN has not been observed. However, individuals with two null variants (which predict no protein production) consistently have classic PKAN. Other combinations of pathogenic variants (i.e., null/missense, homozygous missense, or compound heterozygous missense) yield either classic or atypical phenotypes in no predictable pattern. Homozygosity for the pathogenic missense variant Within families, the phenotype is fairly consistent among affected individuals. Greater variance in age at onset, presenting features, and rate of progression is seen in families with atypical PKAN. ## Nomenclature The eponym Hallervorden-Spatz syndrome (HSS) is no longer favored in view of the unethical activities of these two German neuropathologists before and during World War II [ ## Prevalence No reliable prevalence data on this rare disorder have been collected. An estimate of one to three in 1,000,000 has been suggested. This figure would imply a general population carrier frequency of 1:275-1:500. A founder effect has been described in the Netherlands [ ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with pathogenic variants in ## Differential Diagnosis Pantothenate kinase-associated neurodegeneration (PKAN) is a form of Neurodegeneration with brain iron accumulation multigene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multigene panels vary by laboratory and are likely to change over time; a panel may not include a specific gene of interest. Types of NBIA: Molecular Genetics AD = autosomal dominant; AR = autosomal recessive; BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; FAHN = fatty acid hydroxylase-associated neurodegeneration; MOI = mode of inheritance; MPAN = mitochondrial membrane protein-associated neurodegeneration; PKAN = pantothenate kinase-associated neurodegeneration; XL = X-linked Some individuals with Kufor-Rakeb syndrome have high brain iron [ PKAN can be distinguished from other forms of NBIA by the following findings: Brain MRI In most individuals with non-PKAN NBIA, the globus pallidus is uniformly hypointense on T Iron deposition in the red nucleus and dentate nucleus is seen in neuroferritinopathy and aceruloplasminemia. Cerebellar atrophy is common in PLAN. Bilateral calcification of the globus pallidus, detected by CT scan, has been reported in both PKAN and BPAN [ Absence of seizures in PKAN; prominence of seizures in some forms of non-PKAN NBIA Other disorders to consider: Neuronal ceroid-lipofuscinosis Childhood-onset hereditary Dystonias such as Juvenile Tourette disorder [ One group of neuroacanthocytosis syndromes is associated with lipid malabsorption and primarily affects the spinal cord, cerebellum, and peripheral nervous system. The neurologic findings include the following: A progressive spinocerebellar degeneration with ataxia of gait, dysmetria, and dysarthria A demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia and diminished vibration and position sense Pyramidal tract signs (rare) Cranial nerve involvement (rare) These disorders include the following: Hypobetalipoproteinemia type 1 (FHBL1; OMIM Hypobetalipoproteinemia type 2 (FHBL2; OMIM FHBL1, FHBL2, and ABL share the findings of acanthocytosis, dysarthria, neuropathy, and areflexia, but differ in that ABL, FHBL1, and FHBL2 have pigmentary retinopathy and do not have basal ganglia involvement. ABL, FHBL1, and FHBL2 are caused by pathogenic variants affecting the microsomal triglyceride transfer protein causing vitamin E deficiency. ABL is inherited in an autosomal recessive manner. FHBL1 and FHBL2 have clinical manifestations in both the homozygous and heterozygous states. A second group of neuroacanthocytosis syndromes predominantly affects the central nervous system, in particular the basal ganglia, resulting in a chorea syndrome resembling • Brain MRI • In most individuals with non-PKAN NBIA, the globus pallidus is uniformly hypointense on T • Iron deposition in the red nucleus and dentate nucleus is seen in neuroferritinopathy and aceruloplasminemia. Cerebellar atrophy is common in PLAN. • Bilateral calcification of the globus pallidus, detected by CT scan, has been reported in both PKAN and BPAN [ • In most individuals with non-PKAN NBIA, the globus pallidus is uniformly hypointense on T • Iron deposition in the red nucleus and dentate nucleus is seen in neuroferritinopathy and aceruloplasminemia. Cerebellar atrophy is common in PLAN. • Bilateral calcification of the globus pallidus, detected by CT scan, has been reported in both PKAN and BPAN [ • Absence of seizures in PKAN; prominence of seizures in some forms of non-PKAN NBIA • In most individuals with non-PKAN NBIA, the globus pallidus is uniformly hypointense on T • Iron deposition in the red nucleus and dentate nucleus is seen in neuroferritinopathy and aceruloplasminemia. Cerebellar atrophy is common in PLAN. • Bilateral calcification of the globus pallidus, detected by CT scan, has been reported in both PKAN and BPAN [ • Neuronal ceroid-lipofuscinosis • Childhood-onset hereditary • Dystonias such as • Juvenile • • • • • Tourette disorder [ • A progressive spinocerebellar degeneration with ataxia of gait, dysmetria, and dysarthria • A demyelinating sensorimotor and axonal peripheral neuropathy with hyporeflexia and diminished vibration and position sense • Pyramidal tract signs (rare) • Cranial nerve involvement (rare) • Hypobetalipoproteinemia type 1 (FHBL1; OMIM • Hypobetalipoproteinemia type 2 (FHBL2; OMIM ## Management To establish the extent of disease in an individual diagnosed with pantothenate kinase-associated neurodegeneration (PKAN), the following are recommended if they have not already been completed: Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity, including evaluation of ambulation and speech Ophthalmologic assessment for evidence of retinopathy Screening developmental assessment, with referral for more formal testing if delay is indicated Assessment for physical therapy, occupational therapy, and/or speech therapy Consultation with a clinical geneticist and/or genetic counselor A consensus clinical management guideline for PKAN is available to provide management information at a detailed level [ Symptomatic treatment is aimed primarily at the Intramuscular botulinum toxin Oral baclofen, trihexyphenidyl, and clonazepam: the first-line drugs most commonly effective in PKAN Second-line drugs including clonidine, gabapentin, tetrabenazine, and pregabalin Intrathecal and intraventricular baclofen Deep brain stimulation, used clinically with increasing frequency and some evidence for initial benefit, although it may not be sustained as disease progresses [ Ablative pallidotomy or thalmotomy. These ablative procedures have mainly been replaced by DBS, but in certain individuals may still be useful [ Urgent medical treatment (often hospitalization) for status dystonicus (dystonic storm), which is a common occurrence. The PKAN consensus guideline provides detailed information about approach and management of dystonic storms [ Physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful. Referral for adaptive aids as needed (e.g., a walker or wheelchair for gait abnormalities) Speech therapy and/or assistive communication devices for PKAN-related dysarthria and speech delay Treatment and interventions for retinopathy as per ophthalmology Referral to appropriate community resources for financial services, services for the blind (if retinopathy is present), and special education Recurrent tongue biting from severe orobuccolingual dystonia is a specific challenge that is difficult to manage in PKAN. Customized bite-lock orthodontic appliances can be made and cemented in place to prevent tongue lacerations. Every effort should be made to avoid full dental extraction. Once the individual can no longer maintain an adequate diet orally due to dysphagia or respiratory complications, gastrostomy tube placement is indicated. In later stages of classic disease, tracheostomy may also be indicated. As the disease progresses, episodes of extreme distress may last for days or weeks. It is especially important during these episodes to evaluate for treatable causes of pain. These may include occult GI bleeding, urinary tract infections, mouth lacerations, and occult bone fractures. The combination of osteopenia in a nonambulatory individual with marked stress on long bones from dystonia places individuals with PKAN at especially high risk for fractures without apparent trauma. The following should be performed on a regular basis: Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status Ophthalmologic assessment Oral assessment for consequences of trauma Assessment of ambulation, environmental adaptations, speech abilities, and communication needs to help affected individuals to maintain independence Swallowing evaluation and regular dietary assessments to assure adequate nutrition Anecdotal reports of three sibs with atypical PKAN treated with alpha-tocopherol and idebenone indicated worsening of symptoms, with subsequent improvement once these compounds were stopped [JP Harpey, personal communication]. See Therapies that may have a role in other forms of NBIA but generally do not help individuals with PKAN include levodopa/carbidopa and bromocriptine. Treatment of PKAN with phosphopantothenate, the product of pantothenate kinase, is complicated by the lack of available compound as well as any information about its safety or toxicity in humans or animals. Furthermore, it is unlikely that phosphopantothenate would be readily transported across cell membranes, making the success of this hypothetical treatment doubtful. • Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity, including evaluation of ambulation and speech • Ophthalmologic assessment for evidence of retinopathy • Screening developmental assessment, with referral for more formal testing if delay is indicated • Assessment for physical therapy, occupational therapy, and/or speech therapy • Consultation with a clinical geneticist and/or genetic counselor • Intramuscular botulinum toxin • Oral baclofen, trihexyphenidyl, and clonazepam: the first-line drugs most commonly effective in PKAN • Second-line drugs including clonidine, gabapentin, tetrabenazine, and pregabalin • Intrathecal and intraventricular baclofen • Deep brain stimulation, used clinically with increasing frequency and some evidence for initial benefit, although it may not be sustained as disease progresses [ • Ablative pallidotomy or thalmotomy. These ablative procedures have mainly been replaced by DBS, but in certain individuals may still be useful [ • Urgent medical treatment (often hospitalization) for status dystonicus (dystonic storm), which is a common occurrence. The PKAN consensus guideline provides detailed information about approach and management of dystonic storms [ • Physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful. • Referral for adaptive aids as needed (e.g., a walker or wheelchair for gait abnormalities) • Speech therapy and/or assistive communication devices for PKAN-related dysarthria and speech delay • Treatment and interventions for retinopathy as per ophthalmology • Referral to appropriate community resources for financial services, services for the blind (if retinopathy is present), and special education • Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status • Ophthalmologic assessment • Oral assessment for consequences of trauma • Assessment of ambulation, environmental adaptations, speech abilities, and communication needs to help affected individuals to maintain independence • Swallowing evaluation and regular dietary assessments to assure adequate nutrition • Therapies that may have a role in other forms of NBIA but generally do not help individuals with PKAN include levodopa/carbidopa and bromocriptine. • Treatment of PKAN with phosphopantothenate, the product of pantothenate kinase, is complicated by the lack of available compound as well as any information about its safety or toxicity in humans or animals. Furthermore, it is unlikely that phosphopantothenate would be readily transported across cell membranes, making the success of this hypothetical treatment doubtful. ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with pantothenate kinase-associated neurodegeneration (PKAN), the following are recommended if they have not already been completed: Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity, including evaluation of ambulation and speech Ophthalmologic assessment for evidence of retinopathy Screening developmental assessment, with referral for more formal testing if delay is indicated Assessment for physical therapy, occupational therapy, and/or speech therapy Consultation with a clinical geneticist and/or genetic counselor • Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity, including evaluation of ambulation and speech • Ophthalmologic assessment for evidence of retinopathy • Screening developmental assessment, with referral for more formal testing if delay is indicated • Assessment for physical therapy, occupational therapy, and/or speech therapy • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations A consensus clinical management guideline for PKAN is available to provide management information at a detailed level [ Symptomatic treatment is aimed primarily at the Intramuscular botulinum toxin Oral baclofen, trihexyphenidyl, and clonazepam: the first-line drugs most commonly effective in PKAN Second-line drugs including clonidine, gabapentin, tetrabenazine, and pregabalin Intrathecal and intraventricular baclofen Deep brain stimulation, used clinically with increasing frequency and some evidence for initial benefit, although it may not be sustained as disease progresses [ Ablative pallidotomy or thalmotomy. These ablative procedures have mainly been replaced by DBS, but in certain individuals may still be useful [ Urgent medical treatment (often hospitalization) for status dystonicus (dystonic storm), which is a common occurrence. The PKAN consensus guideline provides detailed information about approach and management of dystonic storms [ Physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful. Referral for adaptive aids as needed (e.g., a walker or wheelchair for gait abnormalities) Speech therapy and/or assistive communication devices for PKAN-related dysarthria and speech delay Treatment and interventions for retinopathy as per ophthalmology Referral to appropriate community resources for financial services, services for the blind (if retinopathy is present), and special education • Intramuscular botulinum toxin • Oral baclofen, trihexyphenidyl, and clonazepam: the first-line drugs most commonly effective in PKAN • Second-line drugs including clonidine, gabapentin, tetrabenazine, and pregabalin • Intrathecal and intraventricular baclofen • Deep brain stimulation, used clinically with increasing frequency and some evidence for initial benefit, although it may not be sustained as disease progresses [ • Ablative pallidotomy or thalmotomy. These ablative procedures have mainly been replaced by DBS, but in certain individuals may still be useful [ • Urgent medical treatment (often hospitalization) for status dystonicus (dystonic storm), which is a common occurrence. The PKAN consensus guideline provides detailed information about approach and management of dystonic storms [ • Physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful. • Referral for adaptive aids as needed (e.g., a walker or wheelchair for gait abnormalities) • Speech therapy and/or assistive communication devices for PKAN-related dysarthria and speech delay • Treatment and interventions for retinopathy as per ophthalmology • Referral to appropriate community resources for financial services, services for the blind (if retinopathy is present), and special education ## Prevention of Secondary Complications Recurrent tongue biting from severe orobuccolingual dystonia is a specific challenge that is difficult to manage in PKAN. Customized bite-lock orthodontic appliances can be made and cemented in place to prevent tongue lacerations. Every effort should be made to avoid full dental extraction. Once the individual can no longer maintain an adequate diet orally due to dysphagia or respiratory complications, gastrostomy tube placement is indicated. In later stages of classic disease, tracheostomy may also be indicated. ## Surveillance As the disease progresses, episodes of extreme distress may last for days or weeks. It is especially important during these episodes to evaluate for treatable causes of pain. These may include occult GI bleeding, urinary tract infections, mouth lacerations, and occult bone fractures. The combination of osteopenia in a nonambulatory individual with marked stress on long bones from dystonia places individuals with PKAN at especially high risk for fractures without apparent trauma. The following should be performed on a regular basis: Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status Ophthalmologic assessment Oral assessment for consequences of trauma Assessment of ambulation, environmental adaptations, speech abilities, and communication needs to help affected individuals to maintain independence Swallowing evaluation and regular dietary assessments to assure adequate nutrition • Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status • Ophthalmologic assessment • Oral assessment for consequences of trauma • Assessment of ambulation, environmental adaptations, speech abilities, and communication needs to help affected individuals to maintain independence • Swallowing evaluation and regular dietary assessments to assure adequate nutrition ## Agents/Circumstances to Avoid Anecdotal reports of three sibs with atypical PKAN treated with alpha-tocopherol and idebenone indicated worsening of symptoms, with subsequent improvement once these compounds were stopped [JP Harpey, personal communication]. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation ## Other Therapies that may have a role in other forms of NBIA but generally do not help individuals with PKAN include levodopa/carbidopa and bromocriptine. Treatment of PKAN with phosphopantothenate, the product of pantothenate kinase, is complicated by the lack of available compound as well as any information about its safety or toxicity in humans or animals. Furthermore, it is unlikely that phosphopantothenate would be readily transported across cell membranes, making the success of this hypothetical treatment doubtful. • Therapies that may have a role in other forms of NBIA but generally do not help individuals with PKAN include levodopa/carbidopa and bromocriptine. • Treatment of PKAN with phosphopantothenate, the product of pantothenate kinase, is complicated by the lack of available compound as well as any information about its safety or toxicity in humans or animals. Furthermore, it is unlikely that phosphopantothenate would be readily transported across cell membranes, making the success of this hypothetical treatment doubtful. ## Genetic Counseling Pantothenate kinase-associated neurodegeneration (PKAN) is inherited in an autosomal recessive manner. The parents of an affected child are expected to be obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Individuals with PKAN rarely reproduce. The offspring of an individual with PKAN are obligate heterozygotes (carriers). The offspring are at risk of being affected only if the proband's reproductive partner is heterozygous for a Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the • The parents of an affected child are expected to be obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Individuals with PKAN rarely reproduce. • The offspring of an individual with PKAN are obligate heterozygotes (carriers). • The offspring are at risk of being affected only if the proband's reproductive partner is heterozygous for a • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Pantothenate kinase-associated neurodegeneration (PKAN) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are expected to be obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Individuals with PKAN rarely reproduce. The offspring of an individual with PKAN are obligate heterozygotes (carriers). The offspring are at risk of being affected only if the proband's reproductive partner is heterozygous for a • The parents of an affected child are expected to be obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Individuals with PKAN rarely reproduce. • The offspring of an individual with PKAN are obligate heterozygotes (carriers). • The offspring are at risk of being affected only if the proband's reproductive partner is heterozygous for a ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • • • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • Germany • ## Molecular Genetics Pantothenate Kinase-Associated Neurodegeneration: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pantothenate Kinase-Associated Neurodegeneration ( Pantothenate kinase-associated neurodegeneration (PKAN) is attributed to a deficiency or complete absence of pantothenate kinase 2, which is encoded by Rod photoreceptors continually generate membranous discs; therefore, the retinopathy frequently observed in classic PKAN may be secondary to this deficit. The biochemical perturbations leading to clinical sequelae are still not completely understood and require further investigation. Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Reference sequence is for the longest isoform, Common pathogenic variants (allele frequency): p.Gly521Arg (25%); p.Thr528Met (8%); p.Arg451Ter (3%) Homozygosity for this allele results in classic disease. Pathogenic variant resulting in PKAN, originally seen in an individual diagnosed with HARP syndrome [ ## Molecular Pathogenesis Pantothenate kinase-associated neurodegeneration (PKAN) is attributed to a deficiency or complete absence of pantothenate kinase 2, which is encoded by Rod photoreceptors continually generate membranous discs; therefore, the retinopathy frequently observed in classic PKAN may be secondary to this deficit. The biochemical perturbations leading to clinical sequelae are still not completely understood and require further investigation. Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Reference sequence is for the longest isoform, Common pathogenic variants (allele frequency): p.Gly521Arg (25%); p.Thr528Met (8%); p.Arg451Ter (3%) Homozygosity for this allele results in classic disease. Pathogenic variant resulting in PKAN, originally seen in an individual diagnosed with HARP syndrome [ ## Chapter Notes Jason Coryell, MS; Oregon Health & Science University (2004-2007) Allison Gregory, MS, CGC (2004-present) Susan J Hayflick, MD (2002-present) 3 August 2017 (sw) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 23 March 2010 (me) Comprehensive update posted live 9 January 2008 (sh) Revision: deletion/duplication analysis no longer available clinically 8 January 2007 (me) Comprehensive update posted live 27 October 2004 (me) Comprehensive update posted live 8 March 2003 (sh) Revision: Table 4; References 25 February 2003 (sh) Revision: Resources 13 August 2002 (me) Review posted live 29 March 2002 (sh) Original submission • 3 August 2017 (sw) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 23 March 2010 (me) Comprehensive update posted live • 9 January 2008 (sh) Revision: deletion/duplication analysis no longer available clinically • 8 January 2007 (me) Comprehensive update posted live • 27 October 2004 (me) Comprehensive update posted live • 8 March 2003 (sh) Revision: Table 4; References • 25 February 2003 (sh) Revision: Resources • 13 August 2002 (me) Review posted live • 29 March 2002 (sh) Original submission ## Author History Jason Coryell, MS; Oregon Health & Science University (2004-2007) Allison Gregory, MS, CGC (2004-present) Susan J Hayflick, MD (2002-present) ## Revision History 3 August 2017 (sw) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 23 March 2010 (me) Comprehensive update posted live 9 January 2008 (sh) Revision: deletion/duplication analysis no longer available clinically 8 January 2007 (me) Comprehensive update posted live 27 October 2004 (me) Comprehensive update posted live 8 March 2003 (sh) Revision: Table 4; References 25 February 2003 (sh) Revision: Resources 13 August 2002 (me) Review posted live 29 March 2002 (sh) Original submission • 3 August 2017 (sw) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 23 March 2010 (me) Comprehensive update posted live • 9 January 2008 (sh) Revision: deletion/duplication analysis no longer available clinically • 8 January 2007 (me) Comprehensive update posted live • 27 October 2004 (me) Comprehensive update posted live • 8 March 2003 (sh) Revision: Table 4; References • 25 February 2003 (sh) Revision: Resources • 13 August 2002 (me) Review posted live • 29 March 2002 (sh) Original submission ## References ## Literature Cited T A. Arrow indicates the "eye of the tiger" change characteristic of PKAN. B. MRI shows globus pallidus hypointensities only, consistent with iron deposition and supporting a diagnosis of non-PKAN NBIA.	[ "L Chiapparini, M Savoiardo, S D’Arrigo, C Reale, G Zorzi, F Zibordi, DM Cordelli, E Franzoni, B Garavaglia, N Nardocci. The \"eye-of-the-tiger\" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration.. Neuropediatrics 2011;42:159-62", "KH Ching, SK Westaway, J Gitschier, JJ Higgins, SJ Hayflick. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration.. Neurology 2002;58:1673-4", "RF Delgado, PR Sanchez, H Speckter, EP Then, R Jiminez, J Oviedo, PR Dellani, B Foerster, P Stoeter. Missense PANK2 mutation without \"eye of the tiger\" sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN).. J Magn Reson Imaging. 2012;35:788-94", "P del Valle-López, R Pérez-García, R Sanguino-Andrés, E González-Pablos. Adult onset Hallervorden-Spatz disease with psychotic symptoms.. Actas Esp Psiquiatr. 2011;39:260-2", "S Dwarakanath, A Zafar, R Yadav, A Arivazhagan, M Netravathi, S Sampath, PK Pal. Does lesioning surgery have a role in the management of multietiological tremor in the era of deep brain stimulation?. Clin Neurol Neurosurg 2014;125:131-6", "RA Egan, RG Weleber, P Hogarth, A Gregory, J Coryell, SK Westaway, J Gitschier, S Das, SJ Hayflick. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome).. Am J Ophthalmol 2005;140:267-74", "A Fasano, G Shahidi, AE Lang, M Rohani. Basal ganglia calcification in case of PKAN.. Parkinsonism Relat Disord 2017;36:98-99", "K Freeman, A Gregory, A Turner, P Blasco, P Hogarth, S Hayflick. Intellectual and adaptive behavior functioning in pantothenate kinase-associated neurodegeneration.. J Intellect Disabil Res 2007;51:417-26", "PJ Garcia-Ruiz, J Ayerbe, L Desojo, C Feliz, J Fernandez. Deep brain stimulation for pantothenate kinase-associated neurodegeneration.. Case Rep Neurol Med 2015;2015", "J Guimarães, JV Santos. Generalized freezing in Hallervorden-Spatz syndrome: case report.. Eur J Neurol 1999;6:509-13", "P Hogarth, A Gregory, MC Kruer, L Sanford, W Wagoner, MR Natowicz, RT Egel, SH Subramony, JG Goldman, E Berry-Kravis, NC Foulds, SR Hammans, I Desguerre, D Rodriguez, C Wilson, A Diedrich, S Green, H Tran, L Reese, RL Woltjer, SJ Hayflick. New form of neurodegeneration with brain iron accumulation: features associated with MPAN.. Neurology 2013;80:268-75", "P Hogarth, MA Kurian, A Gregory, B Csányi, T Zagustin, T Kmiec, P Wood, A Klucken, N Scalise, F Sofia, T Klopstock, G Zorzi, N Nardocci, SJ Hayflick. Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN).. Mol Genet Metab. 2017;120:278-87", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "MC Kruer, M Hiken, A Gregory, A Malandrini, D Clark, P Hogarth, M Grafe, SJ Hayflick, RL Woltjer. Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration.. Brain 2011;134:947-58", "BC Lim, CS Ki, A Cho, H Hwang, KJ Kim, YS Hwang, YE Kim, JY Yun, BS Jeon, YH Lim, SH Paek, JH Chae. Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation.. Eur J Neurol 2012;19:556-61", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "P Rump, HH Lemmink, CC Verschuuren-Bemelmans, PM Grootscholten, JM Fock, SJ Hayflick, SK Westaway, YJ Vos, AJ van Essen. A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect.. Neurogenetics 2005;6:201-7", "V Scarano, MT Pellecchia, A Filla, P Barone. Hallervorden-Spatz syndrome resembling a typical Tourette syndrome.. Mov Disord 2002;17:618-20", "J Schiessl-Weyer, P Roa, F Laccone, B Kluge, A Tichy, E De Almeida Ribeiro, R Prohaska, P Stoeter, U Salzer. Acanthocytosis and the c.680 A>G mutation in the PANK2 gene: a study enrolling a cohort of PKAN patients from the Dominican Republic.. PLos One 2015;10", "SA Schneider, C Paisan-Ruiz, NP Quinn, AJ Lees, H Houlden, J Hardy, KP Bhatia. ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation. Mov Disord 2010;25:979-84", "M Shevell. Hallervorden and history.. N Engl J Med 2003;348:3-4", "KF Swaiman. Hallervorden-Spatz syndrome.. Pediatr Neurol 2001;25:102-8", "RL Woltjer, LC Reese, BE Richardson, H Tran, S Green, T Pham, M Chalupsky, T Light, L Sanford, SY Jeong, J Hamada, LK Schwanemann, C Rogers, A Gregory, P Hogarth, SJ Hayflick. Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus.. Mol Genet Metab 2015;116:289-97", "YW Wu, CP Hess, NS Singhal, C Groden, C Toro. Idiopathic basal ganglia calcifications: an atypical presentation of PKAN.. Pediatr Neurol 2013;49:351-4", "S Yamashita, Y Maeda, H Ohmori, Y Uchida, T Hirano, K Yonemura, E Uyama, M Uchino. Pantothenate kinase-associated neurodegeneration initially presenting as postural tremor alone in a Japanese family with homozygous N245S substitutions in the pantothenate kinase gene.. J Neurol Sci 2004;225:129-33", "EY Yang, A Campbell, SC Bondy. Configuration of thiols dictates their ability to promote iron-induced reactive oxygen species generation.. Redox Rep 2000;5:371-5", "SJ Yoon, YH Koh, RA Floyd, JW Park. Copper, zinc superoxide dismutase enhances DNA damage and mutagenicity induced by cysteine/iron.. Mutat Res 2000;448:97-104", "YM Zhang, CO Rock, S Jackowski. Biochemical properties of human pantothenate kinase 2 isoforms and mutations linked to pantothenate kinase-associated neurodegeneration.. J Biol Chem 2006;281:107-14", "B Zhou, SK Westaway, B Levinson, MA Johnson, J Gitschier, SJ Hayflick. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome.. Nat Genet 2001;28:345-9", "G Zorzi, F Zibordi, L Chiapparini, E Bertini, L Russo, A Piga, F Longo, B Garavaglia, D Aquino, M Savoiardo, A Solari, N Nardocci. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial.. Mov Disord. 2011;26:1756-9" ]	13/8/2002	3/8/2017	9/1/2008	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pkd-ad	pkd-ad	[ "ADPKD", "ADPKD", "Polycystic Kidney Disease 1, Autosomal Dominant", "Polycystic Kidney Disease 2, Autosomal Dominant", "Alpha-1,2-mannosyltransferase ALG9", "DnaJ homolog subfamily B member 11", "Dolichyl-phosphate beta-glucosyltransferase", "Intraflagellar transport protein 140 homolog", "Neutral alpha-glucosidase AB", "Polycystin-1", "Polycystin-2", "ALG5", "ALG9", "DNAJB11", "GANAB", "IFT140", "PKD1", "PKD2", "Polycystic Kidney Disease, Autosomal Dominant" ]	Polycystic Kidney Disease, Autosomal Dominant	Peter C Harris, Vicente E Torres	Summary Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral kidney cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Kidney manifestations include early-onset hypertension, kidney pain, and kidney insufficiency. Approximately 50% of individuals with ADPKD have end-stage kidney disease (ESKD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD), most often in females. Overall, the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of kidney disease and other extra-kidney manifestations. The diagnosis of ADPKD is established in a proband with age-specific kidney imaging criteria and either an affected first-degree relative with ADPKD or a heterozygous pathogenic variant in In most affected families, ADPKD is caused by a heterozygous	## Diagnosis Diagnostic criteria for autosomal dominant polycystic kidney disease (ADPKD) are discussed in the executive summary of the KDIGO Controversies Conference [ ADPKD Multiple bilateral kidney cysts and absence of manifestations suggestive of a different cystic kidney disease Cysts in other organs, especially the liver, but also seminal vesicles, pancreas, and arachnoid membrane Enlargement of the kidneys or liver on physical examination Hypertension in an individual younger than age 35 years An intracranial aneurysm Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. The diagnosis of ADPKD Age-specific ultrasound criteria in an individual with an affected first-degree relative [ The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years The presence of two or more cysts in each kidney in an individual age 40-59 years Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD Note: (1) The positive predictive value of these criteria is described as 100%, if (a) the disorder is Ultrasound Criteria for Diagnosis of ADPKD in Individuals at 50% Risk for ADPKD Based on Family History Derived from ADPKD = autosomal dominant polycystic kidney disease; PKD = polycystic kidney disease; PPV = positive predictive value; SEN = sensitivity Unilateral or bilateral Age-specific MRI criteria are particularly useful when ultrasound results are equivocal [ Note: These MRI criteria may also be more appropriate to use when employing a modern, high-resolution ultrasound scanner that can detect cysts as small as 1-2 mm. The absence of kidney cysts by ultrasound examination virtually excludes a diagnosis of ADPKD caused by a truncating MRI or contrast-enhanced CT examination, which has much higher sensitivity than ultrasound to detect cysts and is routinely used in most transplantation centers to assess potential donor kidney anatomy, provides further assurance for the exclusion of the diagnosis if cysts are absent. When the family-specific pathogenic variant has not been identified: Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one kidney cyst in an individual age 40 years or older has a negative predictive value of 100%. The family history of kidney disease severity can be used as a rough guide to predict the severity of disease in other affected family members, although there is significant intrafamilial variability (see Ultrasound Criteria That Exclude an Individual at 50% Risk for ADPKD from Being a Kidney Donor Derived from ADPKD = autosomal dominant polycystic kidney disease; NPV = negative predictive value; PKD = polycystic kidney disease; SPEC = specificity Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by PKD, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ADPKD NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Specific analysis is required to detect exon or whole-gene deletions/duplications. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to the segmental duplication of Data derived from the subscription-based professional view of Human Gene Mutation Database [ A deletion including • Multiple bilateral kidney cysts and absence of manifestations suggestive of a different cystic kidney disease • Cysts in other organs, especially the liver, but also seminal vesicles, pancreas, and arachnoid membrane • Enlargement of the kidneys or liver on physical examination • Hypertension in an individual younger than age 35 years • An intracranial aneurysm • Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. • The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years • The presence of two or more cysts in each kidney in an individual age 40-59 years • Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD • Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one kidney cyst in an individual age 40 years or older has a negative predictive value of 100%. • The family history of kidney disease severity can be used as a rough guide to predict the severity of disease in other affected family members, although there is significant intrafamilial variability (see • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other inherited disorders characterized by PKD, • For an introduction to comprehensive genomic testing click ## Suggestive Findings ADPKD Multiple bilateral kidney cysts and absence of manifestations suggestive of a different cystic kidney disease Cysts in other organs, especially the liver, but also seminal vesicles, pancreas, and arachnoid membrane Enlargement of the kidneys or liver on physical examination Hypertension in an individual younger than age 35 years An intracranial aneurysm Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. • Multiple bilateral kidney cysts and absence of manifestations suggestive of a different cystic kidney disease • Cysts in other organs, especially the liver, but also seminal vesicles, pancreas, and arachnoid membrane • Enlargement of the kidneys or liver on physical examination • Hypertension in an individual younger than age 35 years • An intracranial aneurysm • Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of ADPKD Age-specific ultrasound criteria in an individual with an affected first-degree relative [ The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years The presence of two or more cysts in each kidney in an individual age 40-59 years Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD Note: (1) The positive predictive value of these criteria is described as 100%, if (a) the disorder is Ultrasound Criteria for Diagnosis of ADPKD in Individuals at 50% Risk for ADPKD Based on Family History Derived from ADPKD = autosomal dominant polycystic kidney disease; PKD = polycystic kidney disease; PPV = positive predictive value; SEN = sensitivity Unilateral or bilateral Age-specific MRI criteria are particularly useful when ultrasound results are equivocal [ Note: These MRI criteria may also be more appropriate to use when employing a modern, high-resolution ultrasound scanner that can detect cysts as small as 1-2 mm. The absence of kidney cysts by ultrasound examination virtually excludes a diagnosis of ADPKD caused by a truncating MRI or contrast-enhanced CT examination, which has much higher sensitivity than ultrasound to detect cysts and is routinely used in most transplantation centers to assess potential donor kidney anatomy, provides further assurance for the exclusion of the diagnosis if cysts are absent. When the family-specific pathogenic variant has not been identified: Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one kidney cyst in an individual age 40 years or older has a negative predictive value of 100%. The family history of kidney disease severity can be used as a rough guide to predict the severity of disease in other affected family members, although there is significant intrafamilial variability (see Ultrasound Criteria That Exclude an Individual at 50% Risk for ADPKD from Being a Kidney Donor Derived from ADPKD = autosomal dominant polycystic kidney disease; NPV = negative predictive value; PKD = polycystic kidney disease; SPEC = specificity Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by PKD, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ADPKD NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Specific analysis is required to detect exon or whole-gene deletions/duplications. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to the segmental duplication of Data derived from the subscription-based professional view of Human Gene Mutation Database [ A deletion including • The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years • The presence of two or more cysts in each kidney in an individual age 40-59 years • Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD • Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one kidney cyst in an individual age 40 years or older has a negative predictive value of 100%. • The family history of kidney disease severity can be used as a rough guide to predict the severity of disease in other affected family members, although there is significant intrafamilial variability (see • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other inherited disorders characterized by PKD, • For an introduction to comprehensive genomic testing click ## Age-Specific Ultrasound Criteria Age-specific ultrasound criteria in an individual with an affected first-degree relative [ The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years The presence of two or more cysts in each kidney in an individual age 40-59 years Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD Note: (1) The positive predictive value of these criteria is described as 100%, if (a) the disorder is Ultrasound Criteria for Diagnosis of ADPKD in Individuals at 50% Risk for ADPKD Based on Family History Derived from ADPKD = autosomal dominant polycystic kidney disease; PKD = polycystic kidney disease; PPV = positive predictive value; SEN = sensitivity Unilateral or bilateral • The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years • The presence of two or more cysts in each kidney in an individual age 40-59 years • Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD ## Age-Specific MRI Criteria Age-specific MRI criteria are particularly useful when ultrasound results are equivocal [ Note: These MRI criteria may also be more appropriate to use when employing a modern, high-resolution ultrasound scanner that can detect cysts as small as 1-2 mm. ## Excluding the Diagnosis The absence of kidney cysts by ultrasound examination virtually excludes a diagnosis of ADPKD caused by a truncating MRI or contrast-enhanced CT examination, which has much higher sensitivity than ultrasound to detect cysts and is routinely used in most transplantation centers to assess potential donor kidney anatomy, provides further assurance for the exclusion of the diagnosis if cysts are absent. When the family-specific pathogenic variant has not been identified: Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one kidney cyst in an individual age 40 years or older has a negative predictive value of 100%. The family history of kidney disease severity can be used as a rough guide to predict the severity of disease in other affected family members, although there is significant intrafamilial variability (see Ultrasound Criteria That Exclude an Individual at 50% Risk for ADPKD from Being a Kidney Donor Derived from ADPKD = autosomal dominant polycystic kidney disease; NPV = negative predictive value; PKD = polycystic kidney disease; SPEC = specificity • Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than one kidney cyst in an individual age 40 years or older has a negative predictive value of 100%. • The family history of kidney disease severity can be used as a rough guide to predict the severity of disease in other affected family members, although there is significant intrafamilial variability (see ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by PKD, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ADPKD NA = not applicable See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Specific analysis is required to detect exon or whole-gene deletions/duplications. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to the segmental duplication of Data derived from the subscription-based professional view of Human Gene Mutation Database [ A deletion including • For an introduction to multigene panels click • When the phenotype is indistinguishable from many other inherited disorders characterized by PKD, • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Although all individuals with autosomal dominant polycystic kidney disease (ADPKD) develop cysts within the kidneys, there is substantial variability in the severity of kidney disease and other manifestations of the disease. Less variability is observed between affected individuals from the same family, but significant intrafamilial variability still exists. The lower incidence of end-stage kidney disease (ESKD) in affected females compared to males suggests that ADPKD is a more severe disease in males. Analysis of individuals with Kidney size has been shown to be a strong predictor of subsequent decline in kidney function, with an htTKV of ≥600 mL/m showing a high predictive value for the individual to develop kidney insufficiency within eight years [ Individuals with Occasionally, enlarged and echogenic kidneys with or without kidney cysts are detected prenatally in a fetus at risk for ADPKD [ Studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis [ Plasma copeptin concentration (a marker of endogenous vasopressin levels) has been associated with various markers of disease severity (positively with TKV and albuminuria and negatively with GFR and effective kidney blood flow) in a cross-sectional analysis of people with ADPKD [ It has long been thought that a decline in kidney function, detected as a rise in serum creatinine, is generally seen only later in the course of disease, typically about a dozen years before ESKD. Once kidney function starts to deteriorate, GFR has been observed to decline rapidly (~4-6 mL/min/yr) [ Another early functional abnormality is a reduction in kidney blood flow, which can be detected in young individuals (when systolic and diastolic blood pressures are still normal) and precedes the development of hypertension [ Increase in kidney vascular resistance and filtration fraction Normal or high peripheral plasma renin activity Resetting of the pressure-natriuresis relationship Salt sensitivity Normal or increased extracellular fluid volume, plasma volume, and cardiac output Partial correction of kidney hemodynamics and sodium handling by converting enzyme inhibition Hypertension is often diagnosed much later than when it first occurs in individuals with ADPKD; 24-hour monitoring of ambulatory blood pressure of children or young adults may reveal elevated blood pressure, attenuated decrease in nocturnal blood pressure, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction [ Early detection and treatment of hypertension in ADPKD is important because cardiovascular disease is the main cause of death. Uncontrolled high blood pressure also increases the risk for: Proteinuria, hematuria, and a faster decline of kidney function; Morbidity and mortality from valvular heart disease and aneurysms; Fetal and maternal complications during pregnancy. An increased risk for KCC in individuals with ADPKD who are on dialysis for ESKD can be explained by the increased incidence of KCC with advanced kidney disease [ When age and other covariants were taken into consideration, the rate of all cancers in individuals with ADPKD after kidney transplantation was reported to be lower than in kidney transplant recipients who did not have ADPKD [ CRISP also found that kidney blood flow (or vascular resistance) is an independent predictor of kidney function decline [ Other factors including heavy use of analgesics may contribute to kidney disease progression in some individuals. Liver cysts are rare in children. The frequency of liver cysts increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is 58% in participants of 15-24 years, 85% in those 25-34 years, and 94% in those 35-46 years [ Liver cysts are usually asymptomatic and rarely cause liver failure. Symptoms, when they occur, are caused by the mass effect of the cysts, the development of complications, or rare associations. Mass effects include: abdominal distention and pain, early satiety, dyspnea, and low back pain. Liver cysts can also cause extrinsic compression of the inferior vena cava, hepatic veins, or bile ducts [ Liver cyst epithelia produce and secrete the carbohydrate antigen 19-9 (CA19-9), a tumor marker for gastrointestinal cancers. The concentration of CA19-9 is increased in the serum of individuals with PLD and markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume [ Complications of PLD include cyst hemorrhage, infection, or rupture. Hemorrhagic cysts may cause fever and masquerade as cholecystitis or cyst infection. Usually cyst infections are monomicrobial, are caused by Enterobacteriaceae, and present with localized pain or tenderness, fever, leukocytosis, elevated erythrocyte sedimentation rate, and high serum concentration of alkaline phosphatase and CA19-9. Elevations of CA19-9, however, can also be observed in other conditions causing abdominal pain and fever, such as acute cholangitis or diverticulitis. CT and MRI examination are helpful in the diagnosis of cyst infection but have low specificity. On CT examination, the following have been associated with infection: fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. Indium-labeled white blood cell scans are more specific but not always conclusive. Dilatation of biliary ducts may be associated with episodes of cholangitis. Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. Cholangiocarcinoma is infrequently associated with ADPKD. Adenomas of the ampulla of Vater have been rarely reported. A recent study found pancreatic cysts occur in 19% of individuals with ADPKD, and papillary mucinous neoplasia in 1% [ An association between ADPKD and pancreatic carcinomas was reported [ Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [ Arachnoid membrane cysts, present in 8% of affected individuals [ Spinal meningeal diverticula may occur with increased frequency, and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [ Ovarian cysts are not associated with ADPKD [ Intracranial aneurysms occur in approximately 10% of individuals with ADPKD [ The mean age of rupture of intracranial aneurysms is lower in individuals with ADPKD than in the general population (39 years vs 51 years). The risk of rupture of asymptomatic intracranial aneurysms depends on the history of rupture from a different site [ In the absence of a history of rupture from a different site, the risk for rupture is as follows: For aneurysms <10 mm in diameter: 0.05% per year For aneurysms 10-24 mm: ~1% per year For aneurysms ≥25 mm: 6% within one year In the presence of a history of rupture from a different site, the risk of rupture is 0.5%-1% per year regardless of size. The risk of rupture of symptomatic aneurysms is higher – approximately 4% per year. Intracranial aneurysm rupture confers a 35% to 55% risk for combined severe morbidity and mortality at three months [ Follow-up studies of individuals with ADPKD with intracranial aneurysms found a moderate risk for the development of new aneurysms or enlargement of an existing one in previously symptomatic individuals and a low risk of enlargement of asymptomatic aneurysms detected by presymptomatic screening [ Individuals with ADPKD may be at increased risk for vasospasm and transient ischemic complications following cerebral angiography. They may also be at increased risk for central retinal arterial and venous occlusions, possibly as a result of enhanced vasoconstriction to adrenergic stimulation and arterial wall remodeling [ Aortic insufficiency may occur in association with dilatation of the aortic root. Although these lesions may progress with time, they rarely require valve replacement. Screening echocardiography is not indicated unless a murmur is detected on examination. Evidence of familial clustering of thoracic aortic dissections in ADPKD also exists [ Mitral valve prolapse, the most common valvular abnormality in ADPKD, has been demonstrated by echocardiography in up to 25% of affected individuals. Several studies have shown increased left ventricular mass, left ventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and exaggerated blood pressure response during exercise even in young normotensive individuals with ADPKD with well-preserved kidney function. Even normotensive individuals with ADPKD may show significant biventricular diastolic dysfunction, suggesting cardiac involvement early in the course of the disease [ Pericardial effusion occurs with an increased frequency in individuals with ADPKD, possibly because of increased compliance of the parietal pericardium. These effusions are generally well tolerated and clinically inconsequential. In the absence of known predisposing factors, extensive investigative and/or therapeutic interventions for silent pericardial effusion in persons with ADPKD are not indicated [ Individuals with ADPKD may be predisposed to idiopathic dilated and hypertrophic obstructed cardiomyopathy and left ventricular noncompaction [ Extracolonic diverticular disease may also occur with increased frequency and become clinically significant in a minority of affected individuals [ As many as one half of in-frame pathogenic variants are hypomorphic and associated with milder kidney disease [ More detailed bioinformatic analysis divided nontruncating Family studies have identified incompletely penetrant nontruncating Truncating Fully penetrant (i.e., nonhypomorphic) biallelic pathogenic variants in either Neonatal-onset ADPKD has also been associated with homozygosity of a hypomorphic Individuals with pathogenic variants in both It has been suggested that early-onset PKD may be caused by a heterozygous pathogenic variant in both Penetrance in ADPKD is age and genotype dependent. The penetrance of multiple bilateral kidney cysts in older adults is close to 100%. However, because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially in individuals with nontruncating Variable disease presentation in a family and apparent The term "adult polycystic kidney disease" (APKD) is no longer in use. ADPKD is the most common potentially lethal single-gene disorder. Its prevalence at birth is approximately 1:1,000, and it affects approximately 300,000 persons in the United States. • Increase in kidney vascular resistance and filtration fraction • Normal or high peripheral plasma renin activity • Resetting of the pressure-natriuresis relationship • Salt sensitivity • Normal or increased extracellular fluid volume, plasma volume, and cardiac output • Partial correction of kidney hemodynamics and sodium handling by converting enzyme inhibition • Proteinuria, hematuria, and a faster decline of kidney function; • Morbidity and mortality from valvular heart disease and aneurysms; • Fetal and maternal complications during pregnancy. • Dilatation of biliary ducts may be associated with episodes of cholangitis. • Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. • Cholangiocarcinoma is infrequently associated with ADPKD. • Adenomas of the ampulla of Vater have been rarely reported. • A recent study found pancreatic cysts occur in 19% of individuals with ADPKD, and papillary mucinous neoplasia in 1% [ • An association between ADPKD and pancreatic carcinomas was reported [ • Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [ • Arachnoid membrane cysts, present in 8% of affected individuals [ • Spinal meningeal diverticula may occur with increased frequency, and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [ • Ovarian cysts are not associated with ADPKD [ • For aneurysms <10 mm in diameter: 0.05% per year • For aneurysms 10-24 mm: ~1% per year • For aneurysms ≥25 mm: 6% within one year ## Clinical Description Although all individuals with autosomal dominant polycystic kidney disease (ADPKD) develop cysts within the kidneys, there is substantial variability in the severity of kidney disease and other manifestations of the disease. Less variability is observed between affected individuals from the same family, but significant intrafamilial variability still exists. The lower incidence of end-stage kidney disease (ESKD) in affected females compared to males suggests that ADPKD is a more severe disease in males. Analysis of individuals with Kidney size has been shown to be a strong predictor of subsequent decline in kidney function, with an htTKV of ≥600 mL/m showing a high predictive value for the individual to develop kidney insufficiency within eight years [ Individuals with Occasionally, enlarged and echogenic kidneys with or without kidney cysts are detected prenatally in a fetus at risk for ADPKD [ Studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis [ Plasma copeptin concentration (a marker of endogenous vasopressin levels) has been associated with various markers of disease severity (positively with TKV and albuminuria and negatively with GFR and effective kidney blood flow) in a cross-sectional analysis of people with ADPKD [ It has long been thought that a decline in kidney function, detected as a rise in serum creatinine, is generally seen only later in the course of disease, typically about a dozen years before ESKD. Once kidney function starts to deteriorate, GFR has been observed to decline rapidly (~4-6 mL/min/yr) [ Another early functional abnormality is a reduction in kidney blood flow, which can be detected in young individuals (when systolic and diastolic blood pressures are still normal) and precedes the development of hypertension [ Increase in kidney vascular resistance and filtration fraction Normal or high peripheral plasma renin activity Resetting of the pressure-natriuresis relationship Salt sensitivity Normal or increased extracellular fluid volume, plasma volume, and cardiac output Partial correction of kidney hemodynamics and sodium handling by converting enzyme inhibition Hypertension is often diagnosed much later than when it first occurs in individuals with ADPKD; 24-hour monitoring of ambulatory blood pressure of children or young adults may reveal elevated blood pressure, attenuated decrease in nocturnal blood pressure, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction [ Early detection and treatment of hypertension in ADPKD is important because cardiovascular disease is the main cause of death. Uncontrolled high blood pressure also increases the risk for: Proteinuria, hematuria, and a faster decline of kidney function; Morbidity and mortality from valvular heart disease and aneurysms; Fetal and maternal complications during pregnancy. An increased risk for KCC in individuals with ADPKD who are on dialysis for ESKD can be explained by the increased incidence of KCC with advanced kidney disease [ When age and other covariants were taken into consideration, the rate of all cancers in individuals with ADPKD after kidney transplantation was reported to be lower than in kidney transplant recipients who did not have ADPKD [ CRISP also found that kidney blood flow (or vascular resistance) is an independent predictor of kidney function decline [ Other factors including heavy use of analgesics may contribute to kidney disease progression in some individuals. Liver cysts are rare in children. The frequency of liver cysts increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is 58% in participants of 15-24 years, 85% in those 25-34 years, and 94% in those 35-46 years [ Liver cysts are usually asymptomatic and rarely cause liver failure. Symptoms, when they occur, are caused by the mass effect of the cysts, the development of complications, or rare associations. Mass effects include: abdominal distention and pain, early satiety, dyspnea, and low back pain. Liver cysts can also cause extrinsic compression of the inferior vena cava, hepatic veins, or bile ducts [ Liver cyst epithelia produce and secrete the carbohydrate antigen 19-9 (CA19-9), a tumor marker for gastrointestinal cancers. The concentration of CA19-9 is increased in the serum of individuals with PLD and markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume [ Complications of PLD include cyst hemorrhage, infection, or rupture. Hemorrhagic cysts may cause fever and masquerade as cholecystitis or cyst infection. Usually cyst infections are monomicrobial, are caused by Enterobacteriaceae, and present with localized pain or tenderness, fever, leukocytosis, elevated erythrocyte sedimentation rate, and high serum concentration of alkaline phosphatase and CA19-9. Elevations of CA19-9, however, can also be observed in other conditions causing abdominal pain and fever, such as acute cholangitis or diverticulitis. CT and MRI examination are helpful in the diagnosis of cyst infection but have low specificity. On CT examination, the following have been associated with infection: fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. Indium-labeled white blood cell scans are more specific but not always conclusive. Dilatation of biliary ducts may be associated with episodes of cholangitis. Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. Cholangiocarcinoma is infrequently associated with ADPKD. Adenomas of the ampulla of Vater have been rarely reported. A recent study found pancreatic cysts occur in 19% of individuals with ADPKD, and papillary mucinous neoplasia in 1% [ An association between ADPKD and pancreatic carcinomas was reported [ Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [ Arachnoid membrane cysts, present in 8% of affected individuals [ Spinal meningeal diverticula may occur with increased frequency, and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [ Ovarian cysts are not associated with ADPKD [ Intracranial aneurysms occur in approximately 10% of individuals with ADPKD [ The mean age of rupture of intracranial aneurysms is lower in individuals with ADPKD than in the general population (39 years vs 51 years). The risk of rupture of asymptomatic intracranial aneurysms depends on the history of rupture from a different site [ In the absence of a history of rupture from a different site, the risk for rupture is as follows: For aneurysms <10 mm in diameter: 0.05% per year For aneurysms 10-24 mm: ~1% per year For aneurysms ≥25 mm: 6% within one year In the presence of a history of rupture from a different site, the risk of rupture is 0.5%-1% per year regardless of size. The risk of rupture of symptomatic aneurysms is higher – approximately 4% per year. Intracranial aneurysm rupture confers a 35% to 55% risk for combined severe morbidity and mortality at three months [ Follow-up studies of individuals with ADPKD with intracranial aneurysms found a moderate risk for the development of new aneurysms or enlargement of an existing one in previously symptomatic individuals and a low risk of enlargement of asymptomatic aneurysms detected by presymptomatic screening [ Individuals with ADPKD may be at increased risk for vasospasm and transient ischemic complications following cerebral angiography. They may also be at increased risk for central retinal arterial and venous occlusions, possibly as a result of enhanced vasoconstriction to adrenergic stimulation and arterial wall remodeling [ Aortic insufficiency may occur in association with dilatation of the aortic root. Although these lesions may progress with time, they rarely require valve replacement. Screening echocardiography is not indicated unless a murmur is detected on examination. Evidence of familial clustering of thoracic aortic dissections in ADPKD also exists [ Mitral valve prolapse, the most common valvular abnormality in ADPKD, has been demonstrated by echocardiography in up to 25% of affected individuals. Several studies have shown increased left ventricular mass, left ventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and exaggerated blood pressure response during exercise even in young normotensive individuals with ADPKD with well-preserved kidney function. Even normotensive individuals with ADPKD may show significant biventricular diastolic dysfunction, suggesting cardiac involvement early in the course of the disease [ Pericardial effusion occurs with an increased frequency in individuals with ADPKD, possibly because of increased compliance of the parietal pericardium. These effusions are generally well tolerated and clinically inconsequential. In the absence of known predisposing factors, extensive investigative and/or therapeutic interventions for silent pericardial effusion in persons with ADPKD are not indicated [ Individuals with ADPKD may be predisposed to idiopathic dilated and hypertrophic obstructed cardiomyopathy and left ventricular noncompaction [ Extracolonic diverticular disease may also occur with increased frequency and become clinically significant in a minority of affected individuals [ • Increase in kidney vascular resistance and filtration fraction • Normal or high peripheral plasma renin activity • Resetting of the pressure-natriuresis relationship • Salt sensitivity • Normal or increased extracellular fluid volume, plasma volume, and cardiac output • Partial correction of kidney hemodynamics and sodium handling by converting enzyme inhibition • Proteinuria, hematuria, and a faster decline of kidney function; • Morbidity and mortality from valvular heart disease and aneurysms; • Fetal and maternal complications during pregnancy. • Dilatation of biliary ducts may be associated with episodes of cholangitis. • Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. • Cholangiocarcinoma is infrequently associated with ADPKD. • Adenomas of the ampulla of Vater have been rarely reported. • A recent study found pancreatic cysts occur in 19% of individuals with ADPKD, and papillary mucinous neoplasia in 1% [ • An association between ADPKD and pancreatic carcinomas was reported [ • Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [ • Arachnoid membrane cysts, present in 8% of affected individuals [ • Spinal meningeal diverticula may occur with increased frequency, and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [ • Ovarian cysts are not associated with ADPKD [ • For aneurysms <10 mm in diameter: 0.05% per year • For aneurysms 10-24 mm: ~1% per year • For aneurysms ≥25 mm: 6% within one year ## Kidney Manifestations Although all individuals with autosomal dominant polycystic kidney disease (ADPKD) develop cysts within the kidneys, there is substantial variability in the severity of kidney disease and other manifestations of the disease. Less variability is observed between affected individuals from the same family, but significant intrafamilial variability still exists. The lower incidence of end-stage kidney disease (ESKD) in affected females compared to males suggests that ADPKD is a more severe disease in males. Analysis of individuals with Kidney size has been shown to be a strong predictor of subsequent decline in kidney function, with an htTKV of ≥600 mL/m showing a high predictive value for the individual to develop kidney insufficiency within eight years [ Individuals with Occasionally, enlarged and echogenic kidneys with or without kidney cysts are detected prenatally in a fetus at risk for ADPKD [ Studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis [ Plasma copeptin concentration (a marker of endogenous vasopressin levels) has been associated with various markers of disease severity (positively with TKV and albuminuria and negatively with GFR and effective kidney blood flow) in a cross-sectional analysis of people with ADPKD [ It has long been thought that a decline in kidney function, detected as a rise in serum creatinine, is generally seen only later in the course of disease, typically about a dozen years before ESKD. Once kidney function starts to deteriorate, GFR has been observed to decline rapidly (~4-6 mL/min/yr) [ Another early functional abnormality is a reduction in kidney blood flow, which can be detected in young individuals (when systolic and diastolic blood pressures are still normal) and precedes the development of hypertension [ Increase in kidney vascular resistance and filtration fraction Normal or high peripheral plasma renin activity Resetting of the pressure-natriuresis relationship Salt sensitivity Normal or increased extracellular fluid volume, plasma volume, and cardiac output Partial correction of kidney hemodynamics and sodium handling by converting enzyme inhibition Hypertension is often diagnosed much later than when it first occurs in individuals with ADPKD; 24-hour monitoring of ambulatory blood pressure of children or young adults may reveal elevated blood pressure, attenuated decrease in nocturnal blood pressure, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction [ Early detection and treatment of hypertension in ADPKD is important because cardiovascular disease is the main cause of death. Uncontrolled high blood pressure also increases the risk for: Proteinuria, hematuria, and a faster decline of kidney function; Morbidity and mortality from valvular heart disease and aneurysms; Fetal and maternal complications during pregnancy. An increased risk for KCC in individuals with ADPKD who are on dialysis for ESKD can be explained by the increased incidence of KCC with advanced kidney disease [ When age and other covariants were taken into consideration, the rate of all cancers in individuals with ADPKD after kidney transplantation was reported to be lower than in kidney transplant recipients who did not have ADPKD [ CRISP also found that kidney blood flow (or vascular resistance) is an independent predictor of kidney function decline [ Other factors including heavy use of analgesics may contribute to kidney disease progression in some individuals. • Increase in kidney vascular resistance and filtration fraction • Normal or high peripheral plasma renin activity • Resetting of the pressure-natriuresis relationship • Salt sensitivity • Normal or increased extracellular fluid volume, plasma volume, and cardiac output • Partial correction of kidney hemodynamics and sodium handling by converting enzyme inhibition • Proteinuria, hematuria, and a faster decline of kidney function; • Morbidity and mortality from valvular heart disease and aneurysms; • Fetal and maternal complications during pregnancy. ## Extra-Kidney Manifestations Liver cysts are rare in children. The frequency of liver cysts increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is 58% in participants of 15-24 years, 85% in those 25-34 years, and 94% in those 35-46 years [ Liver cysts are usually asymptomatic and rarely cause liver failure. Symptoms, when they occur, are caused by the mass effect of the cysts, the development of complications, or rare associations. Mass effects include: abdominal distention and pain, early satiety, dyspnea, and low back pain. Liver cysts can also cause extrinsic compression of the inferior vena cava, hepatic veins, or bile ducts [ Liver cyst epithelia produce and secrete the carbohydrate antigen 19-9 (CA19-9), a tumor marker for gastrointestinal cancers. The concentration of CA19-9 is increased in the serum of individuals with PLD and markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume [ Complications of PLD include cyst hemorrhage, infection, or rupture. Hemorrhagic cysts may cause fever and masquerade as cholecystitis or cyst infection. Usually cyst infections are monomicrobial, are caused by Enterobacteriaceae, and present with localized pain or tenderness, fever, leukocytosis, elevated erythrocyte sedimentation rate, and high serum concentration of alkaline phosphatase and CA19-9. Elevations of CA19-9, however, can also be observed in other conditions causing abdominal pain and fever, such as acute cholangitis or diverticulitis. CT and MRI examination are helpful in the diagnosis of cyst infection but have low specificity. On CT examination, the following have been associated with infection: fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. Indium-labeled white blood cell scans are more specific but not always conclusive. Dilatation of biliary ducts may be associated with episodes of cholangitis. Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. Cholangiocarcinoma is infrequently associated with ADPKD. Adenomas of the ampulla of Vater have been rarely reported. A recent study found pancreatic cysts occur in 19% of individuals with ADPKD, and papillary mucinous neoplasia in 1% [ An association between ADPKD and pancreatic carcinomas was reported [ Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [ Arachnoid membrane cysts, present in 8% of affected individuals [ Spinal meningeal diverticula may occur with increased frequency, and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [ Ovarian cysts are not associated with ADPKD [ Intracranial aneurysms occur in approximately 10% of individuals with ADPKD [ The mean age of rupture of intracranial aneurysms is lower in individuals with ADPKD than in the general population (39 years vs 51 years). The risk of rupture of asymptomatic intracranial aneurysms depends on the history of rupture from a different site [ In the absence of a history of rupture from a different site, the risk for rupture is as follows: For aneurysms <10 mm in diameter: 0.05% per year For aneurysms 10-24 mm: ~1% per year For aneurysms ≥25 mm: 6% within one year In the presence of a history of rupture from a different site, the risk of rupture is 0.5%-1% per year regardless of size. The risk of rupture of symptomatic aneurysms is higher – approximately 4% per year. Intracranial aneurysm rupture confers a 35% to 55% risk for combined severe morbidity and mortality at three months [ Follow-up studies of individuals with ADPKD with intracranial aneurysms found a moderate risk for the development of new aneurysms or enlargement of an existing one in previously symptomatic individuals and a low risk of enlargement of asymptomatic aneurysms detected by presymptomatic screening [ Individuals with ADPKD may be at increased risk for vasospasm and transient ischemic complications following cerebral angiography. They may also be at increased risk for central retinal arterial and venous occlusions, possibly as a result of enhanced vasoconstriction to adrenergic stimulation and arterial wall remodeling [ Aortic insufficiency may occur in association with dilatation of the aortic root. Although these lesions may progress with time, they rarely require valve replacement. Screening echocardiography is not indicated unless a murmur is detected on examination. Evidence of familial clustering of thoracic aortic dissections in ADPKD also exists [ Mitral valve prolapse, the most common valvular abnormality in ADPKD, has been demonstrated by echocardiography in up to 25% of affected individuals. Several studies have shown increased left ventricular mass, left ventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and exaggerated blood pressure response during exercise even in young normotensive individuals with ADPKD with well-preserved kidney function. Even normotensive individuals with ADPKD may show significant biventricular diastolic dysfunction, suggesting cardiac involvement early in the course of the disease [ Pericardial effusion occurs with an increased frequency in individuals with ADPKD, possibly because of increased compliance of the parietal pericardium. These effusions are generally well tolerated and clinically inconsequential. In the absence of known predisposing factors, extensive investigative and/or therapeutic interventions for silent pericardial effusion in persons with ADPKD are not indicated [ Individuals with ADPKD may be predisposed to idiopathic dilated and hypertrophic obstructed cardiomyopathy and left ventricular noncompaction [ Extracolonic diverticular disease may also occur with increased frequency and become clinically significant in a minority of affected individuals [ • Dilatation of biliary ducts may be associated with episodes of cholangitis. • Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. • Cholangiocarcinoma is infrequently associated with ADPKD. • Adenomas of the ampulla of Vater have been rarely reported. • A recent study found pancreatic cysts occur in 19% of individuals with ADPKD, and papillary mucinous neoplasia in 1% [ • An association between ADPKD and pancreatic carcinomas was reported [ • Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [ • Arachnoid membrane cysts, present in 8% of affected individuals [ • Spinal meningeal diverticula may occur with increased frequency, and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [ • Ovarian cysts are not associated with ADPKD [ • For aneurysms <10 mm in diameter: 0.05% per year • For aneurysms 10-24 mm: ~1% per year • For aneurysms ≥25 mm: 6% within one year ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations As many as one half of in-frame pathogenic variants are hypomorphic and associated with milder kidney disease [ More detailed bioinformatic analysis divided nontruncating Family studies have identified incompletely penetrant nontruncating Truncating Fully penetrant (i.e., nonhypomorphic) biallelic pathogenic variants in either Neonatal-onset ADPKD has also been associated with homozygosity of a hypomorphic Individuals with pathogenic variants in both It has been suggested that early-onset PKD may be caused by a heterozygous pathogenic variant in both ## As many as one half of in-frame pathogenic variants are hypomorphic and associated with milder kidney disease [ More detailed bioinformatic analysis divided nontruncating Family studies have identified incompletely penetrant nontruncating ## Truncating ## Biallelic Fully penetrant (i.e., nonhypomorphic) biallelic pathogenic variants in either Neonatal-onset ADPKD has also been associated with homozygosity of a hypomorphic ## Digenic ADPKD Individuals with pathogenic variants in both It has been suggested that early-onset PKD may be caused by a heterozygous pathogenic variant in both ## Penetrance Penetrance in ADPKD is age and genotype dependent. The penetrance of multiple bilateral kidney cysts in older adults is close to 100%. However, because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially in individuals with nontruncating ## Mosaicism Variable disease presentation in a family and apparent ## Nomenclature The term "adult polycystic kidney disease" (APKD) is no longer in use. ## Prevalence ADPKD is the most common potentially lethal single-gene disorder. Its prevalence at birth is approximately 1:1,000, and it affects approximately 300,000 persons in the United States. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Disorders AD = autosomal dominant; ADPLD = autosomal dominant polycystic liver disease; AR = autosomal recessive; ARPKD = autosomal recessive polycystic kidney disease; CDG = congenital disorder of glycosylation; ESKD = end-stage kidney disease; LCA = Leber congenital amaurosis; MOI = mode of inheritance; PLD = polycystic liver disease ## Differential Diagnosis In the absence of a family history of polycystic kidney disease and/or in the presence of atypical presentations, benign simple cysts and other cystic diseases should be considered in the differential diagnosis. Studies of potential kidney donors using contrast-enhanced CT, which detects smaller cysts (1-2 mm), showed that from age 19 to 49 years, 39%, 22%, 7.9%, and 1.6% had at least one cyst ≥2 mm, ≥5 mm, ≥10 mm, and ≥20 mm in diameter, respectively, while from age 50 to 75 years, 63%, 43%, 22%, and 7.8% had at least one cyst ≥2 mm, ≥5 mm, ≥10 mm, and ≥20 mm in diameter, respectively [ Genetic disorders in the differential diagnosis of autosomal dominant polycystic kidney disease (ADPKD) are summarized in Genetic Disorders in the Differential Diagnosis of ADPKD Predominant phenotype is liver disease w/very mild kidney disease (if present). Note: Hematuria; muscle cramps or ↑ CPK; tortuosity of retinal artery; brain small-vessel disease Presentation w/mild PKD & few other phenotypes has been described. Thinning of glomerular basement membrane, microhematuria Occasionally, kidney cysts are part of phenotype. Hair follicle hamartomas, kidney tumors, spontaneous pneumothorax, lung cysts Maturity-onset diabetes of the young, pancreatic disease, ↑ liver enzymes, hypomagnesemia, congenital kidney & urinary tract anomalies Sometimes, presentation of isolated ADPKD-like phenotype Kidney function ↓ w/o ↑ in TKV; no liver cysts Fibrosis rather than cysts is the major kidney phenotype. Hyperplastic frenula, cleft tongue, cleft lip or palate, malpositioned teeth, broad nasal root w/hypoplasia of nasal alae & malar bone, digital abnormalities Usually male lethal during gestation Majority present in neonatal period. Pulmonary hypoplasia, early-onset kidney failure, liver fibrosis rather than cysts, TKV ↓ over time (rather than ↑) Cyst development in kidney & liver, usually w/o kidney insufficiency or ESKD Differentiating from the ADPKD spectrum may require genetic testing. Kidney function ↓ w/o ↑ in TKV; no liver cysts; gout Fibrosis rather than cysts is the major kidney phenotype. AD = autosomal dominant; ADPLD = autosomal dominant polycystic liver disease; ADTKD = autosomal dominant tubulointerstitial kidney disease; AR = autosomal recessive; ARPKD = autosomal recessive polycystic kidney disease; CPK = creatinine phosphokinase; ESKD = end-stage kidney disease; MOI = mode of inheritance; TKV = total kidney volume; XL = X-linked Alport syndrome caused by pathogenic variants in Acquired Disorders in the Differential Diagnosis of ADPKD ADPKD = autosomal dominant polycystic kidney disease; ESKD = end-stage kidney disease • Predominant phenotype is liver disease w/very mild kidney disease (if present). • Note: • Hematuria; muscle cramps or ↑ CPK; tortuosity of retinal artery; brain small-vessel disease • Presentation w/mild PKD & few other phenotypes has been described. • Thinning of glomerular basement membrane, microhematuria • Occasionally, kidney cysts are part of phenotype. • Hair follicle hamartomas, kidney tumors, spontaneous pneumothorax, lung cysts • Maturity-onset diabetes of the young, pancreatic disease, ↑ liver enzymes, hypomagnesemia, congenital kidney & urinary tract anomalies • Sometimes, presentation of isolated ADPKD-like phenotype • Kidney function ↓ w/o ↑ in TKV; no liver cysts • Fibrosis rather than cysts is the major kidney phenotype. • Hyperplastic frenula, cleft tongue, cleft lip or palate, malpositioned teeth, broad nasal root w/hypoplasia of nasal alae & malar bone, digital abnormalities • Usually male lethal during gestation • Majority present in neonatal period. • Pulmonary hypoplasia, early-onset kidney failure, liver fibrosis rather than cysts, TKV ↓ over time (rather than ↑) • Cyst development in kidney & liver, usually w/o kidney insufficiency or ESKD • Differentiating from the ADPKD spectrum may require genetic testing. • Kidney function ↓ w/o ↑ in TKV; no liver cysts; gout • Fibrosis rather than cysts is the major kidney phenotype. ## Management Treatment guidelines formulated at the autosomal dominant polycystic kidney disease (ADPKD) KDIGO conference are summarized in To establish the extent of disease and needs of an individual diagnosed with ADPKD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ADPKD CT or MRI of abdomen w/ & w/o contrast enhancement Kidney ultrasound exam (if CT or MRI is unavailable) CT & MRI are more sensitive to determine extent of cystic disease in kidneys & liver & estimate prognosis. CT (but not MRI) can detect stones & parenchymal calcifications. CT or MRA if visualization of kidney arteries is necessary MRI suggested when iodinated contrast material is contraindicated In persons w/family history of intracranial aneurysms Note: Screening for intracranial aneurysms in persons w/o family history of intracranial aneurysms is usually not recommended. ADPKD = autosomal dominant polycystic kidney disease; MOI = mode of inheritance; MRA = MR angiography Unless otherwise indicated, evaluation should be done at diagnosis in adulthood. Blood pressure that is elevated when measured in the clinic, but normal when measured outside of the clinic MRA is the diagnostic imaging modality of choice for presymptomatic screening because it is noninvasive and does not require intravenous contrast material. Most intracranial aneurysms found in asymptomatic individuals are small, have a low risk of rupture, and require no treatment [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment guidelines formulated at the ADPKD KDIGO conference are summarized in Current therapy for ADPKD is aimed at slowing the progression of declining kidney function and reducing morbidity and mortality from the kidney and extra-kidney complications. Studies have shown that a vasopressin V2 receptor antagonist (tolvaptan) can slow the increase in kidney volume, delay decline in kidney function, and preserve estimated glomerular filtration rate (eGFR) [ The blood pressure goal is ≤110/75 mm Hg in those age 18-50 years and eGFR >60 mL/min; otherwise ≤130/85 mm Hg. The antihypertensive agent(s) of choice in ADPKD have not been clearly established. However, because of the role of the renin angiotensin system in the pathogenesis of hypertension in ADPKD, ACE inhibitors and angiotensin II receptor antagonists may be superior to other agents in individuals with preserved kidney function. ACE inhibitors and angiotensin II receptor blockers increase kidney blood flow, have a low side effect profile, and may reduce vascular smooth muscle proliferation and development of atherosclerosis. The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [ In a nonrandomized study, the administration of ACE inhibitors without diuretics resulted in a lower rate of decline in GFR and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [ A long-term follow up of the Modification of Diet in Kidney Disease (MDRD) study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mm Hg) experienced significantly less ESKD and combined ESKD/death than those randomized to the usual blood pressure target (MAP <107 mm Hg) [ The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of kidney function [ Additional measures to delay ESKD include the following: Lipid control to prevent hyperlipidemia with a low threshold to start statin therapy (aim for LDL ≤100 mg/dL) Low osmolar intake with moderate sodium (2-3 g/day) and dietary protein restriction (0.8-1 g/kg of ideal body weight). The MDRD trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late stage of kidney disease (GFR: 13-55 mL/min per 1.73 m Maintenance of urine osmolality at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up) Control of acidosis with maintenance of serum bicarbonate at ≥22 mEq/L Prevention of hyperphosphatemia by maintaining moderate dietary phosphorus intake (800 mg/day). Moderation of caloric intake and low-impact exercise to maintain normal body mass index (BMI). In the CRISP study BMI ≥30 kg/m After excluding causes of flank pain that may require intervention, such as infection, stone, or tumor, an initial conservative approach to pain management is recommended. When conservative measures fail, therapy can be directed toward cyst decompression with cyst aspiration and sclerosis: In individuals with many cysts contributing to pain, laparoscopic or surgical cyst fenestration through lumbotomy or flank incision, kidney denervation, and (in those who have reached ESKD) nephrectomy may be of benefit: Cyst hemorrhage and gross hematuria are usually self limited and respond well to conservative management with bed rest, analgesics, and adequate hydration to prevent development of obstructing clots. Rarely, episodes of bleeding are severe with extensive subcapsular or retroperitoneal hematoma, significant drop in hematocrit, and hemodynamic instability. These individuals require hospitalization, transfusion, and investigation by CT or angiography. In individuals with unusually severe or persistent hemorrhage, segmental arterial embolization can be successful. If not, surgery may be required to control bleeding. Some reports suggest a role for tranexamic acid in the treatment of life-threatening hematuria [ Gross hematuria persisting for more than one week or developing for the first time in an individual older than age 50 years requires thorough investigation. Small uric acid stones can be missed on nephrotomography and are best detected by CT. CT should be obtained before and after the administration of contrast material to confirm their location within the collecting system and to differentiate calculi from parenchymal calcifications. Dual-absorption CT now facilitates the differentiation of uric acid stones from calcium-containing stones. Excretory urography detects precaliceal tubular ectasia in 15% of individuals with ADPKD. The treatment of nephrolithiasis in individuals with ADPKD is the same as for individuals without ADPKD: High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol. Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [ If cyst infection is suspected, diagnostic imaging should be undertaken to assist in the diagnosis: CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection. Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible. In the appropriate clinical setting of fever, flank pain, and suggestive diagnostic imaging, cyst aspiration under ultrasound or CT guidance should be undertaken to culture the organism and assist in selection of antimicrobial therapy, particularly if blood and urine cultures are negative [ Cyst infection is often difficult to treat. It has a high treatment failure rate despite prolonged therapy with an antibiotic to which the organism is susceptible. Treatment failure results from the inability of certain antibiotics to penetrate the cyst epithelium successfully and achieve therapeutic concentrations within the cyst. The epithelium that lines gradient cysts has functional and ultrastructural characteristics of the distal tubule epithelium. Penetration is via tight junctions, allowing only lipid-soluble agent access. Nongradient cysts, which are more common, allow solute access via diffusion. However, kinetic studies indicate that water-soluble agents penetrate nongradient cysts slowly and irregularly, resulting in unreliable drug concentrations within the cysts. Lipophilic agents have been shown to penetrate both gradient and nongradient cysts equally and reliably. Therapeutic agents of choice include trimethoprim-sulfamethoxazole and fluoroquinolones. Clindamycin, vancomycin, and metronidazole are also able to penetrate cysts well. Chloramphenicol has shown therapeutic efficacy in otherwise refractory disease. If fever persists after one to two weeks of appropriate antimicrobial therapy, percutaneous or surgical drainage of infected cysts should be undertaken. If fever recurs after discontinuation of antibiotics, complicating features such as obstruction, perinephric abscess, or stones should be considered and treated appropriately. If complicating features are not identified, the course of previously effective therapy should be extended; several months may be required to completely eradicate the infection. Actuarial data indicate that individuals with ADPKD do better on dialysis than individuals with ESKD from other causes. Females appear to do better than males. The reason for this improved outcome is unclear but may relate to better-maintained hemoglobin levels through higher endogenous erythropoietin production. Rarely, hemodialysis can be complicated by intradialytic hypotension if the inferior vena cava is compressed by a medially located kidney cyst. Despite kidney size, peritoneal dialysis can usually be performed in individuals with ADPKD, although these individuals are at increased risk for inguinal and umbilical hernias, which require surgical repair. Following transplantation, there is no difference in patient or graft survival between individuals with ADPKD and those with ESKD caused by other conditions, and complications are no greater than in the general population. Complications directly related to ADPKD are rare. One study has suggested an increased risk for thromboembolic complications [ Nephrectomy of the native kidneys is reserved for affected individuals with a history of infected cysts, frequent bleeding, severe hypertension, or massive kidney enlargement. There is no consensus on the optimal timing of nephrectomy; whether nephrectomy is performed before, at, or following transplantation depends to some extent on the indication for the nephrectomy and other considerations [ Most individuals with polycystic liver disease (PLD) have no symptoms and require no treatment. The treatment of symptomatic disease includes the avoidance of estrogens and the use of H2 blockers or proton pump inhibitors for symptomatic relief. Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization. Any of these interventions should be tailored to the individual [ Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s). Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis. Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [ Because individuals with severe PLD have mostly normal liver function, their MELD ( Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [ The management of aneurysms 6.0-9.0 mm in size remains controversial. Surgical intervention is usually indicated for aneurysms >10.0 mm in diameter. For individuals with high surgical risk or with technically difficult-to-manage lesions, endovascular treatment with detachable platinum coils may be indicated. Endovascular treatment appears to be associated with fewer complications than clipping, but the long-term efficacy of this method is as yet unproven [ When the aortic root diameter reaches 55-60 mm, replacement of the aorta is indicated. Guidelines for management of Guidance on surveillance is available in Recommended Surveillance for Individuals with ADPKD CT or MRI of abdomen w/ & w/o contrast enhancement Kidney ultrasound exam (if CT or MRI is unavailable) Every 2-3 yrs in 1st-degree adult relatives of persons w/thoracic aortic dissection Note: If aortic root dilatation is found, refer to cardiologist. Family history of intracranial aneurysms or subarachnoid hemorrhage; Previous rupture of aneurysm; Preparation for elective surgery w/potential hemodynamic instability; High-risk occupation (e.g., airline pilot); Significant anxiety despite adequate risk info. MRA is the diagnostic imaging modality of choice for presymptomatic screening because it is noninvasive and does not require intravenous contrast material. Most intracranial aneurysms found in asymptomatic individuals are small, have a low risk of rupture, and require no treatment [ One of 76 individuals with an initial normal MRA study had a new intracranial aneurysm after a mean follow up of 9.8 years [ Avoid the following: Long-term administration of nephrotoxic agents (e.g., combination analgesics, NSAIDs) Caffeine in large amounts. There is no evidence that low or moderate use of caffeinated beverages accelerates the progression of ADPKD. High-salt diet, smoking, and obesity Use of estrogens and possibly progestogens in individuals with severe polycystic liver disease Evaluations of at-risk relatives include the following: Imaging with abdominal ultrasound, CT, or MRI examination Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. Comprehensive kidney image analysis by ultrasound, contrast-enhanced CT, and/or MRI examination (routine imaging for any kidney donor regardless of disease indication). See If the ADPKD-causing pathogenic variant has been identified in an affected family member, any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the relative's genetic status so that only those who do not have the familial pathogenic variant are evaluated further. (For families with biallelic Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in a potential donor is uninformative (i.e., the result does not prove that a potential donor does not have ADPKD). If the ADPKD-causing pathogenic variant has In potential donors with a small number of cysts, comprehensive genetic analysis with a PKD panel may be helpful to exclude pathogenic variants in known PKD-related genes – apart from the familial variant. Note: Appropriate counseling prior to imaging or molecular testing, including a discussion of possible effects on insurability and employability, is critical. See The literature on pregnancy and PKD is limited. Pregnant women with ADPKD should be monitored closely for the development of hypertension and urinary tract infections. In one study, ADPKD was associated with increased maternal complications during pregnancy but only a slight potential for increased fetal complications [ Pregnant women who develop hypertension during pregnancy or who have impaired kidney function are at increased risk and should be monitored closely for the development of preeclampsia, intrauterine fetal growth restriction, and oligohydramnios. A second-trimester prenatal sonographic examination is indicated if either parent has ADPKD to assess fetal kidney size and echogenicity, presence of fetal kidney cysts, and amniotic fluid volume [ Significant advances in the understanding of the genetics of ADPKD and the mechanisms of cyst growth have revealed additional likely targets for therapeutic intervention. Search • CT or MRI of abdomen w/ & w/o contrast enhancement • Kidney ultrasound exam (if CT or MRI is unavailable) • CT & MRI are more sensitive to determine extent of cystic disease in kidneys & liver & estimate prognosis. • CT (but not MRI) can detect stones & parenchymal calcifications. • CT or MRA if visualization of kidney arteries is necessary • MRI suggested when iodinated contrast material is contraindicated • In persons w/family history of intracranial aneurysms • Note: Screening for intracranial aneurysms in persons w/o family history of intracranial aneurysms is usually not recommended. • The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [ • In a nonrandomized study, the administration of ACE inhibitors without diuretics resulted in a lower rate of decline in GFR and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [ • A long-term follow up of the Modification of Diet in Kidney Disease (MDRD) study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mm Hg) experienced significantly less ESKD and combined ESKD/death than those randomized to the usual blood pressure target (MAP <107 mm Hg) [ • The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of kidney function [ • Lipid control to prevent hyperlipidemia with a low threshold to start statin therapy (aim for LDL ≤100 mg/dL) • Low osmolar intake with moderate sodium (2-3 g/day) and dietary protein restriction (0.8-1 g/kg of ideal body weight). The MDRD trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late stage of kidney disease (GFR: 13-55 mL/min per 1.73 m • Maintenance of urine osmolality at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up) • Control of acidosis with maintenance of serum bicarbonate at ≥22 mEq/L • Prevention of hyperphosphatemia by maintaining moderate dietary phosphorus intake (800 mg/day). • Moderation of caloric intake and low-impact exercise to maintain normal body mass index (BMI). In the CRISP study BMI ≥30 kg/m • High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. • Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol. • Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [ • CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection. • Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible. • Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s). • Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis. • Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [ • Because individuals with severe PLD have mostly normal liver function, their MELD ( • Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [ • CT or MRI of abdomen w/ & w/o contrast enhancement • Kidney ultrasound exam (if CT or MRI is unavailable) • Every 2-3 yrs in 1st-degree adult relatives of persons w/thoracic aortic dissection • Note: If aortic root dilatation is found, refer to cardiologist. • Family history of intracranial aneurysms or subarachnoid hemorrhage; • Previous rupture of aneurysm; • Preparation for elective surgery w/potential hemodynamic instability; • High-risk occupation (e.g., airline pilot); • Significant anxiety despite adequate risk info. • Long-term administration of nephrotoxic agents (e.g., combination analgesics, NSAIDs) • Caffeine in large amounts. There is no evidence that low or moderate use of caffeinated beverages accelerates the progression of ADPKD. • High-salt diet, smoking, and obesity • Use of estrogens and possibly progestogens in individuals with severe polycystic liver disease • Evaluations of at-risk relatives include the following: • Imaging with abdominal ultrasound, CT, or MRI examination • Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic • Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. • Imaging with abdominal ultrasound, CT, or MRI examination • Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic • Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. • Imaging with abdominal ultrasound, CT, or MRI examination • Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic • Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. • Comprehensive kidney image analysis by ultrasound, contrast-enhanced CT, and/or MRI examination (routine imaging for any kidney donor regardless of disease indication). See • If the ADPKD-causing pathogenic variant has been identified in an affected family member, any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the relative's genetic status so that only those who do not have the familial pathogenic variant are evaluated further. (For families with biallelic • Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in a potential donor is uninformative (i.e., the result does not prove that a potential donor does not have ADPKD). • If the ADPKD-causing pathogenic variant has • In potential donors with a small number of cysts, comprehensive genetic analysis with a PKD panel may be helpful to exclude pathogenic variants in known PKD-related genes – apart from the familial variant. • Pregnant women with ADPKD should be monitored closely for the development of hypertension and urinary tract infections. In one study, ADPKD was associated with increased maternal complications during pregnancy but only a slight potential for increased fetal complications [ • Pregnant women who develop hypertension during pregnancy or who have impaired kidney function are at increased risk and should be monitored closely for the development of preeclampsia, intrauterine fetal growth restriction, and oligohydramnios. • A second-trimester prenatal sonographic examination is indicated if either parent has ADPKD to assess fetal kidney size and echogenicity, presence of fetal kidney cysts, and amniotic fluid volume [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with ADPKD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ADPKD CT or MRI of abdomen w/ & w/o contrast enhancement Kidney ultrasound exam (if CT or MRI is unavailable) CT & MRI are more sensitive to determine extent of cystic disease in kidneys & liver & estimate prognosis. CT (but not MRI) can detect stones & parenchymal calcifications. CT or MRA if visualization of kidney arteries is necessary MRI suggested when iodinated contrast material is contraindicated In persons w/family history of intracranial aneurysms Note: Screening for intracranial aneurysms in persons w/o family history of intracranial aneurysms is usually not recommended. ADPKD = autosomal dominant polycystic kidney disease; MOI = mode of inheritance; MRA = MR angiography Unless otherwise indicated, evaluation should be done at diagnosis in adulthood. Blood pressure that is elevated when measured in the clinic, but normal when measured outside of the clinic MRA is the diagnostic imaging modality of choice for presymptomatic screening because it is noninvasive and does not require intravenous contrast material. Most intracranial aneurysms found in asymptomatic individuals are small, have a low risk of rupture, and require no treatment [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse • CT or MRI of abdomen w/ & w/o contrast enhancement • Kidney ultrasound exam (if CT or MRI is unavailable) • CT & MRI are more sensitive to determine extent of cystic disease in kidneys & liver & estimate prognosis. • CT (but not MRI) can detect stones & parenchymal calcifications. • CT or MRA if visualization of kidney arteries is necessary • MRI suggested when iodinated contrast material is contraindicated • In persons w/family history of intracranial aneurysms • Note: Screening for intracranial aneurysms in persons w/o family history of intracranial aneurysms is usually not recommended. ## Treatment of Manifestations Treatment guidelines formulated at the ADPKD KDIGO conference are summarized in Current therapy for ADPKD is aimed at slowing the progression of declining kidney function and reducing morbidity and mortality from the kidney and extra-kidney complications. Studies have shown that a vasopressin V2 receptor antagonist (tolvaptan) can slow the increase in kidney volume, delay decline in kidney function, and preserve estimated glomerular filtration rate (eGFR) [ The blood pressure goal is ≤110/75 mm Hg in those age 18-50 years and eGFR >60 mL/min; otherwise ≤130/85 mm Hg. The antihypertensive agent(s) of choice in ADPKD have not been clearly established. However, because of the role of the renin angiotensin system in the pathogenesis of hypertension in ADPKD, ACE inhibitors and angiotensin II receptor antagonists may be superior to other agents in individuals with preserved kidney function. ACE inhibitors and angiotensin II receptor blockers increase kidney blood flow, have a low side effect profile, and may reduce vascular smooth muscle proliferation and development of atherosclerosis. The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [ In a nonrandomized study, the administration of ACE inhibitors without diuretics resulted in a lower rate of decline in GFR and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [ A long-term follow up of the Modification of Diet in Kidney Disease (MDRD) study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mm Hg) experienced significantly less ESKD and combined ESKD/death than those randomized to the usual blood pressure target (MAP <107 mm Hg) [ The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of kidney function [ Additional measures to delay ESKD include the following: Lipid control to prevent hyperlipidemia with a low threshold to start statin therapy (aim for LDL ≤100 mg/dL) Low osmolar intake with moderate sodium (2-3 g/day) and dietary protein restriction (0.8-1 g/kg of ideal body weight). The MDRD trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late stage of kidney disease (GFR: 13-55 mL/min per 1.73 m Maintenance of urine osmolality at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up) Control of acidosis with maintenance of serum bicarbonate at ≥22 mEq/L Prevention of hyperphosphatemia by maintaining moderate dietary phosphorus intake (800 mg/day). Moderation of caloric intake and low-impact exercise to maintain normal body mass index (BMI). In the CRISP study BMI ≥30 kg/m After excluding causes of flank pain that may require intervention, such as infection, stone, or tumor, an initial conservative approach to pain management is recommended. When conservative measures fail, therapy can be directed toward cyst decompression with cyst aspiration and sclerosis: In individuals with many cysts contributing to pain, laparoscopic or surgical cyst fenestration through lumbotomy or flank incision, kidney denervation, and (in those who have reached ESKD) nephrectomy may be of benefit: Cyst hemorrhage and gross hematuria are usually self limited and respond well to conservative management with bed rest, analgesics, and adequate hydration to prevent development of obstructing clots. Rarely, episodes of bleeding are severe with extensive subcapsular or retroperitoneal hematoma, significant drop in hematocrit, and hemodynamic instability. These individuals require hospitalization, transfusion, and investigation by CT or angiography. In individuals with unusually severe or persistent hemorrhage, segmental arterial embolization can be successful. If not, surgery may be required to control bleeding. Some reports suggest a role for tranexamic acid in the treatment of life-threatening hematuria [ Gross hematuria persisting for more than one week or developing for the first time in an individual older than age 50 years requires thorough investigation. Small uric acid stones can be missed on nephrotomography and are best detected by CT. CT should be obtained before and after the administration of contrast material to confirm their location within the collecting system and to differentiate calculi from parenchymal calcifications. Dual-absorption CT now facilitates the differentiation of uric acid stones from calcium-containing stones. Excretory urography detects precaliceal tubular ectasia in 15% of individuals with ADPKD. The treatment of nephrolithiasis in individuals with ADPKD is the same as for individuals without ADPKD: High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol. Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [ If cyst infection is suspected, diagnostic imaging should be undertaken to assist in the diagnosis: CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection. Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible. In the appropriate clinical setting of fever, flank pain, and suggestive diagnostic imaging, cyst aspiration under ultrasound or CT guidance should be undertaken to culture the organism and assist in selection of antimicrobial therapy, particularly if blood and urine cultures are negative [ Cyst infection is often difficult to treat. It has a high treatment failure rate despite prolonged therapy with an antibiotic to which the organism is susceptible. Treatment failure results from the inability of certain antibiotics to penetrate the cyst epithelium successfully and achieve therapeutic concentrations within the cyst. The epithelium that lines gradient cysts has functional and ultrastructural characteristics of the distal tubule epithelium. Penetration is via tight junctions, allowing only lipid-soluble agent access. Nongradient cysts, which are more common, allow solute access via diffusion. However, kinetic studies indicate that water-soluble agents penetrate nongradient cysts slowly and irregularly, resulting in unreliable drug concentrations within the cysts. Lipophilic agents have been shown to penetrate both gradient and nongradient cysts equally and reliably. Therapeutic agents of choice include trimethoprim-sulfamethoxazole and fluoroquinolones. Clindamycin, vancomycin, and metronidazole are also able to penetrate cysts well. Chloramphenicol has shown therapeutic efficacy in otherwise refractory disease. If fever persists after one to two weeks of appropriate antimicrobial therapy, percutaneous or surgical drainage of infected cysts should be undertaken. If fever recurs after discontinuation of antibiotics, complicating features such as obstruction, perinephric abscess, or stones should be considered and treated appropriately. If complicating features are not identified, the course of previously effective therapy should be extended; several months may be required to completely eradicate the infection. Actuarial data indicate that individuals with ADPKD do better on dialysis than individuals with ESKD from other causes. Females appear to do better than males. The reason for this improved outcome is unclear but may relate to better-maintained hemoglobin levels through higher endogenous erythropoietin production. Rarely, hemodialysis can be complicated by intradialytic hypotension if the inferior vena cava is compressed by a medially located kidney cyst. Despite kidney size, peritoneal dialysis can usually be performed in individuals with ADPKD, although these individuals are at increased risk for inguinal and umbilical hernias, which require surgical repair. Following transplantation, there is no difference in patient or graft survival between individuals with ADPKD and those with ESKD caused by other conditions, and complications are no greater than in the general population. Complications directly related to ADPKD are rare. One study has suggested an increased risk for thromboembolic complications [ Nephrectomy of the native kidneys is reserved for affected individuals with a history of infected cysts, frequent bleeding, severe hypertension, or massive kidney enlargement. There is no consensus on the optimal timing of nephrectomy; whether nephrectomy is performed before, at, or following transplantation depends to some extent on the indication for the nephrectomy and other considerations [ Most individuals with polycystic liver disease (PLD) have no symptoms and require no treatment. The treatment of symptomatic disease includes the avoidance of estrogens and the use of H2 blockers or proton pump inhibitors for symptomatic relief. Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization. Any of these interventions should be tailored to the individual [ Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s). Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis. Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [ Because individuals with severe PLD have mostly normal liver function, their MELD ( Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [ The management of aneurysms 6.0-9.0 mm in size remains controversial. Surgical intervention is usually indicated for aneurysms >10.0 mm in diameter. For individuals with high surgical risk or with technically difficult-to-manage lesions, endovascular treatment with detachable platinum coils may be indicated. Endovascular treatment appears to be associated with fewer complications than clipping, but the long-term efficacy of this method is as yet unproven [ When the aortic root diameter reaches 55-60 mm, replacement of the aorta is indicated. Guidelines for management of • The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [ • In a nonrandomized study, the administration of ACE inhibitors without diuretics resulted in a lower rate of decline in GFR and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [ • A long-term follow up of the Modification of Diet in Kidney Disease (MDRD) study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mm Hg) experienced significantly less ESKD and combined ESKD/death than those randomized to the usual blood pressure target (MAP <107 mm Hg) [ • The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of kidney function [ • Lipid control to prevent hyperlipidemia with a low threshold to start statin therapy (aim for LDL ≤100 mg/dL) • Low osmolar intake with moderate sodium (2-3 g/day) and dietary protein restriction (0.8-1 g/kg of ideal body weight). The MDRD trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late stage of kidney disease (GFR: 13-55 mL/min per 1.73 m • Maintenance of urine osmolality at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up) • Control of acidosis with maintenance of serum bicarbonate at ≥22 mEq/L • Prevention of hyperphosphatemia by maintaining moderate dietary phosphorus intake (800 mg/day). • Moderation of caloric intake and low-impact exercise to maintain normal body mass index (BMI). In the CRISP study BMI ≥30 kg/m • High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. • Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol. • Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [ • CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection. • Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible. • Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s). • Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis. • Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [ • Because individuals with severe PLD have mostly normal liver function, their MELD ( • Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [ ## Vasopressin V2 Receptor Antagonists Studies have shown that a vasopressin V2 receptor antagonist (tolvaptan) can slow the increase in kidney volume, delay decline in kidney function, and preserve estimated glomerular filtration rate (eGFR) [ ## Hypertension The blood pressure goal is ≤110/75 mm Hg in those age 18-50 years and eGFR >60 mL/min; otherwise ≤130/85 mm Hg. The antihypertensive agent(s) of choice in ADPKD have not been clearly established. However, because of the role of the renin angiotensin system in the pathogenesis of hypertension in ADPKD, ACE inhibitors and angiotensin II receptor antagonists may be superior to other agents in individuals with preserved kidney function. ACE inhibitors and angiotensin II receptor blockers increase kidney blood flow, have a low side effect profile, and may reduce vascular smooth muscle proliferation and development of atherosclerosis. The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [ In a nonrandomized study, the administration of ACE inhibitors without diuretics resulted in a lower rate of decline in GFR and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [ A long-term follow up of the Modification of Diet in Kidney Disease (MDRD) study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mm Hg) experienced significantly less ESKD and combined ESKD/death than those randomized to the usual blood pressure target (MAP <107 mm Hg) [ The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of kidney function [ • The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [ • In a nonrandomized study, the administration of ACE inhibitors without diuretics resulted in a lower rate of decline in GFR and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [ • A long-term follow up of the Modification of Diet in Kidney Disease (MDRD) study that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the low blood pressure target (mean arterial pressure [MAP] <92 mm Hg) experienced significantly less ESKD and combined ESKD/death than those randomized to the usual blood pressure target (MAP <107 mm Hg) [ • The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of kidney function [ ## Delaying ESKD Additional measures to delay ESKD include the following: Lipid control to prevent hyperlipidemia with a low threshold to start statin therapy (aim for LDL ≤100 mg/dL) Low osmolar intake with moderate sodium (2-3 g/day) and dietary protein restriction (0.8-1 g/kg of ideal body weight). The MDRD trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late stage of kidney disease (GFR: 13-55 mL/min per 1.73 m Maintenance of urine osmolality at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up) Control of acidosis with maintenance of serum bicarbonate at ≥22 mEq/L Prevention of hyperphosphatemia by maintaining moderate dietary phosphorus intake (800 mg/day). Moderation of caloric intake and low-impact exercise to maintain normal body mass index (BMI). In the CRISP study BMI ≥30 kg/m • Lipid control to prevent hyperlipidemia with a low threshold to start statin therapy (aim for LDL ≤100 mg/dL) • Low osmolar intake with moderate sodium (2-3 g/day) and dietary protein restriction (0.8-1 g/kg of ideal body weight). The MDRD trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late stage of kidney disease (GFR: 13-55 mL/min per 1.73 m • Maintenance of urine osmolality at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up) • Control of acidosis with maintenance of serum bicarbonate at ≥22 mEq/L • Prevention of hyperphosphatemia by maintaining moderate dietary phosphorus intake (800 mg/day). • Moderation of caloric intake and low-impact exercise to maintain normal body mass index (BMI). In the CRISP study BMI ≥30 kg/m ## Flank Pain After excluding causes of flank pain that may require intervention, such as infection, stone, or tumor, an initial conservative approach to pain management is recommended. When conservative measures fail, therapy can be directed toward cyst decompression with cyst aspiration and sclerosis: In individuals with many cysts contributing to pain, laparoscopic or surgical cyst fenestration through lumbotomy or flank incision, kidney denervation, and (in those who have reached ESKD) nephrectomy may be of benefit: ## Cyst Hemorrhage and Gross Hematuria Cyst hemorrhage and gross hematuria are usually self limited and respond well to conservative management with bed rest, analgesics, and adequate hydration to prevent development of obstructing clots. Rarely, episodes of bleeding are severe with extensive subcapsular or retroperitoneal hematoma, significant drop in hematocrit, and hemodynamic instability. These individuals require hospitalization, transfusion, and investigation by CT or angiography. In individuals with unusually severe or persistent hemorrhage, segmental arterial embolization can be successful. If not, surgery may be required to control bleeding. Some reports suggest a role for tranexamic acid in the treatment of life-threatening hematuria [ Gross hematuria persisting for more than one week or developing for the first time in an individual older than age 50 years requires thorough investigation. ## Nephrolithiasis Small uric acid stones can be missed on nephrotomography and are best detected by CT. CT should be obtained before and after the administration of contrast material to confirm their location within the collecting system and to differentiate calculi from parenchymal calcifications. Dual-absorption CT now facilitates the differentiation of uric acid stones from calcium-containing stones. Excretory urography detects precaliceal tubular ectasia in 15% of individuals with ADPKD. The treatment of nephrolithiasis in individuals with ADPKD is the same as for individuals without ADPKD: High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol. Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [ • High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects. • Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol. • Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [ ## Cyst Infection If cyst infection is suspected, diagnostic imaging should be undertaken to assist in the diagnosis: CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection. Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible. In the appropriate clinical setting of fever, flank pain, and suggestive diagnostic imaging, cyst aspiration under ultrasound or CT guidance should be undertaken to culture the organism and assist in selection of antimicrobial therapy, particularly if blood and urine cultures are negative [ Cyst infection is often difficult to treat. It has a high treatment failure rate despite prolonged therapy with an antibiotic to which the organism is susceptible. Treatment failure results from the inability of certain antibiotics to penetrate the cyst epithelium successfully and achieve therapeutic concentrations within the cyst. The epithelium that lines gradient cysts has functional and ultrastructural characteristics of the distal tubule epithelium. Penetration is via tight junctions, allowing only lipid-soluble agent access. Nongradient cysts, which are more common, allow solute access via diffusion. However, kinetic studies indicate that water-soluble agents penetrate nongradient cysts slowly and irregularly, resulting in unreliable drug concentrations within the cysts. Lipophilic agents have been shown to penetrate both gradient and nongradient cysts equally and reliably. Therapeutic agents of choice include trimethoprim-sulfamethoxazole and fluoroquinolones. Clindamycin, vancomycin, and metronidazole are also able to penetrate cysts well. Chloramphenicol has shown therapeutic efficacy in otherwise refractory disease. If fever persists after one to two weeks of appropriate antimicrobial therapy, percutaneous or surgical drainage of infected cysts should be undertaken. If fever recurs after discontinuation of antibiotics, complicating features such as obstruction, perinephric abscess, or stones should be considered and treated appropriately. If complicating features are not identified, the course of previously effective therapy should be extended; several months may be required to completely eradicate the infection. • CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection. • Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible. ## ESKD Actuarial data indicate that individuals with ADPKD do better on dialysis than individuals with ESKD from other causes. Females appear to do better than males. The reason for this improved outcome is unclear but may relate to better-maintained hemoglobin levels through higher endogenous erythropoietin production. Rarely, hemodialysis can be complicated by intradialytic hypotension if the inferior vena cava is compressed by a medially located kidney cyst. Despite kidney size, peritoneal dialysis can usually be performed in individuals with ADPKD, although these individuals are at increased risk for inguinal and umbilical hernias, which require surgical repair. Following transplantation, there is no difference in patient or graft survival between individuals with ADPKD and those with ESKD caused by other conditions, and complications are no greater than in the general population. Complications directly related to ADPKD are rare. One study has suggested an increased risk for thromboembolic complications [ Nephrectomy of the native kidneys is reserved for affected individuals with a history of infected cysts, frequent bleeding, severe hypertension, or massive kidney enlargement. There is no consensus on the optimal timing of nephrectomy; whether nephrectomy is performed before, at, or following transplantation depends to some extent on the indication for the nephrectomy and other considerations [ ## Polycystic Liver Disease Most individuals with polycystic liver disease (PLD) have no symptoms and require no treatment. The treatment of symptomatic disease includes the avoidance of estrogens and the use of H2 blockers or proton pump inhibitors for symptomatic relief. Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization. Any of these interventions should be tailored to the individual [ Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s). Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis. Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [ Because individuals with severe PLD have mostly normal liver function, their MELD ( Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [ • Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s). • Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis. • Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [ • Because individuals with severe PLD have mostly normal liver function, their MELD ( • Selective hepatic artery embolization can be considered for highly symptomatic individuals who are not candidates for surgery [ ## Intracranial Aneurysm The management of aneurysms 6.0-9.0 mm in size remains controversial. Surgical intervention is usually indicated for aneurysms >10.0 mm in diameter. For individuals with high surgical risk or with technically difficult-to-manage lesions, endovascular treatment with detachable platinum coils may be indicated. Endovascular treatment appears to be associated with fewer complications than clipping, but the long-term efficacy of this method is as yet unproven [ ## Aortic Dissection When the aortic root diameter reaches 55-60 mm, replacement of the aorta is indicated. Guidelines for management of ## Surveillance Guidance on surveillance is available in Recommended Surveillance for Individuals with ADPKD CT or MRI of abdomen w/ & w/o contrast enhancement Kidney ultrasound exam (if CT or MRI is unavailable) Every 2-3 yrs in 1st-degree adult relatives of persons w/thoracic aortic dissection Note: If aortic root dilatation is found, refer to cardiologist. Family history of intracranial aneurysms or subarachnoid hemorrhage; Previous rupture of aneurysm; Preparation for elective surgery w/potential hemodynamic instability; High-risk occupation (e.g., airline pilot); Significant anxiety despite adequate risk info. MRA is the diagnostic imaging modality of choice for presymptomatic screening because it is noninvasive and does not require intravenous contrast material. Most intracranial aneurysms found in asymptomatic individuals are small, have a low risk of rupture, and require no treatment [ One of 76 individuals with an initial normal MRA study had a new intracranial aneurysm after a mean follow up of 9.8 years [ • CT or MRI of abdomen w/ & w/o contrast enhancement • Kidney ultrasound exam (if CT or MRI is unavailable) • Every 2-3 yrs in 1st-degree adult relatives of persons w/thoracic aortic dissection • Note: If aortic root dilatation is found, refer to cardiologist. • Family history of intracranial aneurysms or subarachnoid hemorrhage; • Previous rupture of aneurysm; • Preparation for elective surgery w/potential hemodynamic instability; • High-risk occupation (e.g., airline pilot); • Significant anxiety despite adequate risk info. ## Agents/Circumstances to Avoid Avoid the following: Long-term administration of nephrotoxic agents (e.g., combination analgesics, NSAIDs) Caffeine in large amounts. There is no evidence that low or moderate use of caffeinated beverages accelerates the progression of ADPKD. High-salt diet, smoking, and obesity Use of estrogens and possibly progestogens in individuals with severe polycystic liver disease • Long-term administration of nephrotoxic agents (e.g., combination analgesics, NSAIDs) • Caffeine in large amounts. There is no evidence that low or moderate use of caffeinated beverages accelerates the progression of ADPKD. • High-salt diet, smoking, and obesity • Use of estrogens and possibly progestogens in individuals with severe polycystic liver disease ## Evaluation of Relatives at Risk Evaluations of at-risk relatives include the following: Imaging with abdominal ultrasound, CT, or MRI examination Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. Comprehensive kidney image analysis by ultrasound, contrast-enhanced CT, and/or MRI examination (routine imaging for any kidney donor regardless of disease indication). See If the ADPKD-causing pathogenic variant has been identified in an affected family member, any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the relative's genetic status so that only those who do not have the familial pathogenic variant are evaluated further. (For families with biallelic Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in a potential donor is uninformative (i.e., the result does not prove that a potential donor does not have ADPKD). If the ADPKD-causing pathogenic variant has In potential donors with a small number of cysts, comprehensive genetic analysis with a PKD panel may be helpful to exclude pathogenic variants in known PKD-related genes – apart from the familial variant. Note: Appropriate counseling prior to imaging or molecular testing, including a discussion of possible effects on insurability and employability, is critical. See • Evaluations of at-risk relatives include the following: • Imaging with abdominal ultrasound, CT, or MRI examination • Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic • Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. • Imaging with abdominal ultrasound, CT, or MRI examination • Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic • Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. • Imaging with abdominal ultrasound, CT, or MRI examination • Molecular genetic testing if the ADPKD-causing pathogenic variant in the family is known. (For families with biallelic • Note: For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal. • Comprehensive kidney image analysis by ultrasound, contrast-enhanced CT, and/or MRI examination (routine imaging for any kidney donor regardless of disease indication). See • If the ADPKD-causing pathogenic variant has been identified in an affected family member, any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the relative's genetic status so that only those who do not have the familial pathogenic variant are evaluated further. (For families with biallelic • Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in a potential donor is uninformative (i.e., the result does not prove that a potential donor does not have ADPKD). • If the ADPKD-causing pathogenic variant has • In potential donors with a small number of cysts, comprehensive genetic analysis with a PKD panel may be helpful to exclude pathogenic variants in known PKD-related genes – apart from the familial variant. ## Pregnancy Management The literature on pregnancy and PKD is limited. Pregnant women with ADPKD should be monitored closely for the development of hypertension and urinary tract infections. In one study, ADPKD was associated with increased maternal complications during pregnancy but only a slight potential for increased fetal complications [ Pregnant women who develop hypertension during pregnancy or who have impaired kidney function are at increased risk and should be monitored closely for the development of preeclampsia, intrauterine fetal growth restriction, and oligohydramnios. A second-trimester prenatal sonographic examination is indicated if either parent has ADPKD to assess fetal kidney size and echogenicity, presence of fetal kidney cysts, and amniotic fluid volume [ • Pregnant women with ADPKD should be monitored closely for the development of hypertension and urinary tract infections. In one study, ADPKD was associated with increased maternal complications during pregnancy but only a slight potential for increased fetal complications [ • Pregnant women who develop hypertension during pregnancy or who have impaired kidney function are at increased risk and should be monitored closely for the development of preeclampsia, intrauterine fetal growth restriction, and oligohydramnios. • A second-trimester prenatal sonographic examination is indicated if either parent has ADPKD to assess fetal kidney size and echogenicity, presence of fetal kidney cysts, and amniotic fluid volume [ ## Therapies Under Investigation Significant advances in the understanding of the genetics of ADPKD and the mechanisms of cyst growth have revealed additional likely targets for therapeutic intervention. Search ## Genetic Counseling In most affected families, autosomal dominant polycystic kidney disease (ADPKD) is caused by a heterozygous Complex inheritance may play a role in a minority of individuals [ Most individuals diagnosed with ADPKD have an affected parent. 10%-20% of individuals diagnosed with ADPKD have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, The family history of some individuals diagnosed with ADPKD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., imaging and/or molecular genetic testing if the family-specific pathogenic variant is known) have been performed on the parents of the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Substantial variability in severity of kidney disease and other manifestations may be observed between family members with the same pathogenic variant (see If the proband has a known ADPKD-causing pathogenic variant that is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [ If the genetic status of the parents is unknown but kidney image analysis suggests that the parents are unaffected, the recurrence risk to sibs is greater than that of the general population because of the possibility of later onset of disease in a heterozygous parent or parental mosaicism. Parental mosaicism has been reported (see Clinical Description, See Management, Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in an asymptomatic family member is uninformative (i.e., the result does exclude the possibility that the family member has ADPKD). Predictive testing of at-risk asymptomatic family members can also be performed by kidney imaging via ultrasound, CT, or MRI. This is usually informative in older family members or by age 18 years if the disease is severe but may not be informative in families with milder disease, especially in younger individuals (see Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment is not available, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk for discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors It is appropriate to consider testing of symptomatic individuals with PKD, including suspected ADPKD, regardless of age or family history. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the ADPKD-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors • Most individuals diagnosed with ADPKD have an affected parent. • 10%-20% of individuals diagnosed with ADPKD have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ • * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ • * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, • The family history of some individuals diagnosed with ADPKD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., imaging and/or molecular genetic testing if the family-specific pathogenic variant is known) have been performed on the parents of the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ • * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Substantial variability in severity of kidney disease and other manifestations may be observed between family members with the same pathogenic variant (see • If the proband has a known ADPKD-causing pathogenic variant that is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [ • If the genetic status of the parents is unknown but kidney image analysis suggests that the parents are unaffected, the recurrence risk to sibs is greater than that of the general population because of the possibility of later onset of disease in a heterozygous parent or parental mosaicism. Parental mosaicism has been reported (see Clinical Description, • Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in an asymptomatic family member is uninformative (i.e., the result does exclude the possibility that the family member has ADPKD). • Predictive testing of at-risk asymptomatic family members can also be performed by kidney imaging via ultrasound, CT, or MRI. This is usually informative in older family members or by age 18 years if the disease is severe but may not be informative in families with milder disease, especially in younger individuals (see • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment is not available, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk for discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance In most affected families, autosomal dominant polycystic kidney disease (ADPKD) is caused by a heterozygous Complex inheritance may play a role in a minority of individuals [ ## Risk to Family Members (Autosomal Dominant Inheritance) Most individuals diagnosed with ADPKD have an affected parent. 10%-20% of individuals diagnosed with ADPKD have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, The family history of some individuals diagnosed with ADPKD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., imaging and/or molecular genetic testing if the family-specific pathogenic variant is known) have been performed on the parents of the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Substantial variability in severity of kidney disease and other manifestations may be observed between family members with the same pathogenic variant (see If the proband has a known ADPKD-causing pathogenic variant that is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [ If the genetic status of the parents is unknown but kidney image analysis suggests that the parents are unaffected, the recurrence risk to sibs is greater than that of the general population because of the possibility of later onset of disease in a heterozygous parent or parental mosaicism. Parental mosaicism has been reported (see Clinical Description, • Most individuals diagnosed with ADPKD have an affected parent. • 10%-20% of individuals diagnosed with ADPKD have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ • * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ • * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, • The family history of some individuals diagnosed with ADPKD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., imaging and/or molecular genetic testing if the family-specific pathogenic variant is known) have been performed on the parents of the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Parental mosaicism is thought to occur in approximately 0.25% of families with ADPKD [ • * A parent with somatic and germline mosaicism for an ADPKD-causing pathogenic variant may be mildly/minimally affected (see Clinical Description, • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Substantial variability in severity of kidney disease and other manifestations may be observed between family members with the same pathogenic variant (see • If the proband has a known ADPKD-causing pathogenic variant that is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental mosaicism [ • If the genetic status of the parents is unknown but kidney image analysis suggests that the parents are unaffected, the recurrence risk to sibs is greater than that of the general population because of the possibility of later onset of disease in a heterozygous parent or parental mosaicism. Parental mosaicism has been reported (see Clinical Description, ## Related Genetic Counseling Issues See Management, Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in an asymptomatic family member is uninformative (i.e., the result does exclude the possibility that the family member has ADPKD). Predictive testing of at-risk asymptomatic family members can also be performed by kidney imaging via ultrasound, CT, or MRI. This is usually informative in older family members or by age 18 years if the disease is severe but may not be informative in families with milder disease, especially in younger individuals (see Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment is not available, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk for discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors It is appropriate to consider testing of symptomatic individuals with PKD, including suspected ADPKD, regardless of age or family history. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Note: If the family-specific ADPKD-causing pathogenic variant is not known, a "negative" molecular genetic test result in an asymptomatic family member is uninformative (i.e., the result does exclude the possibility that the family member has ADPKD). • Predictive testing of at-risk asymptomatic family members can also be performed by kidney imaging via ultrasound, CT, or MRI. This is usually informative in older family members or by age 18 years if the disease is severe but may not be informative in families with milder disease, especially in younger individuals (see • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment is not available, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk for discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the ADPKD-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors ## Resources United Kingdom United Kingdom Canada • • • • • • United Kingdom • • • United Kingdom • • • • • Canada • • • ## Molecular Genetics Polycystic Kidney Disease, Autosomal Dominant: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Polycystic Kidney Disease, Autosomal Dominant ( There is good evidence that polycystin-1 (PC1) and polycystin-2 (PC2) interact to form a functional polycystin complex with a cryo-EM structure consisting of 3x PC2 and 1x PC1 now available [ The cilium is known to be essential for a number of signaling pathways (e.g., sonic hedgehog and possibly planar cell polarity) that likely play a role in some ciliopathy phenotypes. Proteins causative of syndromic forms of PKD (e.g., Meckel syndrome, However, the precise role of the polycystin complex with respect to the cilium is controversial. It is likely that polycystins have a sensory/mechano-sensory/receptor role [ Another location of polycystins and ARPKD protein (fibrocystin) is in urinary vesicles [ Notable ADPKD = autosomal dominant polycystic kidney disease Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis There is good evidence that polycystin-1 (PC1) and polycystin-2 (PC2) interact to form a functional polycystin complex with a cryo-EM structure consisting of 3x PC2 and 1x PC1 now available [ The cilium is known to be essential for a number of signaling pathways (e.g., sonic hedgehog and possibly planar cell polarity) that likely play a role in some ciliopathy phenotypes. Proteins causative of syndromic forms of PKD (e.g., Meckel syndrome, However, the precise role of the polycystin complex with respect to the cilium is controversial. It is likely that polycystins have a sensory/mechano-sensory/receptor role [ Another location of polycystins and ARPKD protein (fibrocystin) is in urinary vesicles [ Notable ADPKD = autosomal dominant polycystic kidney disease Variants listed in the table have been provided by the authors. ## Chapter Notes Peter C Harris's Vicente E Torres's Dr Harris is supported by grants from NIDDK, DoD, and the PKD Foundation. 29 September 2022 (sw) Comprehensive update posted live 19 July 2018 (sw) Comprehensive update posted live 11 June 2015 (me) Comprehensive update posted live 8 December 2011 (me) Comprehensive update posted live 2 June 2009 (cd) Revision: deletion/duplication analysis available clinically for 15 December 2008 (cd) Revision: FISH (deletion/duplication analysis) no longer listed in the GeneTests Laboratory Directory as being offered for 7 October 2008 (me) Comprehensive update posted live 6 June 2006 (me) Comprehensive update posted live 5 March 2004 (me) Comprehensive update posted live 10 January 2002 (me) Review posted live 22 August 2001 (ph) Original submission • 29 September 2022 (sw) Comprehensive update posted live • 19 July 2018 (sw) Comprehensive update posted live • 11 June 2015 (me) Comprehensive update posted live • 8 December 2011 (me) Comprehensive update posted live • 2 June 2009 (cd) Revision: deletion/duplication analysis available clinically for • 15 December 2008 (cd) Revision: FISH (deletion/duplication analysis) no longer listed in the GeneTests Laboratory Directory as being offered for • 7 October 2008 (me) Comprehensive update posted live • 6 June 2006 (me) Comprehensive update posted live • 5 March 2004 (me) Comprehensive update posted live • 10 January 2002 (me) Review posted live • 22 August 2001 (ph) Original submission ## Author Notes Peter C Harris's Vicente E Torres's ## Acknowledgments Dr Harris is supported by grants from NIDDK, DoD, and the PKD Foundation. ## Revision History 29 September 2022 (sw) Comprehensive update posted live 19 July 2018 (sw) Comprehensive update posted live 11 June 2015 (me) Comprehensive update posted live 8 December 2011 (me) Comprehensive update posted live 2 June 2009 (cd) Revision: deletion/duplication analysis available clinically for 15 December 2008 (cd) Revision: FISH (deletion/duplication analysis) no longer listed in the GeneTests Laboratory Directory as being offered for 7 October 2008 (me) Comprehensive update posted live 6 June 2006 (me) Comprehensive update posted live 5 March 2004 (me) Comprehensive update posted live 10 January 2002 (me) Review posted live 22 August 2001 (ph) Original submission • 29 September 2022 (sw) Comprehensive update posted live • 19 July 2018 (sw) Comprehensive update posted live • 11 June 2015 (me) Comprehensive update posted live • 8 December 2011 (me) Comprehensive update posted live • 2 June 2009 (cd) Revision: deletion/duplication analysis available clinically for • 15 December 2008 (cd) Revision: FISH (deletion/duplication analysis) no longer listed in the GeneTests Laboratory Directory as being offered for • 7 October 2008 (me) Comprehensive update posted live • 6 June 2006 (me) Comprehensive update posted live • 5 March 2004 (me) Comprehensive update posted live • 10 January 2002 (me) Review posted live • 22 August 2001 (ph) Original submission ## References Chapman AB, Devuyst O, Eckardt KU, Gansevoort RT, Harris T, Horie S, Kasiske BL, Odland D, Pei Y, Perrone RD, Pirson Y, Schrier RW, Torra R, Torres VE, Watnick T, Wheeler DC, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 2015. Kidney Int. 2015;88:17-27. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available Gimpel C, Bergmann C, Bockenhauer D, Breysem L, Cadnapaphornchai MA, Cetiner M, Dudley J, Emma F, Konrad M, Harris T, Harris PC, König J, Liebau MC, Marlais M, Mekahli D, Metcalfe AM, Oh J, Perrone RD, Sinha MD, Titieni A, Torra R, Weber S, Winyard PJD, Schaefer F. International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713-26. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Chapman AB, Devuyst O, Eckardt KU, Gansevoort RT, Harris T, Horie S, Kasiske BL, Odland D, Pei Y, Perrone RD, Pirson Y, Schrier RW, Torra R, Torres VE, Watnick T, Wheeler DC, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 2015. Kidney Int. 2015;88:17-27. • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • Gimpel C, Bergmann C, Bockenhauer D, Breysem L, Cadnapaphornchai MA, Cetiner M, Dudley J, Emma F, Konrad M, Harris T, Harris PC, König J, Liebau MC, Marlais M, Mekahli D, Metcalfe AM, Oh J, Perrone RD, Sinha MD, Titieni A, Torra R, Weber S, Winyard PJD, Schaefer F. International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713-26. • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Published Guidelines / Consensus Statements Chapman AB, Devuyst O, Eckardt KU, Gansevoort RT, Harris T, Horie S, Kasiske BL, Odland D, Pei Y, Perrone RD, Pirson Y, Schrier RW, Torra R, Torres VE, Watnick T, Wheeler DC, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 2015. Kidney Int. 2015;88:17-27. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available Gimpel C, Bergmann C, Bockenhauer D, Breysem L, Cadnapaphornchai MA, Cetiner M, Dudley J, Emma F, Konrad M, Harris T, Harris PC, König J, Liebau MC, Marlais M, Mekahli D, Metcalfe AM, Oh J, Perrone RD, Sinha MD, Titieni A, Torra R, Weber S, Winyard PJD, Schaefer F. International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713-26. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Chapman AB, Devuyst O, Eckardt KU, Gansevoort RT, Harris T, Horie S, Kasiske BL, Odland D, Pei Y, Perrone RD, Pirson Y, Schrier RW, Torra R, Torres VE, Watnick T, Wheeler DC, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 2015. Kidney Int. 2015;88:17-27. • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • Gimpel C, Bergmann C, Bockenhauer D, Breysem L, Cadnapaphornchai MA, Cetiner M, Dudley J, Emma F, Konrad M, Harris T, Harris PC, König J, Liebau MC, Marlais M, Mekahli D, Metcalfe AM, Oh J, Perrone RD, Sinha MD, Titieni A, Torra R, Weber S, Winyard PJD, Schaefer F. International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713-26. • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Literature Cited	[]	10/1/2002	29/9/2022	2/6/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pkd-ar	pkd-ar	[ "ARPKD-PKHD1", "ARPKD-PKHD1", "Fibrocystin", "PKHD1", "Autosomal Recessive Polycystic Kidney Disease – PKHD1" ]	Autosomal Recessive Polycystic Kidney Disease –	Kathrin Burgmaier, Charlotte Gimpel, Franz Schaefer, Max Liebau	Summary Autosomal recessive polycystic kidney disease – The molecular diagnosis of ARPKD- ARPKD-	The topic of this Autosomal Recessive Polycystic Kidney Disease – Enlarged hyperechogenic kidneys Variable CKD Inhomogeneous liver parenchyma due to CHF Hepatomegaly Bile duct dilatation / cystic changes Normal biochemical liver function Enlarged hyperechogenic kidneys Micro- & macrocysts Variable CKD Inhomogeneous liver parenchyma due to CHF Hepatomegaly Bile duct dilatation / cystic changes Normal biochemical liver function Enlarged kidneys w/multiple macrocysts ↑ echogenicity ↓ or abrogated cortex-medulla differentiation Possible variable CKD CHF = congenital hepatic fibrosis; CKD = chronic kidney disease • Enlarged hyperechogenic kidneys • Variable CKD • Inhomogeneous liver parenchyma due to CHF • Hepatomegaly • Bile duct dilatation / cystic changes • Normal biochemical liver function • Enlarged hyperechogenic kidneys • Micro- & macrocysts • Variable CKD • Inhomogeneous liver parenchyma due to CHF • Hepatomegaly • Bile duct dilatation / cystic changes • Normal biochemical liver function • Enlarged kidneys w/multiple macrocysts • ↑ echogenicity • ↓ or abrogated cortex-medulla differentiation • Possible variable CKD ## Diagnosis Consensus expert recommendations for the clinical diagnosis of autosomal recessive polycystic kidney disease (ARPKD) were published in 2014 [ Autosomal recessive polycystic kidney disease – Note: (1) Ultrasonography is the imaging method of choice for assessing the kidneys prenatally and in all pediatric age groups because it is cost-effective, painless, widely available, and does not require radiation or sedation. (2) Kidney biopsies With use of modern obstetric ultrasonography, fetuses with severe kidney involvement with oligohydramnios/anhydramnios resulting in a Potter syndrome-like phenotype with pulmonary hypoplasia and characteristic facial and limb findings resulting from fetal compression can be identified. Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. Increased echogenicity Poor corticomedullary differentiation High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ Hepatocellular function is usually preserved early in life [ Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ A relative decrease of kidney length over time [ Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ Family history is consistent with autosomal recessive inheritance (e.g., affected sibs, unaffected parents,* and/or parental consanguinity). Absence of a known family history (e.g., no affected sibs) does not preclude the diagnosis. Note: Pseudodominant inheritance (i.e., an autosomal recessive condition presents in individuals in two or more generations) has been reported in some families (see * Absence of renal enlargement and/or characteristic imaging findings in both parents, as demonstrated by high-resolution ultrasonography examination. The molecular diagnosis of ARPKD- Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Recessive Polycystic Kidney Disease – See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • With use of modern obstetric ultrasonography, fetuses with severe kidney involvement with oligohydramnios/anhydramnios resulting in a Potter syndrome-like phenotype with pulmonary hypoplasia and characteristic facial and limb findings resulting from fetal compression can be identified. • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ ## Suggestive Findings Autosomal recessive polycystic kidney disease – Note: (1) Ultrasonography is the imaging method of choice for assessing the kidneys prenatally and in all pediatric age groups because it is cost-effective, painless, widely available, and does not require radiation or sedation. (2) Kidney biopsies With use of modern obstetric ultrasonography, fetuses with severe kidney involvement with oligohydramnios/anhydramnios resulting in a Potter syndrome-like phenotype with pulmonary hypoplasia and characteristic facial and limb findings resulting from fetal compression can be identified. Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. Increased echogenicity Poor corticomedullary differentiation High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ Hepatocellular function is usually preserved early in life [ Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ A relative decrease of kidney length over time [ Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ Family history is consistent with autosomal recessive inheritance (e.g., affected sibs, unaffected parents,* and/or parental consanguinity). Absence of a known family history (e.g., no affected sibs) does not preclude the diagnosis. Note: Pseudodominant inheritance (i.e., an autosomal recessive condition presents in individuals in two or more generations) has been reported in some families (see * Absence of renal enlargement and/or characteristic imaging findings in both parents, as demonstrated by high-resolution ultrasonography examination. • With use of modern obstetric ultrasonography, fetuses with severe kidney involvement with oligohydramnios/anhydramnios resulting in a Potter syndrome-like phenotype with pulmonary hypoplasia and characteristic facial and limb findings resulting from fetal compression can be identified. • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ ## Perinatal Presentation (prenatal to age 4 weeks) With use of modern obstetric ultrasonography, fetuses with severe kidney involvement with oligohydramnios/anhydramnios resulting in a Potter syndrome-like phenotype with pulmonary hypoplasia and characteristic facial and limb findings resulting from fetal compression can be identified. • With use of modern obstetric ultrasonography, fetuses with severe kidney involvement with oligohydramnios/anhydramnios resulting in a Potter syndrome-like phenotype with pulmonary hypoplasia and characteristic facial and limb findings resulting from fetal compression can be identified. ## Infantile Presentation (age 4 weeks to 1 year) Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. Increased echogenicity Poor corticomedullary differentiation High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ Hepatocellular function is usually preserved early in life [ Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape • Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again. • Increased echogenicity • Poor corticomedullary differentiation • High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla. • Note: In the past this pattern was described by the now-outdated term "salt-and-pepper appearance" (referring to the speckled appearance obtained by older ultrasound transducers). • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. • Typical liver findings on abdominal ultrasound examination are signs of congenital hepatic fibrosis (CHF) that lead to portal hypertension. Note that MRCP, which provides a clear depiction of the biliary duct system, is a sensitive assessment of biliary ductal anatomy. • Signs of portal hypertension include enlarged liver and/or spleen, dilated portal vein, biphasic or retrograde flow in the portal vein, retrograde flow in the splenic vein, portosystemic collateral vessels, and ascites. • Caroli disease (i.e., multifocal cystic dilatation of intrahepatic bile ducts) is evident as saccular dilatations that may show the "central dot sign" (i.e., portal vein within the dilated bile duct). Dilated extrahepatic bile ducts and choledochal cysts are less common [ • Hepatocellular function is usually preserved early in life [ • Laboratory markers of portal hypertension include thrombocytopenia and increased prothrombin time, which correlate with splenic volume. Thrombocytopenia may rapidly develop during episodes of infection or sepsis. Although rare, variceal bleeding has been described in young children. ## Childhood / Young Adulthood Presentation (age >1 year) Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ A relative decrease of kidney length over time [ Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation [ • A relative decrease of kidney length over time [ • • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ • Thrombocytopenia is the best predictor of portal hypertension and splenomegaly; prothrombin time increases with higher spleen volume [ • Gamma-glutamyl transferase can be markedly elevated during the disease course, while liver transaminases are only mildly elevated, if at all [ ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs, unaffected parents,* and/or parental consanguinity). Absence of a known family history (e.g., no affected sibs) does not preclude the diagnosis. Note: Pseudodominant inheritance (i.e., an autosomal recessive condition presents in individuals in two or more generations) has been reported in some families (see * Absence of renal enlargement and/or characteristic imaging findings in both parents, as demonstrated by high-resolution ultrasonography examination. ## Establishing the Diagnosis The molecular diagnosis of ARPKD- Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Recessive Polycystic Kidney Disease – See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Recessive Polycystic Kidney Disease – See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics Autosomal recessive polycystic kidney disease – Note: (1) Because some data on ARPKD predates the understanding of its heterogeneous genetic causes, information in this section is based on study cohorts with ARPKD in general as well as cohorts with ARPKD- Autosomal Recessive Polycystic Kidney Disease: Comparison of Clinical Findings at Presentation by Age at Presentation Based on +++ = always present; ++ = frequently present; + = rarely present; (+) = very rarely present; NA = not applicable Respiratory support was required in 23% of infants (78/333) in a large retrospective European study [ Hypertension, often severe and resistant to multidrug therapy, is usually noted within the first few weeks of life and may improve over time [ Urine output is usually not diminished; rather, polyuria and polydipsia are consistent with a kidney concentrating defect [ Improvement in kidney function over the first year of life can occur comparable to that of normal kidney development or other congenital kidney diseases. Subsequent yearly loss of glomerular filtration rate (GFR) was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring kidney replacement therapy (KRT; dialysis or kidney transplantation [KTx]) in the first two decades of life [ Urinary tract infections are common [ Although histologic hepatic fibrosis is invariably present at birth, clinical, radiographic, or laboratory evidence of liver disease may be absent in newborns and infants [ In 115 children with ARPKD with a mean age of 29 days at diagnosis, 46% had clinical evidence of liver involvement over a mean observation time of 4.92 years, with positive correlation of detection of clinical signs of hepatic fibrosis with increasing age [ Aggressive nutritional support in the first two years of life has improved growth rates even in children with moderately to severely impaired kidney function and portal hypertension. In one study growth did not seem to differ in children with ARPKD from children with other kidney diseases [ Kidney involvement ranges from enlarged kidneys with multiple macrocysts, increased echogenicity, reduced or abrogated cortex-medulla differentiation, and CKD in some individuals to only mild functional and structural kidney disease in individuals with liver-predominant phenotypes. In an international cohort of 70 children, Subsequent yearly loss of GFR was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring KRT in the first two decades of life [ Urinary tract infections are common [ Some individuals with CHF develop progressive portal hypertension with an increased risk of esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding. Bleeding from esophageal varices contributes significantly to morbidity and mortality [ In a study that challenged many assumptions about the timing of liver involvement in ARPKD, In a subset of individuals with ARPKD- Approximately 20%-30% of affected infants die in the neonatal period or within the first year of life, primarily of respiratory insufficiency or superimposed pulmonary infections [ Of those children with an ARPKD phenotype who survived beyond age one year, subsequent one-year survival was approximately 85%-87%, and ten-year survival was 82% [ In a large cohort of 164 neonatal survivors, At age five years, 86% had not progressed to KF requiring KRT or died due to KF; At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. In another large cohort of 304 neonatal survivors, Prenatal findings of oligo- or anhydramnios and detection of kidney cysts and kidney enlargement have been associated with a higher likelihood of need for dialysis in the first year of life [ Need for respiratory support has been associated with the need for KRT or worse kidney prognosis [ In a cohort of 304 neonatal survivors, Data from the European Society for Pediatric Nephrology / European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry show very good outcomes after combined liver and kidney transplantation (CLKTx) but suggest a higher peri-interventional mortality with a 6.7-fold age- and sex-adjusted risk for death after CLKTx when compared to KTx [ In ARPKD- Autosomal Recessive Polycystic Kidney Disease Most truncating variants expected to result in complete loss of protein function ("null variants") & assoc w/most severe phenotypes (compared to persons w/at least 1 missense variant) Assoc w/poorer kidney & liver outcomes w/early/perinatal demise in most persons KRT = 34% Signs of portal hypertension = 42% Substantial hepatic complications = 78% No major difference in kidney & liver outcomes between these groups in several studies Typically, mild-to-moderate phenotypes in persons w/at least 1 missense variant KRT = 64%-82% Signs of portal hypertension = 36%-46% Substantial hepatic complications = 77%-80% KRT= kidney replacement therapy Includes pathogenic variants, likely pathogenic variants, and variants of uncertain significance Autosomal Recessive Polycystic Kidney Disease Less frequently assoc w/KF In 35 persons w/1 null variant & 1 missense variant in this region, substantial hepatic complications were absent during observation period in childhood. KRT = 95% Signs of portal hypertension = 51% Substantial hepatic complications = 94% Milder presentation Observed in children surviving neonatal period KRT = 30%-59% Signs of portal hypertension = 53% Substantial hepatic complications = 86% Poorer liver outcomes Predominant liver phenotype in persons w/variants around amino acids 2831-2840 & 3051-3209 KRT = 72% Signs of portal hypertension = 13% Substantial hepatic complications = 48% KF = kidney failure; KRT = kidney replacement therapy Variant location referrs specifically to the location of the corresponding missense variant(s) in individuals with either null/missense or biallelic missense variants. For biallelic missense variants to be included in this table, both had to be within the same region to be assigned to a specific group. Autosomal recessive polycystic kidney disease (ARPKD) – a broad term referring to all individuals with a clinical diagnosis of ARPKD – encompasses individuals with a molecular diagnosis (e.g., ARPKD- When ARPKD was first described, it was assumed that pathogenic variants in a single gene were causative and that ARPKD study cohorts were genetically homogeneous. However, the Current proposed polycystic kidney disease (PKD) nomenclature is based on phenotype and mode of inheritance, with the recent addition of genetic etiology; for example, the title of this Designations used previously to refer to ARPKD include the following: "Infantile polycystic kidney disease" and "Potter syndrome I" Perinatal, neonatal, infantile, and juvenile polycystic kidney disease (based on clinical and histologic findings in the kidneys and liver) [ The incidence of ARPKD in live births in Europe was proposed to be about 1:20,000 with a corresponding carrier frequency of 1:70 [ Based on an electronic health record system, The The Afrikaner pathogenic founder variant Pathogenic founder variants in the Ashkenazi Jewish population are • In a large cohort of 164 neonatal survivors, • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • In another large cohort of 304 neonatal survivors, • Prenatal findings of oligo- or anhydramnios and detection of kidney cysts and kidney enlargement have been associated with a higher likelihood of need for dialysis in the first year of life [ • Need for respiratory support has been associated with the need for KRT or worse kidney prognosis [ • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • Most truncating variants expected to result in complete loss of protein function ("null variants") & assoc w/most severe phenotypes (compared to persons w/at least 1 missense variant) • Assoc w/poorer kidney & liver outcomes w/early/perinatal demise in most persons • KRT = 34% • Signs of portal hypertension = 42% • Substantial hepatic complications = 78% • No major difference in kidney & liver outcomes between these groups in several studies • Typically, mild-to-moderate phenotypes in persons w/at least 1 missense variant • KRT = 64%-82% • Signs of portal hypertension = 36%-46% • Substantial hepatic complications = 77%-80% • Less frequently assoc w/KF • In 35 persons w/1 null variant & 1 missense variant in this region, substantial hepatic complications were absent during observation period in childhood. • KRT = 95% • Signs of portal hypertension = 51% • Substantial hepatic complications = 94% • Milder presentation • Observed in children surviving neonatal period • KRT = 30%-59% • Signs of portal hypertension = 53% • Substantial hepatic complications = 86% • Poorer liver outcomes • Predominant liver phenotype in persons w/variants around amino acids 2831-2840 & 3051-3209 • KRT = 72% • Signs of portal hypertension = 13% • Substantial hepatic complications = 48% • "Infantile polycystic kidney disease" and "Potter syndrome I" • Perinatal, neonatal, infantile, and juvenile polycystic kidney disease (based on clinical and histologic findings in the kidneys and liver) [ ## Clinical Description Autosomal recessive polycystic kidney disease – Note: (1) Because some data on ARPKD predates the understanding of its heterogeneous genetic causes, information in this section is based on study cohorts with ARPKD in general as well as cohorts with ARPKD- Autosomal Recessive Polycystic Kidney Disease: Comparison of Clinical Findings at Presentation by Age at Presentation Based on +++ = always present; ++ = frequently present; + = rarely present; (+) = very rarely present; NA = not applicable Respiratory support was required in 23% of infants (78/333) in a large retrospective European study [ Hypertension, often severe and resistant to multidrug therapy, is usually noted within the first few weeks of life and may improve over time [ Urine output is usually not diminished; rather, polyuria and polydipsia are consistent with a kidney concentrating defect [ Improvement in kidney function over the first year of life can occur comparable to that of normal kidney development or other congenital kidney diseases. Subsequent yearly loss of glomerular filtration rate (GFR) was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring kidney replacement therapy (KRT; dialysis or kidney transplantation [KTx]) in the first two decades of life [ Urinary tract infections are common [ Although histologic hepatic fibrosis is invariably present at birth, clinical, radiographic, or laboratory evidence of liver disease may be absent in newborns and infants [ In 115 children with ARPKD with a mean age of 29 days at diagnosis, 46% had clinical evidence of liver involvement over a mean observation time of 4.92 years, with positive correlation of detection of clinical signs of hepatic fibrosis with increasing age [ Aggressive nutritional support in the first two years of life has improved growth rates even in children with moderately to severely impaired kidney function and portal hypertension. In one study growth did not seem to differ in children with ARPKD from children with other kidney diseases [ Kidney involvement ranges from enlarged kidneys with multiple macrocysts, increased echogenicity, reduced or abrogated cortex-medulla differentiation, and CKD in some individuals to only mild functional and structural kidney disease in individuals with liver-predominant phenotypes. In an international cohort of 70 children, Subsequent yearly loss of GFR was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring KRT in the first two decades of life [ Urinary tract infections are common [ Some individuals with CHF develop progressive portal hypertension with an increased risk of esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding. Bleeding from esophageal varices contributes significantly to morbidity and mortality [ In a study that challenged many assumptions about the timing of liver involvement in ARPKD, In a subset of individuals with ARPKD- Approximately 20%-30% of affected infants die in the neonatal period or within the first year of life, primarily of respiratory insufficiency or superimposed pulmonary infections [ Of those children with an ARPKD phenotype who survived beyond age one year, subsequent one-year survival was approximately 85%-87%, and ten-year survival was 82% [ In a large cohort of 164 neonatal survivors, At age five years, 86% had not progressed to KF requiring KRT or died due to KF; At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. In another large cohort of 304 neonatal survivors, Prenatal findings of oligo- or anhydramnios and detection of kidney cysts and kidney enlargement have been associated with a higher likelihood of need for dialysis in the first year of life [ Need for respiratory support has been associated with the need for KRT or worse kidney prognosis [ In a cohort of 304 neonatal survivors, Data from the European Society for Pediatric Nephrology / European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry show very good outcomes after combined liver and kidney transplantation (CLKTx) but suggest a higher peri-interventional mortality with a 6.7-fold age- and sex-adjusted risk for death after CLKTx when compared to KTx [ • In a large cohort of 164 neonatal survivors, • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • In another large cohort of 304 neonatal survivors, • Prenatal findings of oligo- or anhydramnios and detection of kidney cysts and kidney enlargement have been associated with a higher likelihood of need for dialysis in the first year of life [ • Need for respiratory support has been associated with the need for KRT or worse kidney prognosis [ • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. ## Perinatal and Infantile Presentation (prenatal to age 1 year) Respiratory support was required in 23% of infants (78/333) in a large retrospective European study [ Hypertension, often severe and resistant to multidrug therapy, is usually noted within the first few weeks of life and may improve over time [ Urine output is usually not diminished; rather, polyuria and polydipsia are consistent with a kidney concentrating defect [ Improvement in kidney function over the first year of life can occur comparable to that of normal kidney development or other congenital kidney diseases. Subsequent yearly loss of glomerular filtration rate (GFR) was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring kidney replacement therapy (KRT; dialysis or kidney transplantation [KTx]) in the first two decades of life [ Urinary tract infections are common [ Although histologic hepatic fibrosis is invariably present at birth, clinical, radiographic, or laboratory evidence of liver disease may be absent in newborns and infants [ In 115 children with ARPKD with a mean age of 29 days at diagnosis, 46% had clinical evidence of liver involvement over a mean observation time of 4.92 years, with positive correlation of detection of clinical signs of hepatic fibrosis with increasing age [ Aggressive nutritional support in the first two years of life has improved growth rates even in children with moderately to severely impaired kidney function and portal hypertension. In one study growth did not seem to differ in children with ARPKD from children with other kidney diseases [ ## Respiratory support was required in 23% of infants (78/333) in a large retrospective European study [ Hypertension, often severe and resistant to multidrug therapy, is usually noted within the first few weeks of life and may improve over time [ ## Urine output is usually not diminished; rather, polyuria and polydipsia are consistent with a kidney concentrating defect [ Improvement in kidney function over the first year of life can occur comparable to that of normal kidney development or other congenital kidney diseases. Subsequent yearly loss of glomerular filtration rate (GFR) was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring kidney replacement therapy (KRT; dialysis or kidney transplantation [KTx]) in the first two decades of life [ Urinary tract infections are common [ ## Although histologic hepatic fibrosis is invariably present at birth, clinical, radiographic, or laboratory evidence of liver disease may be absent in newborns and infants [ In 115 children with ARPKD with a mean age of 29 days at diagnosis, 46% had clinical evidence of liver involvement over a mean observation time of 4.92 years, with positive correlation of detection of clinical signs of hepatic fibrosis with increasing age [ ## Aggressive nutritional support in the first two years of life has improved growth rates even in children with moderately to severely impaired kidney function and portal hypertension. In one study growth did not seem to differ in children with ARPKD from children with other kidney diseases [ ## Childhood / Young Adulthood Presentation (age >1 year) Kidney involvement ranges from enlarged kidneys with multiple macrocysts, increased echogenicity, reduced or abrogated cortex-medulla differentiation, and CKD in some individuals to only mild functional and structural kidney disease in individuals with liver-predominant phenotypes. In an international cohort of 70 children, Subsequent yearly loss of GFR was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring KRT in the first two decades of life [ Urinary tract infections are common [ Some individuals with CHF develop progressive portal hypertension with an increased risk of esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding. Bleeding from esophageal varices contributes significantly to morbidity and mortality [ In a study that challenged many assumptions about the timing of liver involvement in ARPKD, In a subset of individuals with ARPKD- ## Kidney involvement ranges from enlarged kidneys with multiple macrocysts, increased echogenicity, reduced or abrogated cortex-medulla differentiation, and CKD in some individuals to only mild functional and structural kidney disease in individuals with liver-predominant phenotypes. In an international cohort of 70 children, Subsequent yearly loss of GFR was −1.4 mL/min/1.73m More than 50% of affected individuals progress to KF requiring KRT in the first two decades of life [ Urinary tract infections are common [ ## Some individuals with CHF develop progressive portal hypertension with an increased risk of esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding. Bleeding from esophageal varices contributes significantly to morbidity and mortality [ In a study that challenged many assumptions about the timing of liver involvement in ARPKD, In a subset of individuals with ARPKD- ## Other ## Prognosis Approximately 20%-30% of affected infants die in the neonatal period or within the first year of life, primarily of respiratory insufficiency or superimposed pulmonary infections [ Of those children with an ARPKD phenotype who survived beyond age one year, subsequent one-year survival was approximately 85%-87%, and ten-year survival was 82% [ In a large cohort of 164 neonatal survivors, At age five years, 86% had not progressed to KF requiring KRT or died due to KF; At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. In another large cohort of 304 neonatal survivors, Prenatal findings of oligo- or anhydramnios and detection of kidney cysts and kidney enlargement have been associated with a higher likelihood of need for dialysis in the first year of life [ Need for respiratory support has been associated with the need for KRT or worse kidney prognosis [ In a cohort of 304 neonatal survivors, Data from the European Society for Pediatric Nephrology / European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry show very good outcomes after combined liver and kidney transplantation (CLKTx) but suggest a higher peri-interventional mortality with a 6.7-fold age- and sex-adjusted risk for death after CLKTx when compared to KTx [ • In a large cohort of 164 neonatal survivors, • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • In another large cohort of 304 neonatal survivors, • Prenatal findings of oligo- or anhydramnios and detection of kidney cysts and kidney enlargement have been associated with a higher likelihood of need for dialysis in the first year of life [ • Need for respiratory support has been associated with the need for KRT or worse kidney prognosis [ • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. • At age five years, 86% had not progressed to KF requiring KRT or died due to KF; • At age ten years, 71% had not progressed to KF requiring KRT or died due to KF; • At age 20 years, 42% had not progressed to KF requiring KRT or died due to KF. ## Genotype-Phenotype Correlations In ARPKD- Autosomal Recessive Polycystic Kidney Disease Most truncating variants expected to result in complete loss of protein function ("null variants") & assoc w/most severe phenotypes (compared to persons w/at least 1 missense variant) Assoc w/poorer kidney & liver outcomes w/early/perinatal demise in most persons KRT = 34% Signs of portal hypertension = 42% Substantial hepatic complications = 78% No major difference in kidney & liver outcomes between these groups in several studies Typically, mild-to-moderate phenotypes in persons w/at least 1 missense variant KRT = 64%-82% Signs of portal hypertension = 36%-46% Substantial hepatic complications = 77%-80% KRT= kidney replacement therapy Includes pathogenic variants, likely pathogenic variants, and variants of uncertain significance Autosomal Recessive Polycystic Kidney Disease Less frequently assoc w/KF In 35 persons w/1 null variant & 1 missense variant in this region, substantial hepatic complications were absent during observation period in childhood. KRT = 95% Signs of portal hypertension = 51% Substantial hepatic complications = 94% Milder presentation Observed in children surviving neonatal period KRT = 30%-59% Signs of portal hypertension = 53% Substantial hepatic complications = 86% Poorer liver outcomes Predominant liver phenotype in persons w/variants around amino acids 2831-2840 & 3051-3209 KRT = 72% Signs of portal hypertension = 13% Substantial hepatic complications = 48% KF = kidney failure; KRT = kidney replacement therapy Variant location referrs specifically to the location of the corresponding missense variant(s) in individuals with either null/missense or biallelic missense variants. For biallelic missense variants to be included in this table, both had to be within the same region to be assigned to a specific group. • Most truncating variants expected to result in complete loss of protein function ("null variants") & assoc w/most severe phenotypes (compared to persons w/at least 1 missense variant) • Assoc w/poorer kidney & liver outcomes w/early/perinatal demise in most persons • KRT = 34% • Signs of portal hypertension = 42% • Substantial hepatic complications = 78% • No major difference in kidney & liver outcomes between these groups in several studies • Typically, mild-to-moderate phenotypes in persons w/at least 1 missense variant • KRT = 64%-82% • Signs of portal hypertension = 36%-46% • Substantial hepatic complications = 77%-80% • Less frequently assoc w/KF • In 35 persons w/1 null variant & 1 missense variant in this region, substantial hepatic complications were absent during observation period in childhood. • KRT = 95% • Signs of portal hypertension = 51% • Substantial hepatic complications = 94% • Milder presentation • Observed in children surviving neonatal period • KRT = 30%-59% • Signs of portal hypertension = 53% • Substantial hepatic complications = 86% • Poorer liver outcomes • Predominant liver phenotype in persons w/variants around amino acids 2831-2840 & 3051-3209 • KRT = 72% • Signs of portal hypertension = 13% • Substantial hepatic complications = 48% ## Nomenclature Autosomal recessive polycystic kidney disease (ARPKD) – a broad term referring to all individuals with a clinical diagnosis of ARPKD – encompasses individuals with a molecular diagnosis (e.g., ARPKD- When ARPKD was first described, it was assumed that pathogenic variants in a single gene were causative and that ARPKD study cohorts were genetically homogeneous. However, the Current proposed polycystic kidney disease (PKD) nomenclature is based on phenotype and mode of inheritance, with the recent addition of genetic etiology; for example, the title of this Designations used previously to refer to ARPKD include the following: "Infantile polycystic kidney disease" and "Potter syndrome I" Perinatal, neonatal, infantile, and juvenile polycystic kidney disease (based on clinical and histologic findings in the kidneys and liver) [ • "Infantile polycystic kidney disease" and "Potter syndrome I" • Perinatal, neonatal, infantile, and juvenile polycystic kidney disease (based on clinical and histologic findings in the kidneys and liver) [ ## Prevalence The incidence of ARPKD in live births in Europe was proposed to be about 1:20,000 with a corresponding carrier frequency of 1:70 [ Based on an electronic health record system, The The Afrikaner pathogenic founder variant Pathogenic founder variants in the Ashkenazi Jewish population are ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant kidney- and liver-related morbidity and mortality in children. Among individuals with ARPKD, ARPKD caused by biallelic pathogenic variants in less commonly involved genes (e.g., Phenocopies of ARPKD associated with pathogenic variants in Autosomal dominant polycystic kidney disease (ADPKD), which may resemble ARPKD in some individuals, such as individuals with very early-onset ADPKD [ Pathogenic It is important to note that not all individuals with prenatal detection of enlarged and/or hyperechogenic kidneys have ARPKD [ Genes of Interest in the Differential Diagnosis of Autosomal Recessive Polycystic Kidney Disease – Progressive cyst development & bilaterally enlarged polycystic kidneys Systemic disease w/cysts in other organs (e.g., liver, seminal vesicles, pancreas, arachnoid membrane) & non-cystic anomalies (e.g., intracranial aneurysms & dolichoectasias, dilatation of the aortic root & dissection of the thoracic aorta, mitral valve prolapse, colonic diverticulae, abdominal wall hernias) Cerebral & extracerebral aneurysms, a common & potentially severe complication of ADPKD, have only been reported in 9 persons w/ARPKD. ADPKD usually presents in adulthood; however, 1%-2% of affected persons present as newborns, often with features indistinguishable from those of ARPKD- Specific heterozygous CHF – an invariable finding in ARPKD- Kidney ultrasonography may often distinguish ADPKD & ARPKD- Bilaterally enlarged hyperechogenic kidneys pre- & perinatally Liver: no cysts; no CHF in early childhood; Biallelic hypomorphic pathogenic variants in KF at age 8.5 yrs in 1 person w/compound homozygosity for 2 AR Bilaterally enlarged hyperechogenic kidneys: multiple small cysts, some macrocysts, poor corticomedullary differentiation Liver: no cysts, liver elasticity (FibroScan 7 persons from 4 families: KF at age 12, 18, 20, & 26 yrs 4 children from 3 consanguineous families: KF at age 9 yrs; homozygous for c.193T>C (p.Cys65Arg) Multiple bilateral medullary & cortical cysts Liver: mild CHF Enlarged kidneys w/multiple cysts Liver cysts CHF in 1/17 persons Hyperinsulinemia: often w/hypoglycemic seizures, mostly in 1st yr of life ARPKD-like kidney disease & hyperinsulinemia in childhood 17 persons from 11 families w/cysts of various sizes in enlarged kidneys; predominantly glomerulocystic disease; 1 person w/prenatal polyhydramnios Infantile NPH: moderately enlarged cystic kidneys w/cortical hyperechogenicity Prenatal manifestation w/oligo- & anhydramnios, postnatal hypertension, & CKD Liver: possible CHF Possible situs inversus, tapetoretinal degeneration Kidney cysts are the most frequently detected feature, although other renal phenotypes (single kidney, renal hypoplasia/dysplasia) can also occur. Extrakidney phenotypes are common & incl Primary criteria: retinal degeneration (cone-rod dystrophy), central obesity, postaxial polydactyly, learning disabilities, hypogonadism &/or genitourinary malformations, & kidney malformations (e.g., ranging from single unilateral & multiple bilateral cysts) Additional secondary criteria incl cataract, speech disorders, behavioral disorders, polyuria, or craniofacial dysmorphism Highly variable kidney phenotype w/structural anomalies & parenchymal disease incl PKD-mimicking phenotypes & kidney dysplasia phenotypes CKD in 31% of children & 42% of adults AD = autosomal dominant; ADPKD = autosomal dominant polycystic kidney disease; AR = autosomal recessive; ARPKD = autosomal recessive polycystic kidney disease; BBS = Bardet-Biedl syndrome; CHF = congenital hepatic fibrosis; CKD = chronic kidney disease; KF = kidney failure; MODY = maturity-onset diabetes of the young; MOI = mode of inheritance; NPH = nephronophthisis; PKD = polycystic kidney disease More than 20 genes are known to be associated with nephronophthisis (NPH); the NPH-related genes of primary interest in the differential diagnosis of ARPKD- More than 25 genes are known to be associated with Bardet-Biedl syndrome (BBS); the BBS-related genes of primary interest in the differential diagnosis of ARPKD- Calcifications that can occur in ARPKD- • ARPKD caused by biallelic pathogenic variants in less commonly involved genes (e.g., • Phenocopies of ARPKD associated with pathogenic variants in • Autosomal dominant polycystic kidney disease (ADPKD), which may resemble ARPKD in some individuals, such as individuals with very early-onset ADPKD [ • Pathogenic • Progressive cyst development & bilaterally enlarged polycystic kidneys • Systemic disease w/cysts in other organs (e.g., liver, seminal vesicles, pancreas, arachnoid membrane) & non-cystic anomalies (e.g., intracranial aneurysms & dolichoectasias, dilatation of the aortic root & dissection of the thoracic aorta, mitral valve prolapse, colonic diverticulae, abdominal wall hernias) • Cerebral & extracerebral aneurysms, a common & potentially severe complication of ADPKD, have only been reported in 9 persons w/ARPKD. • ADPKD usually presents in adulthood; however, 1%-2% of affected persons present as newborns, often with features indistinguishable from those of ARPKD- • Specific heterozygous • CHF – an invariable finding in ARPKD- • Kidney ultrasonography may often distinguish ADPKD & ARPKD- • Bilaterally enlarged hyperechogenic kidneys pre- & perinatally • Liver: no cysts; no CHF in early childhood; • Biallelic hypomorphic pathogenic variants in • KF at age 8.5 yrs in 1 person w/compound homozygosity for 2 • Bilaterally enlarged hyperechogenic kidneys: multiple small cysts, some macrocysts, poor corticomedullary differentiation • Liver: no cysts, liver elasticity (FibroScan • 7 persons from 4 families: KF at age 12, 18, 20, & 26 yrs • 4 children from 3 consanguineous families: KF at age 9 yrs; homozygous for c.193T>C (p.Cys65Arg) • Multiple bilateral medullary & cortical cysts • Liver: mild CHF • Enlarged kidneys w/multiple cysts • Liver cysts • CHF in 1/17 persons • Hyperinsulinemia: often w/hypoglycemic seizures, mostly in 1st yr of life • ARPKD-like kidney disease & hyperinsulinemia in childhood • 17 persons from 11 families w/cysts of various sizes in enlarged kidneys; predominantly glomerulocystic disease; 1 person w/prenatal polyhydramnios • Infantile NPH: moderately enlarged cystic kidneys w/cortical hyperechogenicity • Prenatal manifestation w/oligo- & anhydramnios, postnatal hypertension, & CKD • Liver: possible CHF • Possible situs inversus, tapetoretinal degeneration • Kidney cysts are the most frequently detected feature, although other renal phenotypes (single kidney, renal hypoplasia/dysplasia) can also occur. • Extrakidney phenotypes are common & incl • Primary criteria: retinal degeneration (cone-rod dystrophy), central obesity, postaxial polydactyly, learning disabilities, hypogonadism &/or genitourinary malformations, & kidney malformations (e.g., ranging from single unilateral & multiple bilateral cysts) • Additional secondary criteria incl cataract, speech disorders, behavioral disorders, polyuria, or craniofacial dysmorphism • Highly variable kidney phenotype w/structural anomalies & parenchymal disease incl PKD-mimicking phenotypes & kidney dysplasia phenotypes • CKD in 31% of children & 42% of adults ## Management Consensus expert recommendations for the management of autosomal recessive polycystic kidney disease (ARPKD) [ Note: Because some data on ARPKD predates the understanding of its heterogeneous genetic causes, information in this section is based on both study cohorts with ARPKD in general and cohorts with ARPKD- To establish the extent of disease and needs in an individual diagnosed with ARPKD- If possible, delivery should take place at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. Assess postnatal respiratory status, including physical examination, pulse oximetry, blood gas analysis, chest radiographs, and echocardiography (as clinically indicated). Measure blood pressure regularly (and train parents in home measurements if elevated). Assess: Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). Perform urinalysis: To assess urinary concentration and detect proteinuria; In case of fever or biochemical signs of infection to identify potential urinary tract infections. Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and magnetic resonance cholangiopancreatography [MRCP]). Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. Perform echocardiography as clinically indicated, such as in case of arterial hypertension. Perform cranial sonography to assess for structural brain defects and intraventricular hemorrhage at initial examination. Set up evaluation by interdisciplinary team including psychologists and social workers to assess type of support needed by the family. Set up consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- Consider initiating interdisciplinary and interprofessional shared decision-making processes early in challenging clinical situations potentially requiring decisions on palliative treatment approaches or restrictions on specific treatment modes. Assess need for family support and resources including community or Assess kidney function, including serum concentrations of BUN, creatinine, and cystatin C. Assess serum electrolyte concentrations and perform blood gas analysis to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). Measure blood pressure. If elevated, home blood pressure monitoring during follow up can be helpful in distinguishing fixed hypertension from "white coat" hypertension (i.e., high blood pressure that occurs during medical examinations). Perform urinalysis: To assess urinary concentration and detect proteinuria; In case of fever or biochemical signs of infection to identify potential urinary tract infections. Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and MRCP). Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. Perform echocardiography as clinically indicated, such as in case of arterial hypertension. Perform neurodevelopmental examination, EEG, head sonography, and/or cranial MRT (if clinically indicated). Perform lung function tests (if clinically indicated). Set up an interdisciplinary and interprofessional team including psychologists and social workers for family support. Set up a consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- Assess need for family support and resources including community or There is currently no cure for autosomal recessive polycystic kidney disease – Initial management of affected infants focuses on stabilization of pulmonary and kidney function. When massively enlarged kidneys are considered to prevent diaphragmatic excursion and/or cause severe feeding intolerance and/or massive arterial hypertension, some have advocated unilateral or bilateral nephrectomy; however, evidence supporting this approach is limited and mainly focused on nutritional aspects [ Unilateral nephrectomy may be of value, but the contralateral kidney may show marked rapid enlargement following unilateral nephrectomy [ Bilateral nephrectomies with placement of a peritoneal dialysis catheter have been suggested as a strategy for early management of critically ill infants. The expected benefits regarding nutrition or arterial hypertension must be weighed against the following risks: Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ A very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation processes of autonomic cardiovascular control occur, is recommended. Neonates with oliguria or anuria may require dialysis within the first days of life. Peritoneal dialysis is the modality of choice [ Hyponatremia is common and should be treated according to standard recommendations depending on the individual's volume status [ Early recognition and treatment of dehydration, insufficient weight gain, and/or poor growth is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tube placement may be required. As caloric intake relies on fluid intake in the early months of life, sufficient caloric intake should be monitored and modified as needed by a nutrition specialist. Early recognition of arterial hypertension is essential. In many individuals, hypertension is so severe that it requires multiple antihypertensive medications. Following general CKD recommendations targeting blood pressure values in the 50th percentile seems reasonable [ Early recognition and treatment of urinary tract infections is important. Nephrotoxic agents like aminoglycosides should be avoided when possible. With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (e.g., pneumococcus, Feeding intolerance and growth failure can be significant even in the absence of KF, especially in young infants. Nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tube, is often required to optimize weight gain and growth. Concerns about the potential risk of bleeding after gastrostomy tube placement in individuals with ARPKD and portal hypertension were addressed in a global survey (in which respondents were mainly European pediatric nephrologists) that identified very few complications and support by most respondents for gastrostomy tube placement in these children [ A subanalysis from the American Chronic Kidney Disease in Children (CKiD) cohort did not find evidence for an ARPKD-specific effect on growth when comparing children with a mean age of 7.9 years to age-matched control groups with other underlying congenital kidney diseases [ Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Treatment with growth hormone should be guided by standard recommendations for pediatric CKD. In addition to the treatments listed in KTx is the treatment of choice for children with KF, as graft survival is good. Previous or simultaneous nephrectomy of native ARPKD kidney(s) may be required. Peritoneal dialysis is the method of choice for chronic dialysis in children. In young children with ARPKD, maintenance peritoneal dialysis can be performed with only minor modifications compared to children with other early-onset kidney diseases [ Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. Imaging studies may be supportive. Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ Note: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [ In severe instances of intractable portal hypertension or severe dual renal and hepatobiliary disease, LTx or simultaneous/combined liver and kidney transplantation (CLKTx) is a viable option. A study from the United Network for Organ Sharing (UNOS) database reported superior five-year kidney transplant organ survival in individuals starting from six months after CLKTx compared to individuals after isolated KTx [ In summary, individual decision making regarding single or combined transplantation is indispensable because clear-cut criteria evaluating risks and benefits for decision making in individuals with ARPKD remain to be defined. To monitor existing manifestations in all individuals regardless of age of initial presentation, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Blood pressure. Monitor at regular physician's visits as well as at home if indicated (see Kidney function. Close monitoring for the complications of CKD should be undertaken by the treating pediatric nephrologist according to standard practices. Electrolyte balance. Monitor via serum concentrations of sodium, potassium, chloride, and hydrogen bicarbonate. Mineral balance. Monitor via serum concentrations of calcium, phosphorous, magnesium, and 25-hydroxyvitamin D. Hydration status. Monitor at periodic physician's visits as well as at home if indicated. Nutritional status. Plot growth on standard growth charts. Set up nutrition consultation as indicated. Hepatoportal involvement. Perform physical examination; obtain complete blood counts, prothrombin time, and serum concentrations of albumin, 25-hydroxyvitamin D, and other fat-soluble vitamins. Abdominal ultrasound, liver elastography, and MRCP For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ Individuals with hypertension should avoid sympathomimetic agents. In general, unless the clinical situation warrants their use, avoid known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides. High-salt diet, smoking, and obesity should be avoided. Minimize use of potentially hepatotoxic agents (e.g., acetaminophen doses >30 mg/kg/day, herbal supplements, and alcohol). While work in cell and animal models suggests that caffeine, theophylline-like agents, and calcium channel blockers may exacerbate the formation and growth of renal cysts, this hypothesis has not been rigorously studied in individuals with ARPKD. Thus, the clinical relevance of these observations remains unclear. See Very little is known about pregnancy outcomes for women with ARPKD. As both kidney and liver phenotypes show clinical variability, comprehensive recommendations cannot currently be given. In general, women with CKD face an increased risk of pregnancy-related decline in renal function, preeclampsia, and impaired fetal outcomes [ In a small case series of four pregnant women with ARPKD and live birth deliveries, three had uncomplicated pregnancies (in two of three the diagnosis of ARPKD was established after delivery) and one had transient worsening of kidney function [ Recent studies in two animal models of ARPKD suggest that tesevatinib (TSV), a unique multikinase inhibitor, markedly slows the progression of both renal cystic disease and hepatobiliary disease [ Two multinational open-label Phase III trials on the effects of tolvaptan in ARPKD- Search • If possible, delivery should take place at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. • Assess postnatal respiratory status, including physical examination, pulse oximetry, blood gas analysis, chest radiographs, and echocardiography (as clinically indicated). • Measure blood pressure regularly (and train parents in home measurements if elevated). • Assess: • Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; • Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; • Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • Perform urinalysis: • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. • Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. • Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and magnetic resonance cholangiopancreatography [MRCP]). • Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. • Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. • Perform echocardiography as clinically indicated, such as in case of arterial hypertension. • Perform cranial sonography to assess for structural brain defects and intraventricular hemorrhage at initial examination. • Set up evaluation by interdisciplinary team including psychologists and social workers to assess type of support needed by the family. • Set up consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- • Consider initiating interdisciplinary and interprofessional shared decision-making processes early in challenging clinical situations potentially requiring decisions on palliative treatment approaches or restrictions on specific treatment modes. • Assess need for family support and resources including community or • Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; • Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Assess kidney function, including serum concentrations of BUN, creatinine, and cystatin C. • Assess serum electrolyte concentrations and perform blood gas analysis to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • Measure blood pressure. If elevated, home blood pressure monitoring during follow up can be helpful in distinguishing fixed hypertension from "white coat" hypertension (i.e., high blood pressure that occurs during medical examinations). • Perform urinalysis: • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. • Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. • Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and MRCP). • Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. • Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. • Perform echocardiography as clinically indicated, such as in case of arterial hypertension. • Perform neurodevelopmental examination, EEG, head sonography, and/or cranial MRT (if clinically indicated). • Perform lung function tests (if clinically indicated). • Set up an interdisciplinary and interprofessional team including psychologists and social workers for family support. • Set up a consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- • Assess need for family support and resources including community or • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Unilateral nephrectomy may be of value, but the contralateral kidney may show marked rapid enlargement following unilateral nephrectomy [ • Bilateral nephrectomies with placement of a peritoneal dialysis catheter have been suggested as a strategy for early management of critically ill infants. The expected benefits regarding nutrition or arterial hypertension must be weighed against the following risks: • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • A very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation processes of autonomic cardiovascular control occur, is recommended. • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • Neonates with oliguria or anuria may require dialysis within the first days of life. Peritoneal dialysis is the modality of choice [ • Hyponatremia is common and should be treated according to standard recommendations depending on the individual's volume status [ • Early recognition and treatment of dehydration, insufficient weight gain, and/or poor growth is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tube placement may be required. As caloric intake relies on fluid intake in the early months of life, sufficient caloric intake should be monitored and modified as needed by a nutrition specialist. • Early recognition of arterial hypertension is essential. In many individuals, hypertension is so severe that it requires multiple antihypertensive medications. Following general CKD recommendations targeting blood pressure values in the 50th percentile seems reasonable [ • Early recognition and treatment of urinary tract infections is important. Nephrotoxic agents like aminoglycosides should be avoided when possible. • With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (e.g., pneumococcus, • Feeding intolerance and growth failure can be significant even in the absence of KF, especially in young infants. Nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tube, is often required to optimize weight gain and growth. • Concerns about the potential risk of bleeding after gastrostomy tube placement in individuals with ARPKD and portal hypertension were addressed in a global survey (in which respondents were mainly European pediatric nephrologists) that identified very few complications and support by most respondents for gastrostomy tube placement in these children [ • A subanalysis from the American Chronic Kidney Disease in Children (CKiD) cohort did not find evidence for an ARPKD-specific effect on growth when comparing children with a mean age of 7.9 years to age-matched control groups with other underlying congenital kidney diseases [ • Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Treatment with growth hormone should be guided by standard recommendations for pediatric CKD. • KTx is the treatment of choice for children with KF, as graft survival is good. Previous or simultaneous nephrectomy of native ARPKD kidney(s) may be required. • Peritoneal dialysis is the method of choice for chronic dialysis in children. In young children with ARPKD, maintenance peritoneal dialysis can be performed with only minor modifications compared to children with other early-onset kidney diseases [ • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Note: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [ • In severe instances of intractable portal hypertension or severe dual renal and hepatobiliary disease, LTx or simultaneous/combined liver and kidney transplantation (CLKTx) is a viable option. • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Blood pressure. Monitor at regular physician's visits as well as at home if indicated (see • Kidney function. Close monitoring for the complications of CKD should be undertaken by the treating pediatric nephrologist according to standard practices. • Electrolyte balance. Monitor via serum concentrations of sodium, potassium, chloride, and hydrogen bicarbonate. • Mineral balance. Monitor via serum concentrations of calcium, phosphorous, magnesium, and 25-hydroxyvitamin D. • Hydration status. Monitor at periodic physician's visits as well as at home if indicated. • Nutritional status. Plot growth on standard growth charts. Set up nutrition consultation as indicated. • Hepatoportal involvement. Perform physical examination; obtain complete blood counts, prothrombin time, and serum concentrations of albumin, 25-hydroxyvitamin D, and other fat-soluble vitamins. • Abdominal ultrasound, liver elastography, and MRCP • For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ • Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ • If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ • MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ • For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ • Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ • If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ • MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ • For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ • Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ • If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ • MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ARPKD- If possible, delivery should take place at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. Assess postnatal respiratory status, including physical examination, pulse oximetry, blood gas analysis, chest radiographs, and echocardiography (as clinically indicated). Measure blood pressure regularly (and train parents in home measurements if elevated). Assess: Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). Perform urinalysis: To assess urinary concentration and detect proteinuria; In case of fever or biochemical signs of infection to identify potential urinary tract infections. Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and magnetic resonance cholangiopancreatography [MRCP]). Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. Perform echocardiography as clinically indicated, such as in case of arterial hypertension. Perform cranial sonography to assess for structural brain defects and intraventricular hemorrhage at initial examination. Set up evaluation by interdisciplinary team including psychologists and social workers to assess type of support needed by the family. Set up consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- Consider initiating interdisciplinary and interprofessional shared decision-making processes early in challenging clinical situations potentially requiring decisions on palliative treatment approaches or restrictions on specific treatment modes. Assess need for family support and resources including community or Assess kidney function, including serum concentrations of BUN, creatinine, and cystatin C. Assess serum electrolyte concentrations and perform blood gas analysis to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). Measure blood pressure. If elevated, home blood pressure monitoring during follow up can be helpful in distinguishing fixed hypertension from "white coat" hypertension (i.e., high blood pressure that occurs during medical examinations). Perform urinalysis: To assess urinary concentration and detect proteinuria; In case of fever or biochemical signs of infection to identify potential urinary tract infections. Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and MRCP). Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. Perform echocardiography as clinically indicated, such as in case of arterial hypertension. Perform neurodevelopmental examination, EEG, head sonography, and/or cranial MRT (if clinically indicated). Perform lung function tests (if clinically indicated). Set up an interdisciplinary and interprofessional team including psychologists and social workers for family support. Set up a consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- Assess need for family support and resources including community or • If possible, delivery should take place at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. • Assess postnatal respiratory status, including physical examination, pulse oximetry, blood gas analysis, chest radiographs, and echocardiography (as clinically indicated). • Measure blood pressure regularly (and train parents in home measurements if elevated). • Assess: • Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; • Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; • Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • Perform urinalysis: • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. • Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. • Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and magnetic resonance cholangiopancreatography [MRCP]). • Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. • Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. • Perform echocardiography as clinically indicated, such as in case of arterial hypertension. • Perform cranial sonography to assess for structural brain defects and intraventricular hemorrhage at initial examination. • Set up evaluation by interdisciplinary team including psychologists and social workers to assess type of support needed by the family. • Set up consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- • Consider initiating interdisciplinary and interprofessional shared decision-making processes early in challenging clinical situations potentially requiring decisions on palliative treatment approaches or restrictions on specific treatment modes. • Assess need for family support and resources including community or • Kidney function, including serum concentrations of blood urea nitrogen (BUN), creatinine, and cystatin C; • Serum electrolyte concentrations and blood gases to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Assess kidney function, including serum concentrations of BUN, creatinine, and cystatin C. • Assess serum electrolyte concentrations and perform blood gas analysis to identify electrolyte and acid-base anomalies (e.g., hyponatremia, hyperkalemia, acidosis). • Measure blood pressure. If elevated, home blood pressure monitoring during follow up can be helpful in distinguishing fixed hypertension from "white coat" hypertension (i.e., high blood pressure that occurs during medical examinations). • Perform urinalysis: • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. • Perform clinical and sonographic assessment of intravascular volume status for possible volume depletion or overload. • Perform kidney ultrasonography to determine kidney volumes and height-adjusted total kidney volumes. • Further abdominal ultrasound should be performed to evaluate anomalies of the liver (signs of congenital hepatic fibrosis, hepatomegaly, periportal fibrosis, liver cysts, bile duct cysts), signs of portal hypertension (diminished portal blood flow, collateral vessels, splenomegaly, ascites), and the potential need for further diagnostics (including liver elastography and MRCP). • Assess feeding, weight gain, and linear growth accompanied by consultation with nutritional experts as appropriate. Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Measure liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, coagulation studies), 25-hydroxyvitamin D levels and potentially other fat-soluble vitamin levels, and complete blood counts. • Perform physical examination of the liver to assess for hepatomegaly/splenomegaly. • Perform echocardiography as clinically indicated, such as in case of arterial hypertension. • Perform neurodevelopmental examination, EEG, head sonography, and/or cranial MRT (if clinically indicated). • Perform lung function tests (if clinically indicated). • Set up an interdisciplinary and interprofessional team including psychologists and social workers for family support. • Set up a consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of ARPKD- • Assess need for family support and resources including community or • To assess urinary concentration and detect proteinuria; • In case of fever or biochemical signs of infection to identify potential urinary tract infections. ## Treatment of Manifestations There is currently no cure for autosomal recessive polycystic kidney disease – Initial management of affected infants focuses on stabilization of pulmonary and kidney function. When massively enlarged kidneys are considered to prevent diaphragmatic excursion and/or cause severe feeding intolerance and/or massive arterial hypertension, some have advocated unilateral or bilateral nephrectomy; however, evidence supporting this approach is limited and mainly focused on nutritional aspects [ Unilateral nephrectomy may be of value, but the contralateral kidney may show marked rapid enlargement following unilateral nephrectomy [ Bilateral nephrectomies with placement of a peritoneal dialysis catheter have been suggested as a strategy for early management of critically ill infants. The expected benefits regarding nutrition or arterial hypertension must be weighed against the following risks: Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ A very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation processes of autonomic cardiovascular control occur, is recommended. Neonates with oliguria or anuria may require dialysis within the first days of life. Peritoneal dialysis is the modality of choice [ Hyponatremia is common and should be treated according to standard recommendations depending on the individual's volume status [ Early recognition and treatment of dehydration, insufficient weight gain, and/or poor growth is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tube placement may be required. As caloric intake relies on fluid intake in the early months of life, sufficient caloric intake should be monitored and modified as needed by a nutrition specialist. Early recognition of arterial hypertension is essential. In many individuals, hypertension is so severe that it requires multiple antihypertensive medications. Following general CKD recommendations targeting blood pressure values in the 50th percentile seems reasonable [ Early recognition and treatment of urinary tract infections is important. Nephrotoxic agents like aminoglycosides should be avoided when possible. With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (e.g., pneumococcus, Feeding intolerance and growth failure can be significant even in the absence of KF, especially in young infants. Nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tube, is often required to optimize weight gain and growth. Concerns about the potential risk of bleeding after gastrostomy tube placement in individuals with ARPKD and portal hypertension were addressed in a global survey (in which respondents were mainly European pediatric nephrologists) that identified very few complications and support by most respondents for gastrostomy tube placement in these children [ A subanalysis from the American Chronic Kidney Disease in Children (CKiD) cohort did not find evidence for an ARPKD-specific effect on growth when comparing children with a mean age of 7.9 years to age-matched control groups with other underlying congenital kidney diseases [ Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Treatment with growth hormone should be guided by standard recommendations for pediatric CKD. In addition to the treatments listed in KTx is the treatment of choice for children with KF, as graft survival is good. Previous or simultaneous nephrectomy of native ARPKD kidney(s) may be required. Peritoneal dialysis is the method of choice for chronic dialysis in children. In young children with ARPKD, maintenance peritoneal dialysis can be performed with only minor modifications compared to children with other early-onset kidney diseases [ Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. Imaging studies may be supportive. Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ Note: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [ In severe instances of intractable portal hypertension or severe dual renal and hepatobiliary disease, LTx or simultaneous/combined liver and kidney transplantation (CLKTx) is a viable option. A study from the United Network for Organ Sharing (UNOS) database reported superior five-year kidney transplant organ survival in individuals starting from six months after CLKTx compared to individuals after isolated KTx [ In summary, individual decision making regarding single or combined transplantation is indispensable because clear-cut criteria evaluating risks and benefits for decision making in individuals with ARPKD remain to be defined. • Unilateral nephrectomy may be of value, but the contralateral kidney may show marked rapid enlargement following unilateral nephrectomy [ • Bilateral nephrectomies with placement of a peritoneal dialysis catheter have been suggested as a strategy for early management of critically ill infants. The expected benefits regarding nutrition or arterial hypertension must be weighed against the following risks: • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • A very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation processes of autonomic cardiovascular control occur, is recommended. • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • Neonates with oliguria or anuria may require dialysis within the first days of life. Peritoneal dialysis is the modality of choice [ • Hyponatremia is common and should be treated according to standard recommendations depending on the individual's volume status [ • Early recognition and treatment of dehydration, insufficient weight gain, and/or poor growth is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tube placement may be required. As caloric intake relies on fluid intake in the early months of life, sufficient caloric intake should be monitored and modified as needed by a nutrition specialist. • Early recognition of arterial hypertension is essential. In many individuals, hypertension is so severe that it requires multiple antihypertensive medications. Following general CKD recommendations targeting blood pressure values in the 50th percentile seems reasonable [ • Early recognition and treatment of urinary tract infections is important. Nephrotoxic agents like aminoglycosides should be avoided when possible. • With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (e.g., pneumococcus, • Feeding intolerance and growth failure can be significant even in the absence of KF, especially in young infants. Nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tube, is often required to optimize weight gain and growth. • Concerns about the potential risk of bleeding after gastrostomy tube placement in individuals with ARPKD and portal hypertension were addressed in a global survey (in which respondents were mainly European pediatric nephrologists) that identified very few complications and support by most respondents for gastrostomy tube placement in these children [ • A subanalysis from the American Chronic Kidney Disease in Children (CKiD) cohort did not find evidence for an ARPKD-specific effect on growth when comparing children with a mean age of 7.9 years to age-matched control groups with other underlying congenital kidney diseases [ • Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Treatment with growth hormone should be guided by standard recommendations for pediatric CKD. • KTx is the treatment of choice for children with KF, as graft survival is good. Previous or simultaneous nephrectomy of native ARPKD kidney(s) may be required. • Peritoneal dialysis is the method of choice for chronic dialysis in children. In young children with ARPKD, maintenance peritoneal dialysis can be performed with only minor modifications compared to children with other early-onset kidney diseases [ • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Note: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [ • In severe instances of intractable portal hypertension or severe dual renal and hepatobiliary disease, LTx or simultaneous/combined liver and kidney transplantation (CLKTx) is a viable option. • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ ## Perinatal and Infantile Presentation (prenatal to age 1 year) Initial management of affected infants focuses on stabilization of pulmonary and kidney function. When massively enlarged kidneys are considered to prevent diaphragmatic excursion and/or cause severe feeding intolerance and/or massive arterial hypertension, some have advocated unilateral or bilateral nephrectomy; however, evidence supporting this approach is limited and mainly focused on nutritional aspects [ Unilateral nephrectomy may be of value, but the contralateral kidney may show marked rapid enlargement following unilateral nephrectomy [ Bilateral nephrectomies with placement of a peritoneal dialysis catheter have been suggested as a strategy for early management of critically ill infants. The expected benefits regarding nutrition or arterial hypertension must be weighed against the following risks: Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ A very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation processes of autonomic cardiovascular control occur, is recommended. Neonates with oliguria or anuria may require dialysis within the first days of life. Peritoneal dialysis is the modality of choice [ Hyponatremia is common and should be treated according to standard recommendations depending on the individual's volume status [ Early recognition and treatment of dehydration, insufficient weight gain, and/or poor growth is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tube placement may be required. As caloric intake relies on fluid intake in the early months of life, sufficient caloric intake should be monitored and modified as needed by a nutrition specialist. Early recognition of arterial hypertension is essential. In many individuals, hypertension is so severe that it requires multiple antihypertensive medications. Following general CKD recommendations targeting blood pressure values in the 50th percentile seems reasonable [ Early recognition and treatment of urinary tract infections is important. Nephrotoxic agents like aminoglycosides should be avoided when possible. With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (e.g., pneumococcus, Feeding intolerance and growth failure can be significant even in the absence of KF, especially in young infants. Nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tube, is often required to optimize weight gain and growth. Concerns about the potential risk of bleeding after gastrostomy tube placement in individuals with ARPKD and portal hypertension were addressed in a global survey (in which respondents were mainly European pediatric nephrologists) that identified very few complications and support by most respondents for gastrostomy tube placement in these children [ A subanalysis from the American Chronic Kidney Disease in Children (CKiD) cohort did not find evidence for an ARPKD-specific effect on growth when comparing children with a mean age of 7.9 years to age-matched control groups with other underlying congenital kidney diseases [ Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. Treatment with growth hormone should be guided by standard recommendations for pediatric CKD. • Unilateral nephrectomy may be of value, but the contralateral kidney may show marked rapid enlargement following unilateral nephrectomy [ • Bilateral nephrectomies with placement of a peritoneal dialysis catheter have been suggested as a strategy for early management of critically ill infants. The expected benefits regarding nutrition or arterial hypertension must be weighed against the following risks: • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • A very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation processes of autonomic cardiovascular control occur, is recommended. • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • Maturation of native kidney function is no longer possible and life-long kidney replacement therapy (KRT) is necessary after bilateral nephrectomies. • There are reports of arterial hypotension after bilateral nephrectomies possibly associated with neurologic damage in young children who are on peritoneal dialysis [ • Very early bilateral nephrectomies (i.e., age ≤3 months) and hypotensive episodes were identified as independent risk factors for severe neurologic complications in a study of a mostly European cohort of individuals with ARPKD [ • Neonates with oliguria or anuria may require dialysis within the first days of life. Peritoneal dialysis is the modality of choice [ • Hyponatremia is common and should be treated according to standard recommendations depending on the individual's volume status [ • Early recognition and treatment of dehydration, insufficient weight gain, and/or poor growth is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tube placement may be required. As caloric intake relies on fluid intake in the early months of life, sufficient caloric intake should be monitored and modified as needed by a nutrition specialist. • Early recognition of arterial hypertension is essential. In many individuals, hypertension is so severe that it requires multiple antihypertensive medications. Following general CKD recommendations targeting blood pressure values in the 50th percentile seems reasonable [ • Early recognition and treatment of urinary tract infections is important. Nephrotoxic agents like aminoglycosides should be avoided when possible. • With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (e.g., pneumococcus, • Feeding intolerance and growth failure can be significant even in the absence of KF, especially in young infants. Nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tube, is often required to optimize weight gain and growth. • Concerns about the potential risk of bleeding after gastrostomy tube placement in individuals with ARPKD and portal hypertension were addressed in a global survey (in which respondents were mainly European pediatric nephrologists) that identified very few complications and support by most respondents for gastrostomy tube placement in these children [ • A subanalysis from the American Chronic Kidney Disease in Children (CKiD) cohort did not find evidence for an ARPKD-specific effect on growth when comparing children with a mean age of 7.9 years to age-matched control groups with other underlying congenital kidney diseases [ • Aggressive nutritional support in the first two years of life may improve growth rates even in children with moderately to severely impaired kidney function and portal hypertension. • Treatment with growth hormone should be guided by standard recommendations for pediatric CKD. ## Childhood / Young Adulthood Presentation (age >1 year) In addition to the treatments listed in KTx is the treatment of choice for children with KF, as graft survival is good. Previous or simultaneous nephrectomy of native ARPKD kidney(s) may be required. Peritoneal dialysis is the method of choice for chronic dialysis in children. In young children with ARPKD, maintenance peritoneal dialysis can be performed with only minor modifications compared to children with other early-onset kidney diseases [ Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. Imaging studies may be supportive. Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ Note: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [ In severe instances of intractable portal hypertension or severe dual renal and hepatobiliary disease, LTx or simultaneous/combined liver and kidney transplantation (CLKTx) is a viable option. A study from the United Network for Organ Sharing (UNOS) database reported superior five-year kidney transplant organ survival in individuals starting from six months after CLKTx compared to individuals after isolated KTx [ In summary, individual decision making regarding single or combined transplantation is indispensable because clear-cut criteria evaluating risks and benefits for decision making in individuals with ARPKD remain to be defined. • KTx is the treatment of choice for children with KF, as graft survival is good. Previous or simultaneous nephrectomy of native ARPKD kidney(s) may be required. • Peritoneal dialysis is the method of choice for chronic dialysis in children. In young children with ARPKD, maintenance peritoneal dialysis can be performed with only minor modifications compared to children with other early-onset kidney diseases [ • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ • Note: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [ • In severe instances of intractable portal hypertension or severe dual renal and hepatobiliary disease, LTx or simultaneous/combined liver and kidney transplantation (CLKTx) is a viable option. • Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively. • Alkaline phosphatase and gamma-glutamyl transferase may be elevated during episodes of acute ascending cholangitis and may be helpful in establishing a diagnosis, but normal liver enzymes do not exclude cholangitis. • Imaging studies may be supportive. • Recurrent cholangitis can contribute to bile duct damage with resulting cholestasis and the need for liver transplantation (LTx). • The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial. Antibiotic prophylaxis may be considered for six to 12 weeks after an episode of ascending cholangitis, in the post-transplant period, or in states of enhanced immunosuppression; however, there are no general recommendations for antibiotic prophylaxis [ ## Surveillance To monitor existing manifestations in all individuals regardless of age of initial presentation, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Blood pressure. Monitor at regular physician's visits as well as at home if indicated (see Kidney function. Close monitoring for the complications of CKD should be undertaken by the treating pediatric nephrologist according to standard practices. Electrolyte balance. Monitor via serum concentrations of sodium, potassium, chloride, and hydrogen bicarbonate. Mineral balance. Monitor via serum concentrations of calcium, phosphorous, magnesium, and 25-hydroxyvitamin D. Hydration status. Monitor at periodic physician's visits as well as at home if indicated. Nutritional status. Plot growth on standard growth charts. Set up nutrition consultation as indicated. Hepatoportal involvement. Perform physical examination; obtain complete blood counts, prothrombin time, and serum concentrations of albumin, 25-hydroxyvitamin D, and other fat-soluble vitamins. Abdominal ultrasound, liver elastography, and MRCP For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ • Blood pressure. Monitor at regular physician's visits as well as at home if indicated (see • Kidney function. Close monitoring for the complications of CKD should be undertaken by the treating pediatric nephrologist according to standard practices. • Electrolyte balance. Monitor via serum concentrations of sodium, potassium, chloride, and hydrogen bicarbonate. • Mineral balance. Monitor via serum concentrations of calcium, phosphorous, magnesium, and 25-hydroxyvitamin D. • Hydration status. Monitor at periodic physician's visits as well as at home if indicated. • Nutritional status. Plot growth on standard growth charts. Set up nutrition consultation as indicated. • Hepatoportal involvement. Perform physical examination; obtain complete blood counts, prothrombin time, and serum concentrations of albumin, 25-hydroxyvitamin D, and other fat-soluble vitamins. • Abdominal ultrasound, liver elastography, and MRCP • For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ • Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ • If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ • MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ • For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ • Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ • If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ • MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ • For signs of portal hypertension (such as splenomegaly or abnormal portal Doppler flow), abdominal ultrasound is suggested in regular intervals tailored according to individual disease course and previous imaging findings (e.g., every 1-3 years) [ • Increased liver and spleen shear wave speed in ultrasound elastography with acoustic radiation force impulse can detect liver fibrosis and portal hypertension [ • If liver involvement is confirmed, it may be advisable to search for aggravation (i.e., check portal vessels and possible development of collateral circulation via color and duplex Doppler ultrasound) at shorter intervals [ • MRI and MRCP, a more sensitive measurement for biliary ectasia, should be considered in individuals with clinical complications of liver disease and/or during detailed liver assessment prior to KTx [ ## Agents/Circumstances to Avoid Individuals with hypertension should avoid sympathomimetic agents. In general, unless the clinical situation warrants their use, avoid known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides. High-salt diet, smoking, and obesity should be avoided. Minimize use of potentially hepatotoxic agents (e.g., acetaminophen doses >30 mg/kg/day, herbal supplements, and alcohol). While work in cell and animal models suggests that caffeine, theophylline-like agents, and calcium channel blockers may exacerbate the formation and growth of renal cysts, this hypothesis has not been rigorously studied in individuals with ARPKD. Thus, the clinical relevance of these observations remains unclear. ## Evaluation of Relatives at Risk See ## Pregnancy Management Very little is known about pregnancy outcomes for women with ARPKD. As both kidney and liver phenotypes show clinical variability, comprehensive recommendations cannot currently be given. In general, women with CKD face an increased risk of pregnancy-related decline in renal function, preeclampsia, and impaired fetal outcomes [ In a small case series of four pregnant women with ARPKD and live birth deliveries, three had uncomplicated pregnancies (in two of three the diagnosis of ARPKD was established after delivery) and one had transient worsening of kidney function [ ## Therapies Under Investigation Recent studies in two animal models of ARPKD suggest that tesevatinib (TSV), a unique multikinase inhibitor, markedly slows the progression of both renal cystic disease and hepatobiliary disease [ Two multinational open-label Phase III trials on the effects of tolvaptan in ARPKD- Search ## Genetic Counseling By definition, autosomal recessive polycystic kidney disease – Note: In rare families, pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported [ The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a A single- or multiexon Uniparental isodisomy for the parental chromosome with the Individuals who are heterozygous for a If both parents are known to be heterozygous for a While previous data described pronounced intrafamilial variability in survival among affected sibs, a more recent study of 70 sibs surviving the neonatal period found comparable clinical courses of kidney and hepatobiliary disease during follow up, suggesting a strong effect of the underlying genotype [ Heterozygotes for a Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known heterozygotes for an No systematic data are available on the sensitivity and specificity of prenatal ultrasound examination in diagnosis of ARPKD in pregnancies at 25% risk. Karyotype or array comparative genomic hybridization (CGH) and detailed fetal ultrasonography can be performed to evaluate for the presence of a chromosomal anomaly and/or other congenital anomalies in a fetus not known to be at increased risk for ARPKD- Molecular genetic testing of Kidney and liver ultrasound examinations of both parents of fetuses with ARPKD- Prenatal hyperechogenicity and enlargement of the fetal kidneys alone are not sufficient to definitively diagnose ARPKD- Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. If possible, delivery should occur at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. Prenatal assessment of the lungs remains challenging. Early oligohydramnios seems to be associated with more severe outcomes. Data on serial amnioinfusions are insufficient to support a general recommendation [ There is a potential risk of abdominal dystocia with vaginal delivery [ • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a • A single- or multiexon • Uniparental isodisomy for the parental chromosome with the • A single- or multiexon • Uniparental isodisomy for the parental chromosome with the • Individuals who are heterozygous for a • A single- or multiexon • Uniparental isodisomy for the parental chromosome with the • If both parents are known to be heterozygous for a • While previous data described pronounced intrafamilial variability in survival among affected sibs, a more recent study of 70 sibs surviving the neonatal period found comparable clinical courses of kidney and hepatobiliary disease during follow up, suggesting a strong effect of the underlying genotype [ • Heterozygotes for a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known heterozygotes for an • Karyotype or array comparative genomic hybridization (CGH) and detailed fetal ultrasonography can be performed to evaluate for the presence of a chromosomal anomaly and/or other congenital anomalies in a fetus not known to be at increased risk for ARPKD- • Molecular genetic testing of • Kidney and liver ultrasound examinations of both parents of fetuses with ARPKD- • Prenatal hyperechogenicity and enlargement of the fetal kidneys alone are not sufficient to definitively diagnose ARPKD- • If possible, delivery should occur at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. Prenatal assessment of the lungs remains challenging. Early oligohydramnios seems to be associated with more severe outcomes. Data on serial amnioinfusions are insufficient to support a general recommendation [ • There is a potential risk of abdominal dystocia with vaginal delivery [ ## Mode of Inheritance By definition, autosomal recessive polycystic kidney disease – Note: In rare families, pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported [ ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a A single- or multiexon Uniparental isodisomy for the parental chromosome with the Individuals who are heterozygous for a If both parents are known to be heterozygous for a While previous data described pronounced intrafamilial variability in survival among affected sibs, a more recent study of 70 sibs surviving the neonatal period found comparable clinical courses of kidney and hepatobiliary disease during follow up, suggesting a strong effect of the underlying genotype [ Heterozygotes for a • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a • A single- or multiexon • Uniparental isodisomy for the parental chromosome with the • A single- or multiexon • Uniparental isodisomy for the parental chromosome with the • Individuals who are heterozygous for a • A single- or multiexon • Uniparental isodisomy for the parental chromosome with the • If both parents are known to be heterozygous for a • While previous data described pronounced intrafamilial variability in survival among affected sibs, a more recent study of 70 sibs surviving the neonatal period found comparable clinical courses of kidney and hepatobiliary disease during follow up, suggesting a strong effect of the underlying genotype [ • Heterozygotes for a ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known heterozygotes for an • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known heterozygotes for an ## Prenatal Testing and Preimplantation Genetic Testing No systematic data are available on the sensitivity and specificity of prenatal ultrasound examination in diagnosis of ARPKD in pregnancies at 25% risk. Karyotype or array comparative genomic hybridization (CGH) and detailed fetal ultrasonography can be performed to evaluate for the presence of a chromosomal anomaly and/or other congenital anomalies in a fetus not known to be at increased risk for ARPKD- Molecular genetic testing of Kidney and liver ultrasound examinations of both parents of fetuses with ARPKD- Prenatal hyperechogenicity and enlargement of the fetal kidneys alone are not sufficient to definitively diagnose ARPKD- Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. If possible, delivery should occur at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. Prenatal assessment of the lungs remains challenging. Early oligohydramnios seems to be associated with more severe outcomes. Data on serial amnioinfusions are insufficient to support a general recommendation [ There is a potential risk of abdominal dystocia with vaginal delivery [ • Karyotype or array comparative genomic hybridization (CGH) and detailed fetal ultrasonography can be performed to evaluate for the presence of a chromosomal anomaly and/or other congenital anomalies in a fetus not known to be at increased risk for ARPKD- • Molecular genetic testing of • Kidney and liver ultrasound examinations of both parents of fetuses with ARPKD- • Prenatal hyperechogenicity and enlargement of the fetal kidneys alone are not sufficient to definitively diagnose ARPKD- • If possible, delivery should occur at a center with ample experience in intensive care neonatology and pediatric nephrology that can offer multidisciplinary postnatal treatment. Prenatal assessment of the lungs remains challenging. Early oligohydramnios seems to be associated with more severe outcomes. Data on serial amnioinfusions are insufficient to support a general recommendation [ • There is a potential risk of abdominal dystocia with vaginal delivery [ ## Resources United Kingdom Canada • • • • • • • • United Kingdom • • • • • Canada • • • ## Molecular Genetics Autosomal Recessive Polycystic Kidney Disease – PKHD1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Autosomal Recessive Polycystic Kidney Disease – PKHD1 ( In addition to localization in cilia, fibrocystin also localizes to cell junctions, and fragments of the fibrocystin cytoplasmic tail have been found in the cell nucleus and in mitochondria [ Data from multiple preclinical models suggest that fibrocystin regulates intracellular signaling cascades (also involved in the development of ADPKD [ Deficiency of fibrocystin in the liver may promote fibrosis through recruitment of macrophages [ Because private Most frequent Possibly occurs at a mutational hot spot & may have a single European origin Founder variant in Ashkenazi Jewish population Variants listed in the table have been provided by the authors. • Most frequent • Possibly occurs at a mutational hot spot & may have a single European origin • Founder variant in Ashkenazi Jewish population ## Molecular Pathogenesis In addition to localization in cilia, fibrocystin also localizes to cell junctions, and fragments of the fibrocystin cytoplasmic tail have been found in the cell nucleus and in mitochondria [ Data from multiple preclinical models suggest that fibrocystin regulates intracellular signaling cascades (also involved in the development of ADPKD [ Deficiency of fibrocystin in the liver may promote fibrosis through recruitment of macrophages [ Because private Most frequent Possibly occurs at a mutational hot spot & may have a single European origin Founder variant in Ashkenazi Jewish population Variants listed in the table have been provided by the authors. • Most frequent • Possibly occurs at a mutational hot spot & may have a single European origin • Founder variant in Ashkenazi Jewish population ## Chapter Notes Max Liebau and Kathrin Burgmaier are actively involved in clinical research regarding individuals with ARPKD or ARPKD- We thank the authors of previous versions of this chapter for their outstanding work. We thank the German Society for Pediatric Nephrology (GPN), the European Society for Paediatric Nephrology (WGs: Inherited Kidney Diseases and WG CAKUT), and the ESCAPE Network for their continuous support. ML is supported by the German Research Council (DFG Grant LI2397/5-1). FS, CG, and ML are supported by the German Federal Ministry of Research and Education (NEOCYST consortium; BMBF grants 01GM2203B and 01GM2203D). FS and ML are supported by EU-Horizon grants (TheRaCil Consortium: Project ID 101080717). KB was supported by the Koeln Fortune program and the GEROK program of the Medical Faculty of University of Cologne as well as the Marga and Walter Boll-Foundation. The authors of this publication are members of the European Reference Network for Rare Kidney Diseases (ERKNet – project ID No. 739532). Ellis D Avner, MD; Medical College and Children's Health System of Wisconsin (2001-2024)Kathrin Burgmaier, MD (2024-present)Charlotte Gimpel, MD(2024-present)Max Liebau, MD(2024-present)Katherine MacRae Dell, MD; Case Western Reserve University School of Medicine (2001-2014]Franz Schaefer, MD(2024-present)William E Sweeney, MS; Medical College and Children's Health System of Wisconsin (2014-2024) 4 April 2024 (bp) Comprehensive update posted live 15 September 2016 (ha) Comprehensive update posted live 6 March 2014 (me) Comprehensive update posted live 22 September 2011 (me) Comprehensive update posted live 7 August 2008 (me) Comprehensive update posted live 21 March 2006 (me) Comprehensive update posted live 23 October 2003 (me) Comprehensive update posted live 19 July 2001 (me) Review posted live April 2001 (kmd) Original submission • 4 April 2024 (bp) Comprehensive update posted live • 15 September 2016 (ha) Comprehensive update posted live • 6 March 2014 (me) Comprehensive update posted live • 22 September 2011 (me) Comprehensive update posted live • 7 August 2008 (me) Comprehensive update posted live • 21 March 2006 (me) Comprehensive update posted live • 23 October 2003 (me) Comprehensive update posted live • 19 July 2001 (me) Review posted live • April 2001 (kmd) Original submission ## Author Notes Max Liebau and Kathrin Burgmaier are actively involved in clinical research regarding individuals with ARPKD or ARPKD- ## Acknowledgments We thank the authors of previous versions of this chapter for their outstanding work. We thank the German Society for Pediatric Nephrology (GPN), the European Society for Paediatric Nephrology (WGs: Inherited Kidney Diseases and WG CAKUT), and the ESCAPE Network for their continuous support. ML is supported by the German Research Council (DFG Grant LI2397/5-1). FS, CG, and ML are supported by the German Federal Ministry of Research and Education (NEOCYST consortium; BMBF grants 01GM2203B and 01GM2203D). FS and ML are supported by EU-Horizon grants (TheRaCil Consortium: Project ID 101080717). KB was supported by the Koeln Fortune program and the GEROK program of the Medical Faculty of University of Cologne as well as the Marga and Walter Boll-Foundation. The authors of this publication are members of the European Reference Network for Rare Kidney Diseases (ERKNet – project ID No. 739532). ## Author History Ellis D Avner, MD; Medical College and Children's Health System of Wisconsin (2001-2024)Kathrin Burgmaier, MD (2024-present)Charlotte Gimpel, MD(2024-present)Max Liebau, MD(2024-present)Katherine MacRae Dell, MD; Case Western Reserve University School of Medicine (2001-2014]Franz Schaefer, MD(2024-present)William E Sweeney, MS; Medical College and Children's Health System of Wisconsin (2014-2024) ## Revision History 4 April 2024 (bp) Comprehensive update posted live 15 September 2016 (ha) Comprehensive update posted live 6 March 2014 (me) Comprehensive update posted live 22 September 2011 (me) Comprehensive update posted live 7 August 2008 (me) Comprehensive update posted live 21 March 2006 (me) Comprehensive update posted live 23 October 2003 (me) Comprehensive update posted live 19 July 2001 (me) Review posted live April 2001 (kmd) Original submission • 4 April 2024 (bp) Comprehensive update posted live • 15 September 2016 (ha) Comprehensive update posted live • 6 March 2014 (me) Comprehensive update posted live • 22 September 2011 (me) Comprehensive update posted live • 7 August 2008 (me) Comprehensive update posted live • 21 March 2006 (me) Comprehensive update posted live • 23 October 2003 (me) Comprehensive update posted live • 19 July 2001 (me) Review posted live • April 2001 (kmd) Original submission ## References ## Literature Cited	[]	19/7/2001	4/4/2024	14/2/2019	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pknd	pknd	[ "Paroxysmal Kinesigenic Choreoathetosis", "Paroxysmal Kinesigenic Dyskinesia", "Paroxysmal Kinesigenic Choreoathetosis", "Paroxysmal Kinesigenic Dyskinesia", "Proline-rich transmembrane protein 2", "PRRT2", "Familial Paroxysmal Kinesigenic Dyskinesia" ]	Familial Paroxysmal Kinesigenic Dyskinesia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Sian Spacey, Paul Adams	Summary Familial paroxysmal kinesigenic dyskinesia (referred to as familial PKD in this entry) is characterized by unilateral or bilateral involuntary movements precipitated by other sudden movements such as standing up from a sitting position, being startled, or changes in velocity; attacks include combinations of dystonia, choreoathetosis, and ballism, are sometimes preceded by an aura, and do not involve loss of consciousness. Attacks can be as frequent as 100 per day to as few as one per month. Attacks are usually a few seconds to five minutes in duration but can last several hours. Age of onset, severity and combinations of symptoms vary. Age of onset, typically in childhood and adolescence, ranges from four months to 57 years. The phenotype of PKD can include benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine, migraine with and without aura, and episodic ataxia. Familial PKD is predominantly seen in males. The diagnosis of familial PKD is based on the clinical findings of attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movements that occur many times per day and can be prevented or reduced in frequency by phenytoin or carbamezepine. Heterozygous pathogenic variants in Familial PKD is inherited in an autosomal dominant manner. More than 90% of individuals with familial PKD have an affected parent. The proportion of cases caused by	## Diagnosis The following findings support the clinical diagnosis of familial paroxysmal kinesigenic dyskinesia (PKD) [ Attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movement (e.g., having the individual stand up suddenly or walk briskly up and down the hall) Attack duration lasting seconds to minutes Attack frequency as high as 100 times/day No loss of consciousness during the attack Reduction in attack frequency or prevention by the anticonvulsants phenytoin or carbamazepine Note: The diagnosis of PKD can be further confirmed with a trial of low-dose phenytoin (100 mg) or carbamezepine (250 mg), which is usually sufficient to eliminate attacks. A normal interictal neurologic examination A normal ictal and interictal EEG A normal MRI A family history consistent with autosomal dominant inheritance Summary of Molecular Genetic Testing Used in Familial Paroxysmal Kinesigenic Dyskinesia See See The ability of the test method used to detect a variant that is present in the indicated gene Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. • Attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movement (e.g., having the individual stand up suddenly or walk briskly up and down the hall) • Attack duration lasting seconds to minutes • Attack frequency as high as 100 times/day • No loss of consciousness during the attack • Reduction in attack frequency or prevention by the anticonvulsants phenytoin or carbamazepine • Note: The diagnosis of PKD can be further confirmed with a trial of low-dose phenytoin (100 mg) or carbamezepine (250 mg), which is usually sufficient to eliminate attacks. • A normal interictal neurologic examination • A normal ictal and interictal EEG • A normal MRI • A family history consistent with autosomal dominant inheritance ## Clinical Diagnosis The following findings support the clinical diagnosis of familial paroxysmal kinesigenic dyskinesia (PKD) [ Attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movement (e.g., having the individual stand up suddenly or walk briskly up and down the hall) Attack duration lasting seconds to minutes Attack frequency as high as 100 times/day No loss of consciousness during the attack Reduction in attack frequency or prevention by the anticonvulsants phenytoin or carbamazepine Note: The diagnosis of PKD can be further confirmed with a trial of low-dose phenytoin (100 mg) or carbamezepine (250 mg), which is usually sufficient to eliminate attacks. A normal interictal neurologic examination A normal ictal and interictal EEG A normal MRI A family history consistent with autosomal dominant inheritance • Attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movement (e.g., having the individual stand up suddenly or walk briskly up and down the hall) • Attack duration lasting seconds to minutes • Attack frequency as high as 100 times/day • No loss of consciousness during the attack • Reduction in attack frequency or prevention by the anticonvulsants phenytoin or carbamazepine • Note: The diagnosis of PKD can be further confirmed with a trial of low-dose phenytoin (100 mg) or carbamezepine (250 mg), which is usually sufficient to eliminate attacks. • A normal interictal neurologic examination • A normal ictal and interictal EEG • A normal MRI • A family history consistent with autosomal dominant inheritance ## Molecular Genetic Testing Summary of Molecular Genetic Testing Used in Familial Paroxysmal Kinesigenic Dyskinesia See See The ability of the test method used to detect a variant that is present in the indicated gene Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. ## Testing Strategy ## Clinical Characteristics Familial paroxysmal kinesigenic dyskinesia (PKD) is characterized by unilateral or bilateral involuntary movements precipitated by sudden movements, being startled, or changes in velocity [ Attack frequency ranges from 100 per day to as few as one per month [ Familial PKD has been associated with infantile seizures [ Age of onset is typically in childhood or adolescence but ranges from four months to 57 years [ Familial PKD occurs more frequently in males than in females (~4:1 ratio) [ While initially described as different conditions, benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine, migraine with and without aura, and episodic ataxia may represent part of the clinical spectrum of PKD (see Diffusion tensor imaging, performed on seven individuals with PKD, demonstrated significantly higher fractional anisotropy in the right thalamus compared to controls. Persons with PKD also had lower mean diffusivity values in the left thalamus compared to controls, confirming ultrastructural abnormalities in the thalamus of those with PKD [ Considerable variation in phenotype is seen between families with the same pathogenic variant, suggesting a complex interaction between the mutated allele, genetic background, and non-genetic factors [ The penetrance for familial PKD has been reported to be between 80% and 90% in both males and females [ Anticipation has not been observed. Familial PKD is classified as a paroxysmal dyskinesia. All of the disorders included in the dyskinesia category are characterized by intermittent occurrence of dystonia, chorea, and ballism of varying duration. The nomenclature used to classify the paroxysmal dyskinesias has been evolving over the past 60 years. A recent study by Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours Normal neurologic examination results between attacks and exclusion of secondary causes Onset of attack in infancy or early childhood Precipitation of attacks by caffeine and alcohol consumption Family history of movement disorder meeting all four preceding criteria Paroxysmal dystonic choreoathetosis (PDC) included prolonged attacks (2 minutes to 4 hours) not precipitated by sudden movement or prolonged exertion. Paroxysmal kinesigenic choreoathetosis (PKC) included short attacks (seconds to 5 minutes) induced by sudden movement. An intermediate form included attacks (5-30 minutes in duration) precipitated by continued exertion rather than sudden movement. PKD is rare; prevalence is estimated at 1:150,000. The autosomal dominantly inherited form (familial form) is more common than the simplex form (i.e., the occurrence of a single affected individual in a family). • A recent study by • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks and exclusion of secondary causes • Onset of attack in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all four preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks and exclusion of secondary causes • Onset of attack in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all four preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks and exclusion of secondary causes • Onset of attack in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all four preceding criteria • Paroxysmal dystonic choreoathetosis (PDC) included prolonged attacks (2 minutes to 4 hours) not precipitated by sudden movement or prolonged exertion. • Paroxysmal kinesigenic choreoathetosis (PKC) included short attacks (seconds to 5 minutes) induced by sudden movement. • An intermediate form included attacks (5-30 minutes in duration) precipitated by continued exertion rather than sudden movement. ## Clinical Description Familial paroxysmal kinesigenic dyskinesia (PKD) is characterized by unilateral or bilateral involuntary movements precipitated by sudden movements, being startled, or changes in velocity [ Attack frequency ranges from 100 per day to as few as one per month [ Familial PKD has been associated with infantile seizures [ Age of onset is typically in childhood or adolescence but ranges from four months to 57 years [ Familial PKD occurs more frequently in males than in females (~4:1 ratio) [ While initially described as different conditions, benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine, migraine with and without aura, and episodic ataxia may represent part of the clinical spectrum of PKD (see Diffusion tensor imaging, performed on seven individuals with PKD, demonstrated significantly higher fractional anisotropy in the right thalamus compared to controls. Persons with PKD also had lower mean diffusivity values in the left thalamus compared to controls, confirming ultrastructural abnormalities in the thalamus of those with PKD [ ## Genotype-Phenotype Correlations Considerable variation in phenotype is seen between families with the same pathogenic variant, suggesting a complex interaction between the mutated allele, genetic background, and non-genetic factors [ ## Penetrance The penetrance for familial PKD has been reported to be between 80% and 90% in both males and females [ ## Anticipation Anticipation has not been observed. ## Nomenclature Familial PKD is classified as a paroxysmal dyskinesia. All of the disorders included in the dyskinesia category are characterized by intermittent occurrence of dystonia, chorea, and ballism of varying duration. The nomenclature used to classify the paroxysmal dyskinesias has been evolving over the past 60 years. A recent study by Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours Normal neurologic examination results between attacks and exclusion of secondary causes Onset of attack in infancy or early childhood Precipitation of attacks by caffeine and alcohol consumption Family history of movement disorder meeting all four preceding criteria Paroxysmal dystonic choreoathetosis (PDC) included prolonged attacks (2 minutes to 4 hours) not precipitated by sudden movement or prolonged exertion. Paroxysmal kinesigenic choreoathetosis (PKC) included short attacks (seconds to 5 minutes) induced by sudden movement. An intermediate form included attacks (5-30 minutes in duration) precipitated by continued exertion rather than sudden movement. • A recent study by • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks and exclusion of secondary causes • Onset of attack in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all four preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks and exclusion of secondary causes • Onset of attack in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all four preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks and exclusion of secondary causes • Onset of attack in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all four preceding criteria • Paroxysmal dystonic choreoathetosis (PDC) included prolonged attacks (2 minutes to 4 hours) not precipitated by sudden movement or prolonged exertion. • Paroxysmal kinesigenic choreoathetosis (PKC) included short attacks (seconds to 5 minutes) induced by sudden movement. • An intermediate form included attacks (5-30 minutes in duration) precipitated by continued exertion rather than sudden movement. ## Prevalence PKD is rare; prevalence is estimated at 1:150,000. The autosomal dominantly inherited form (familial form) is more common than the simplex form (i.e., the occurrence of a single affected individual in a family). ## Genetically Related (Allelic) Disorders While initially described as different conditions, the following phenotypes may actually represent the clinical spectrum of PKD, as opposed to separate, allelic conditions (see Some individuals with febrile seizures (FS) and febrile seizures plus (FS+) have been found to have Other individuals from families with ## Differential Diagnosis Paroxysmal dyskinesias can occur sporadically or as a feature of a number of hereditary disorders. Sporadic causes of paroxysmal dyskinesias include lesions of the basal ganglia caused by multiple sclerosis [ Focal seizures can present with paroxysms of dystonia; EEG is an essential part of the investigation. Dyskinesias seen in association with rheumatic fever (Sydenham’s chorea) are associated with a raised anti-streptolysin O (ASO) titer and normal cerebrospinal fluid. Chorea gravidarum can present with paroxysms of chorea in the first trimester of pregnancy and usually resolves after delivery. Paroxysmal chorea can also be seen with systemic lupus erythematosus, diabetes mellitus, hypoparathyroidism, pseudohypoparathyroidism, and thyrotoxicosis. The relevant blood work should be done if these etiologies are being considered [ Most of the hereditary causes of paroxysmal dyskinesias need to be considered: PED with epilepsy is observed in A single family with PED has been linked to the pericentric region of chromosome 16 [ The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. Other hereditary causes of dyskinesias that may be considered include the following: • PED with epilepsy is observed in • A single family with PED has been linked to the pericentric region of chromosome 16 [ • The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. • PED with epilepsy is observed in • A single family with PED has been linked to the pericentric region of chromosome 16 [ • The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. • PED with epilepsy is observed in • A single family with PED has been linked to the pericentric region of chromosome 16 [ • The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. ## Sporadic Causes Sporadic causes of paroxysmal dyskinesias include lesions of the basal ganglia caused by multiple sclerosis [ Focal seizures can present with paroxysms of dystonia; EEG is an essential part of the investigation. Dyskinesias seen in association with rheumatic fever (Sydenham’s chorea) are associated with a raised anti-streptolysin O (ASO) titer and normal cerebrospinal fluid. Chorea gravidarum can present with paroxysms of chorea in the first trimester of pregnancy and usually resolves after delivery. Paroxysmal chorea can also be seen with systemic lupus erythematosus, diabetes mellitus, hypoparathyroidism, pseudohypoparathyroidism, and thyrotoxicosis. The relevant blood work should be done if these etiologies are being considered [ ## Autosomal Recessive Cause ## Autosomal Dominant Causes Most of the hereditary causes of paroxysmal dyskinesias need to be considered: PED with epilepsy is observed in A single family with PED has been linked to the pericentric region of chromosome 16 [ The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. Other hereditary causes of dyskinesias that may be considered include the following: • PED with epilepsy is observed in • A single family with PED has been linked to the pericentric region of chromosome 16 [ • The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. • PED with epilepsy is observed in • A single family with PED has been linked to the pericentric region of chromosome 16 [ • The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. • PED with epilepsy is observed in • A single family with PED has been linked to the pericentric region of chromosome 16 [ • The locus for autosomal recessive rolandic epilepsy with PED and writer’s cramp has been mapped to 16p12-11.2. ## Management To establish the extent of disease and needs in an individual diagnosed with familial paroxysmal kinesigenic dyskinesia (PKD), the following evaluations are recommended: MRI to rule out secondary causes of PKD EEG to rule out seizures as a cause of the dyskinesias Clinical genetics consultation and testing for pathogenic variants in Attack frequency is reduced or prevented by the anticonvulsants phenytoin or carbamezepine, typically at lower doses than are used to treat epilepsy [ Other anticonvulsants proven to be effective include oxcarbazepine [ Individuals with PKD can be monitored every one to two years, particularly with respect to medication needs and doses. See Pregnant women who are on anticonvulsants therapy for PKD are recommended to take folic acid 5 mg/day. Because of the risk of teratogenic effects related to anticonvulsants, women with mild symptoms related to PKD may wish to consider discontinuing anticonvulsant therapy during pregnancy. Search • MRI to rule out secondary causes of PKD • EEG to rule out seizures as a cause of the dyskinesias • Clinical genetics consultation and testing for pathogenic variants in ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with familial paroxysmal kinesigenic dyskinesia (PKD), the following evaluations are recommended: MRI to rule out secondary causes of PKD EEG to rule out seizures as a cause of the dyskinesias Clinical genetics consultation and testing for pathogenic variants in • MRI to rule out secondary causes of PKD • EEG to rule out seizures as a cause of the dyskinesias • Clinical genetics consultation and testing for pathogenic variants in ## Treatment of Manifestations Attack frequency is reduced or prevented by the anticonvulsants phenytoin or carbamezepine, typically at lower doses than are used to treat epilepsy [ Other anticonvulsants proven to be effective include oxcarbazepine [ ## Surveillance Individuals with PKD can be monitored every one to two years, particularly with respect to medication needs and doses. ## Evaluation of Relatives at Risk See ## Pregnancy Management Pregnant women who are on anticonvulsants therapy for PKD are recommended to take folic acid 5 mg/day. Because of the risk of teratogenic effects related to anticonvulsants, women with mild symptoms related to PKD may wish to consider discontinuing anticonvulsant therapy during pregnancy. ## Therapies Under Investigation Search ## Genetic Counseling Familial paroxysmal kinesigenic dyskinesia (PKD) is inherited in an autosomal dominant manner. More than 90% of individuals with familial PKD have an affected parent. A proband with familial PKD may have the disorder as the result of a Recommendations for the evaluation of parents of an individual with an apparent If a parent of a proband is affected or has a Because familial PKD demonstrates incomplete penetrance, a clinically unaffected parent may still have a pathogenic variant in The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Requests for prenatal testing for conditions which (like familial PKD) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate. • More than 90% of individuals with familial PKD have an affected parent. • A proband with familial PKD may have the disorder as the result of a • Recommendations for the evaluation of parents of an individual with an apparent • If a parent of a proband is affected or has a • Because familial PKD demonstrates incomplete penetrance, a clinically unaffected parent may still have a pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Familial paroxysmal kinesigenic dyskinesia (PKD) is inherited in an autosomal dominant manner. ## Risk to Family Members More than 90% of individuals with familial PKD have an affected parent. A proband with familial PKD may have the disorder as the result of a Recommendations for the evaluation of parents of an individual with an apparent If a parent of a proband is affected or has a Because familial PKD demonstrates incomplete penetrance, a clinically unaffected parent may still have a pathogenic variant in • More than 90% of individuals with familial PKD have an affected parent. • A proband with familial PKD may have the disorder as the result of a • Recommendations for the evaluation of parents of an individual with an apparent • If a parent of a proband is affected or has a • Because familial PKD demonstrates incomplete penetrance, a clinically unaffected parent may still have a pathogenic variant in ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Diagnosis Once the Requests for prenatal testing for conditions which (like familial PKD) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate. ## Resources One East Wacker Drive Suite 1730 Chicago IL 60601-1905 • • One East Wacker Drive • Suite 1730 • Chicago IL 60601-1905 • ## Molecular Genetics Familial Paroxysmal Kinesigenic Dyskinesia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Familial Paroxysmal Kinesigenic Dyskinesia ( Note on variant classification: Variants listed in the table have been provided by the authors. Note on nomenclature: Variant designation that does not conform to current naming conventions ## References ## Literature Cited ## Chapter Notes 11 January 2018 (ma) Chapter retired: covered in 27 June 2013 (me) Comprehensive update posted live 15 March 2012 (cd) Revision: prenatal testing available clinically for 16 February 2012 (cd) Revision: mutations in 31 March 2011 (me) Comprehensive update posted live 26 August 2008 (cg) Comprehensive update posted live 24 June 2005 (ca) Review posted to live Web site 2 December 2004 (ss) Original submission • 11 January 2018 (ma) Chapter retired: covered in • 27 June 2013 (me) Comprehensive update posted live • 15 March 2012 (cd) Revision: prenatal testing available clinically for • 16 February 2012 (cd) Revision: mutations in • 31 March 2011 (me) Comprehensive update posted live • 26 August 2008 (cg) Comprehensive update posted live • 24 June 2005 (ca) Review posted to live Web site • 2 December 2004 (ss) Original submission ## Revision History 11 January 2018 (ma) Chapter retired: covered in 27 June 2013 (me) Comprehensive update posted live 15 March 2012 (cd) Revision: prenatal testing available clinically for 16 February 2012 (cd) Revision: mutations in 31 March 2011 (me) Comprehensive update posted live 26 August 2008 (cg) Comprehensive update posted live 24 June 2005 (ca) Review posted to live Web site 2 December 2004 (ss) Original submission • 11 January 2018 (ma) Chapter retired: covered in • 27 June 2013 (me) Comprehensive update posted live • 15 March 2012 (cd) Revision: prenatal testing available clinically for • 16 February 2012 (cd) Revision: mutations in • 31 March 2011 (me) Comprehensive update posted live • 26 August 2008 (cg) Comprehensive update posted live • 24 June 2005 (ca) Review posted to live Web site • 2 December 2004 (ss) Original submission	[ "Y Baba, ZK Wszolek, MM Normand. 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J Child Neurol 2004;19:300-1", "JL Wang, L Cao, XH Li, ZM Hu, JD Li, JG Zhang, Y Liang, A San, N Li, SQ Chen, JF Guo, H Jiang, L Shen, L Zheng, X Mao, WQ Yan, Y Zhou, YT Shi, SX Ai, MZ Dai, P Zhang, K Xia, SD Chen, BS Tang. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.. Brain. 2011;134:3493-501", "DJ Yen, DE Shan, SR Lu. Hyperthyroidism presenting as recurrent short paroxysmal kinesigenic dyskinesia.. Mov Disord 1998;13:361-3", "B Zhou, Q Chen, Q Gong, H Tang, D Zhou. The thalamic ultrastructural abnormalities in paroxysmal kinesigenic choreoathetosis: a diffusion tensor imaging study.. J Neurol. 2010a;257:405-9", "B Zhou, Q Chen, Q Zhang, L Chen, Q Gong, H Shang, H Tang, D Zhou. Hyperactive putamen in patients with paroxysmal kinesigenic choreoathetosis: a resting-state functional magnetic resonance imaging study.. Mov Disord. 2010b;25:1226-31", "J Zhou, G Li, C Chen, D Liu, B Xiao. Familial pure paroxysmal kinesigenic dyskinesia in Han population from the Chinese mainland: a new subtype?. Epilepsy Res. 2008;80:171-9" ]	24/6/2005	27/6/2013	15/3/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pku	pku	[ "Hyperphenylalaninemia", "PAH Deficiency", "Phenylketonuria (PKU)", "PAH Deficiency", "Hyperphenylalaninemia", "Phenylketonuria (PKU)", "Phenylalanine-4-hydroxylase", "PAH", "Phenylalanine Hydroxylase Deficiency" ]	Phenylalanine Hydroxylase Deficiency	Georgianne Arnold, Jerry Vockley	Summary The phenotypes in individuals with phenylalanine hydroxylase (PAH) deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. Maternal phenylketonuria (MPKU) syndrome occurs in offspring of mothers with inadequately treated PAH deficiency during pregnancy and results from the toxic effects of elevated blood phenylalanine (Phe) concentrations on the developing fetus. PAH deficiency treated from birth is characterized by the following, even with adherence to a low Phe diet: (1) a modest but measurable decrease in intellectual functioning as well variable impairments in executive function, attention, and fine motor functions; (2) an increased prevalence of mental health concerns including anxiety and depression; and (3) neurologic problems (including hypertonia, paraplegia, movement disorders, and seizures), which may improve or resolve with lowering blood Phe concentration. Late-diagnosed or untreated PAH deficiency is characterized by irreversible neurocognitive impairment (intellectual disability), neurobehavioral/psychological issues, neurologic manifestations (motor disturbances including movement disorders and seizures), and microcephaly. Although lowering blood Phe concentration sometimes improves neurobehavioral/psychological issues and motor disturbances, it does not reduce neurocognitive impairment. MPKU syndrome is characterized by intellectual disability, neurobehavioral/psychiatric manifestations, congenital heart defects, and other birth defects. The diagnosis of PAH deficiency is established in all neonates following an out-of-range newborn screening result with (1) biochemical testing (plasma amino acid analysis) and (2) molecular genetic testing to identify the causative biallelic PAH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Recently published recommendations from the American College of Medical Genetics and Genomics (ACMG) for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency [ A diagnosis of PAH deficiency should be suspected due to an out-of-range newborn screening (NBS) result prior to onset of suggestive findings (see NBS for PAH deficiency is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify phenylalanine (Phe) and tyrosine (Tyr) concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the United States (US), see In the US most NBS laboratories determine their own cutoff levels for out-of-range test results; thus, newborns with an NBS result with elevated Phe concentrations must undergo additional testing as soon as possible to determine its etiology (see Establishing the Diagnosis, For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs. If a metabolic specialist is not available, the following treatment should be considered (see Verify the abnormal result with the state screening laboratory. Ascertain that the infant is clinically well. Consult the ACMG Obtain follow-up plasma or serum amino acid analysis and urine/blood pterin analysis. Note: Do not initiate dietary Phe restriction before confirmatory testing is sent. A symptomatic individual can have either (1) typical findings associated with late-diagnosed PAH deficiency or (2) untreated infantile-onset PAH deficiency resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PAH deficiency Epilepsy Any level of irreversible intellectual disability and neurobehavioral/psychiatric manifestations including emotional and social problems and autistic features Neurologic findings including movement disorders, sensory manifestations, tremors, and Parkinson-like features (particularly in adults) Musty body odor Eczema Decreased skin and hair pigmentation White matter abnormalities, particularly parietal and frontal with some temporal involvement (involving mostly periventricular and central white matter) Occasional cerebral or cerebellar atrophy [ Restricted diffusion The diagnosis of PAH deficiency The biochemical diagnosis of PAH deficiency is established in a proband with the following [Vockley et al 2104, Blood phenylalanine concentrations >120 umol/L Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, Note: Because blood Phe concentrations rise in the days after delivery, these recommendations are based on follow-up blood testing obtained after the NBS result. Phenylalanine-to-tyrosine (Phe:Tyr) ratio ≥3 Absence of defects in biopterin synthesis or recycling* based on quantitative assay of pterins. Note: Because these assays are best performed in specialized centers and are not readily available in many countries, follow up of abnormal NBS result with molecular genetic testing is increasingly common. Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). * The molecular diagnosis of PAH deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, or comprehensive genomic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Ninety-seven percent of individuals with PAH deficiency can be identified by sequencing all exons and flanking intron regions; exon deletion/duplication identified by MLPA accounts for 2%-3% of pathogenic • Verify the abnormal result with the state screening laboratory. • Ascertain that the infant is clinically well. • Consult the ACMG • Obtain follow-up plasma or serum amino acid analysis and urine/blood pterin analysis. • Epilepsy • Any level of irreversible intellectual disability and neurobehavioral/psychiatric manifestations including emotional and social problems and autistic features • Neurologic findings including movement disorders, sensory manifestations, tremors, and Parkinson-like features (particularly in adults) • Musty body odor • Eczema • Decreased skin and hair pigmentation • White matter abnormalities, particularly parietal and frontal with some temporal involvement (involving mostly periventricular and central white matter) • Occasional cerebral or cerebellar atrophy [ • Restricted diffusion • Blood phenylalanine concentrations >120 umol/L • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Note: Because blood Phe concentrations rise in the days after delivery, these recommendations are based on follow-up blood testing obtained after the NBS result. • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Phenylalanine-to-tyrosine (Phe:Tyr) ratio ≥3 • Absence of defects in biopterin synthesis or recycling* based on quantitative assay of pterins. Note: Because these assays are best performed in specialized centers and are not readily available in many countries, follow up of abnormal NBS result with molecular genetic testing is increasingly common. • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • * • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings A diagnosis of PAH deficiency should be suspected due to an out-of-range newborn screening (NBS) result prior to onset of suggestive findings (see NBS for PAH deficiency is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify phenylalanine (Phe) and tyrosine (Tyr) concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the United States (US), see In the US most NBS laboratories determine their own cutoff levels for out-of-range test results; thus, newborns with an NBS result with elevated Phe concentrations must undergo additional testing as soon as possible to determine its etiology (see Establishing the Diagnosis, For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs. If a metabolic specialist is not available, the following treatment should be considered (see Verify the abnormal result with the state screening laboratory. Ascertain that the infant is clinically well. Consult the ACMG Obtain follow-up plasma or serum amino acid analysis and urine/blood pterin analysis. Note: Do not initiate dietary Phe restriction before confirmatory testing is sent. A symptomatic individual can have either (1) typical findings associated with late-diagnosed PAH deficiency or (2) untreated infantile-onset PAH deficiency resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PAH deficiency Epilepsy Any level of irreversible intellectual disability and neurobehavioral/psychiatric manifestations including emotional and social problems and autistic features Neurologic findings including movement disorders, sensory manifestations, tremors, and Parkinson-like features (particularly in adults) Musty body odor Eczema Decreased skin and hair pigmentation White matter abnormalities, particularly parietal and frontal with some temporal involvement (involving mostly periventricular and central white matter) Occasional cerebral or cerebellar atrophy [ Restricted diffusion • Verify the abnormal result with the state screening laboratory. • Ascertain that the infant is clinically well. • Consult the ACMG • Obtain follow-up plasma or serum amino acid analysis and urine/blood pterin analysis. • Epilepsy • Any level of irreversible intellectual disability and neurobehavioral/psychiatric manifestations including emotional and social problems and autistic features • Neurologic findings including movement disorders, sensory manifestations, tremors, and Parkinson-like features (particularly in adults) • Musty body odor • Eczema • Decreased skin and hair pigmentation • White matter abnormalities, particularly parietal and frontal with some temporal involvement (involving mostly periventricular and central white matter) • Occasional cerebral or cerebellar atrophy [ • Restricted diffusion ## Scenario 1: Out-of-Range Newborn Screening (NBS) Result NBS for PAH deficiency is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify phenylalanine (Phe) and tyrosine (Tyr) concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the United States (US), see In the US most NBS laboratories determine their own cutoff levels for out-of-range test results; thus, newborns with an NBS result with elevated Phe concentrations must undergo additional testing as soon as possible to determine its etiology (see Establishing the Diagnosis, For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs. If a metabolic specialist is not available, the following treatment should be considered (see Verify the abnormal result with the state screening laboratory. Ascertain that the infant is clinically well. Consult the ACMG Obtain follow-up plasma or serum amino acid analysis and urine/blood pterin analysis. Note: Do not initiate dietary Phe restriction before confirmatory testing is sent. • Verify the abnormal result with the state screening laboratory. • Ascertain that the infant is clinically well. • Consult the ACMG • Obtain follow-up plasma or serum amino acid analysis and urine/blood pterin analysis. ## Scenario 2: Symptomatic Individual A symptomatic individual can have either (1) typical findings associated with late-diagnosed PAH deficiency or (2) untreated infantile-onset PAH deficiency resulting from any of the following: NBS not performed, false negative NBS result, clinical findings prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. PAH deficiency Epilepsy Any level of irreversible intellectual disability and neurobehavioral/psychiatric manifestations including emotional and social problems and autistic features Neurologic findings including movement disorders, sensory manifestations, tremors, and Parkinson-like features (particularly in adults) Musty body odor Eczema Decreased skin and hair pigmentation White matter abnormalities, particularly parietal and frontal with some temporal involvement (involving mostly periventricular and central white matter) Occasional cerebral or cerebellar atrophy [ Restricted diffusion • Epilepsy • Any level of irreversible intellectual disability and neurobehavioral/psychiatric manifestations including emotional and social problems and autistic features • Neurologic findings including movement disorders, sensory manifestations, tremors, and Parkinson-like features (particularly in adults) • Musty body odor • Eczema • Decreased skin and hair pigmentation • White matter abnormalities, particularly parietal and frontal with some temporal involvement (involving mostly periventricular and central white matter) • Occasional cerebral or cerebellar atrophy [ • Restricted diffusion ## Establishing the Diagnosis The diagnosis of PAH deficiency The biochemical diagnosis of PAH deficiency is established in a proband with the following [Vockley et al 2104, Blood phenylalanine concentrations >120 umol/L Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, Note: Because blood Phe concentrations rise in the days after delivery, these recommendations are based on follow-up blood testing obtained after the NBS result. Phenylalanine-to-tyrosine (Phe:Tyr) ratio ≥3 Absence of defects in biopterin synthesis or recycling* based on quantitative assay of pterins. Note: Because these assays are best performed in specialized centers and are not readily available in many countries, follow up of abnormal NBS result with molecular genetic testing is increasingly common. Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). * The molecular diagnosis of PAH deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, or comprehensive genomic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Ninety-seven percent of individuals with PAH deficiency can be identified by sequencing all exons and flanking intron regions; exon deletion/duplication identified by MLPA accounts for 2%-3% of pathogenic • Blood phenylalanine concentrations >120 umol/L • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Note: Because blood Phe concentrations rise in the days after delivery, these recommendations are based on follow-up blood testing obtained after the NBS result. • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Phenylalanine-to-tyrosine (Phe:Tyr) ratio ≥3 • Absence of defects in biopterin synthesis or recycling* based on quantitative assay of pterins. Note: Because these assays are best performed in specialized centers and are not readily available in many countries, follow up of abnormal NBS result with molecular genetic testing is increasingly common. • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • * • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Biochemical Testing The biochemical diagnosis of PAH deficiency is established in a proband with the following [Vockley et al 2104, Blood phenylalanine concentrations >120 umol/L Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, Note: Because blood Phe concentrations rise in the days after delivery, these recommendations are based on follow-up blood testing obtained after the NBS result. Phenylalanine-to-tyrosine (Phe:Tyr) ratio ≥3 Absence of defects in biopterin synthesis or recycling* based on quantitative assay of pterins. Note: Because these assays are best performed in specialized centers and are not readily available in many countries, follow up of abnormal NBS result with molecular genetic testing is increasingly common. Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). * • Blood phenylalanine concentrations >120 umol/L • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Note: Because blood Phe concentrations rise in the days after delivery, these recommendations are based on follow-up blood testing obtained after the NBS result. • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Phenylalanine-to-tyrosine (Phe:Tyr) ratio ≥3 • Absence of defects in biopterin synthesis or recycling* based on quantitative assay of pterins. Note: Because these assays are best performed in specialized centers and are not readily available in many countries, follow up of abnormal NBS result with molecular genetic testing is increasingly common. • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • * • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). • Blood phenylalanine concentrations >360 umol/L require treatment in some form for life (see Management, • Blood phenylalanine concentrations >120 umol/L but <360 umol/L require regular monitoring for at least the first two years of life as dietary protein intake increases, followed by monitoring every one or two years as indicated (see Management, • Quantitative assay of pterins (neopterin and biopterins) in urine or blood. If abnormal, reflex to quantitative assay of erythrocyte dihydropterine reductase (DHPR) activity if available (typically on dried blood spot). Reference values are available for different age groups. • Abnormal pterin concentrations in urine or reduced red blood cell DHPR activity (from dried blood spots) should prompt enzyme testing for possible deficiencies of the following enzymes: GTP cyclohydrolase (AR-GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), DHPR, or pterin carbinolamine-4α-dehydratase (PCD). ## Molecular Genetic Testing The molecular diagnosis of PAH deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, or comprehensive genomic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Ninety-seven percent of individuals with PAH deficiency can be identified by sequencing all exons and flanking intron regions; exon deletion/duplication identified by MLPA accounts for 2%-3% of pathogenic • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The phenotypes in individuals with phenylalanine hydroxylase (PAH) deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. In addition, maternal phenylketonuria (MPKU) syndrome is important to consider in offspring of mothers with inadequately treated PAH deficiency during pregnancy, as elevated blood phenylalanine (Phe) concentrations are toxic to the developing fetus [ Individuals with early-treated PKU also have an increased prevalence of mental health concerns, including anxiety and depression [ Evidence is emerging that lowering blood Phe concentrations in adults who have had persistently elevated blood Phe concentrations can improve both neuropsychological function [ Persistent severe hyperphenylalaninemia is characterized by irreversible neurocognitive impairment (intellectual disability), neurobehavioral/psychological issues, neurologic manifestations (motor disturbances including movement disorders and seizures), and microcephaly. Although treatment (see Management, Decreased skin and hair pigmentation result from associated inhibition of tyrosinase and low blood tyrosine concentrations. The excretion of excessive Phe and its metabolites can create a musty body odor and skin conditions such as eczema. Elevated blood Phe concentrations are teratogenic during pregnancy. MPKU syndrome results from exposure of a fetus of a woman who has PAH deficiency to blood Phe concentrations >360umol/L due either to poorly treated or untreated PAH deficiency during pregnancy. Rarely, a woman can be unaware of her diagnosis of PAH deficiency and, thus, bear children with MPKU syndrome [ Risks to the offspring of a woman with high blood Phe concentrations during pregnancy include the following [ Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. Although genotype can be predictive of sapropterin dihydrochloride responsiveness (see Management, "Traditional" PAH terminology is not used in the 2023 ACMG practice guideline for PAH deficiency diagnosis and management [ "Phenylketonuria (PKU)" refers specifically to severe PAH deficiency associated, in an untreated state, with plasma Phe concentrations >1,000 µmol/L [ "Non-PKU hyperphenylalaninemia (non-PKU HPA)" describes plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but <1,000 µmol/L when an individual is on a normal diet [ "Variant PKU" refers to individuals who do not fit the description for either PKU or non-PKU HPA [ "Mild hyperphenylalaninemia (HPA)" refers to individuals with an untreated blood phenylalanine concentration of 360-600 µmol/L. The term "classic PKU" is most often used to refer to severe PAH deficiency associated with a complete or near-complete deficiency of PAH activity [ • • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • "Phenylketonuria (PKU)" refers specifically to severe PAH deficiency associated, in an untreated state, with plasma Phe concentrations >1,000 µmol/L [ • "Non-PKU hyperphenylalaninemia (non-PKU HPA)" describes plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but <1,000 µmol/L when an individual is on a normal diet [ • "Variant PKU" refers to individuals who do not fit the description for either PKU or non-PKU HPA [ • "Mild hyperphenylalaninemia (HPA)" refers to individuals with an untreated blood phenylalanine concentration of 360-600 µmol/L. ## Clinical Description The phenotypes in individuals with phenylalanine hydroxylase (PAH) deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. In addition, maternal phenylketonuria (MPKU) syndrome is important to consider in offspring of mothers with inadequately treated PAH deficiency during pregnancy, as elevated blood phenylalanine (Phe) concentrations are toxic to the developing fetus [ Individuals with early-treated PKU also have an increased prevalence of mental health concerns, including anxiety and depression [ Evidence is emerging that lowering blood Phe concentrations in adults who have had persistently elevated blood Phe concentrations can improve both neuropsychological function [ Persistent severe hyperphenylalaninemia is characterized by irreversible neurocognitive impairment (intellectual disability), neurobehavioral/psychological issues, neurologic manifestations (motor disturbances including movement disorders and seizures), and microcephaly. Although treatment (see Management, Decreased skin and hair pigmentation result from associated inhibition of tyrosinase and low blood tyrosine concentrations. The excretion of excessive Phe and its metabolites can create a musty body odor and skin conditions such as eczema. Elevated blood Phe concentrations are teratogenic during pregnancy. MPKU syndrome results from exposure of a fetus of a woman who has PAH deficiency to blood Phe concentrations >360umol/L due either to poorly treated or untreated PAH deficiency during pregnancy. Rarely, a woman can be unaware of her diagnosis of PAH deficiency and, thus, bear children with MPKU syndrome [ Risks to the offspring of a woman with high blood Phe concentrations during pregnancy include the following [ Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. ## PAH Deficiency Treated from Birth Individuals with early-treated PKU also have an increased prevalence of mental health concerns, including anxiety and depression [ Evidence is emerging that lowering blood Phe concentrations in adults who have had persistently elevated blood Phe concentrations can improve both neuropsychological function [ ## Late-Diagnosed or Untreated PAH Deficiency Persistent severe hyperphenylalaninemia is characterized by irreversible neurocognitive impairment (intellectual disability), neurobehavioral/psychological issues, neurologic manifestations (motor disturbances including movement disorders and seizures), and microcephaly. Although treatment (see Management, Decreased skin and hair pigmentation result from associated inhibition of tyrosinase and low blood tyrosine concentrations. The excretion of excessive Phe and its metabolites can create a musty body odor and skin conditions such as eczema. ## MPKU Syndrome Elevated blood Phe concentrations are teratogenic during pregnancy. MPKU syndrome results from exposure of a fetus of a woman who has PAH deficiency to blood Phe concentrations >360umol/L due either to poorly treated or untreated PAH deficiency during pregnancy. Rarely, a woman can be unaware of her diagnosis of PAH deficiency and, thus, bear children with MPKU syndrome [ Risks to the offspring of a woman with high blood Phe concentrations during pregnancy include the following [ Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. • Risk of microcephaly is 5%-18% when maternal blood Phe concentration is optimized prior to ten weeks' gestation. • Risk of microcephaly is 67% if appropriate maternal blood Phe concentrations are not achieved by 30 weeks' gestation. • Risk of microcephaly is >90% if appropriate maternal blood Phe concentrations are never achieved during the pregnancy. ## Genotype-Phenotype Correlations Although genotype can be predictive of sapropterin dihydrochloride responsiveness (see Management, ## Nomenclature "Traditional" PAH terminology is not used in the 2023 ACMG practice guideline for PAH deficiency diagnosis and management [ "Phenylketonuria (PKU)" refers specifically to severe PAH deficiency associated, in an untreated state, with plasma Phe concentrations >1,000 µmol/L [ "Non-PKU hyperphenylalaninemia (non-PKU HPA)" describes plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but <1,000 µmol/L when an individual is on a normal diet [ "Variant PKU" refers to individuals who do not fit the description for either PKU or non-PKU HPA [ "Mild hyperphenylalaninemia (HPA)" refers to individuals with an untreated blood phenylalanine concentration of 360-600 µmol/L. The term "classic PKU" is most often used to refer to severe PAH deficiency associated with a complete or near-complete deficiency of PAH activity [ • "Phenylketonuria (PKU)" refers specifically to severe PAH deficiency associated, in an untreated state, with plasma Phe concentrations >1,000 µmol/L [ • "Non-PKU hyperphenylalaninemia (non-PKU HPA)" describes plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but <1,000 µmol/L when an individual is on a normal diet [ • "Variant PKU" refers to individuals who do not fit the description for either PKU or non-PKU HPA [ • "Mild hyperphenylalaninemia (HPA)" refers to individuals with an untreated blood phenylalanine concentration of 360-600 µmol/L. ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis In principle, BH4 deficiencies are treatable. Treatment requires the normalization of BH4 availability and blood Phe concentration and restoration of the BH4-dependent hydroxylation of tyrosine and tryptophan. This is achieved by BH4 supplementation along with dietary modification, neurotransmitter precursor replacement therapy, and supplements of folinic acid in dihydropterine reductase (DHPR) deficiency. However, residual neurologic manifestations such as movement abnormalities can persist. The treatment should be initiated early and probably continued for life [ Autosomal Recessive Disorders Known to Cause Hyperphenylalaninemia Typical (severe) forms have the following variable but common findings: ID, convulsions, disturbance of tone & posture, drowsiness, irritability, abnormal movements, recurrent hyperthermia w/o infections, hypersalivation, & swallowing difficulties. Microcephaly is common in PTPS & DHPR deficiencies. Plasma Phe concentrations can vary from slightly above normal (>120 µmol/L) to as high as 2,500 µmol/L. Note: Mild forms of BH4 deficiency have no clinical signs. Benign transient HPA Affected persons are at risk for MODY-type diabetes at puberty. Phenotypic spectrum ranges from mild autistic features or hyperactivity to severe ID, dystonia, & parkinsonism. Blood Phe concentrations are ↑ w/low concentrations of biogenic amine in CSF. Late diagnosis results in permanent neurologic disability, while early diagnosis & treatment w/levodopa/carbidopa & 5-hydroxytryptophan allows normal development. Phe concentrations return to normal w/BH4 treatment. BH4 = tetrahydrobiopterin; CSF = cerebrospinal fluid; HPA = hyperphenylalaninemia; ID = intellectual disability; MOI = mode of inheritance; Phe = phenylalanine Sometimes referred to as "primapterinuria" • Typical (severe) forms have the following variable but common findings: ID, convulsions, disturbance of tone & posture, drowsiness, irritability, abnormal movements, recurrent hyperthermia w/o infections, hypersalivation, & swallowing difficulties. • Microcephaly is common in PTPS & DHPR deficiencies. Plasma Phe concentrations can vary from slightly above normal (>120 µmol/L) to as high as 2,500 µmol/L. • Note: Mild forms of BH4 deficiency have no clinical signs. • Benign transient HPA • Affected persons are at risk for MODY-type diabetes at puberty. • Phenotypic spectrum ranges from mild autistic features or hyperactivity to severe ID, dystonia, & parkinsonism. • Blood Phe concentrations are ↑ w/low concentrations of biogenic amine in CSF. • Late diagnosis results in permanent neurologic disability, while early diagnosis & treatment w/levodopa/carbidopa & 5-hydroxytryptophan allows normal development. • Phe concentrations return to normal w/BH4 treatment. ## Management Recently published guidelines for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency in the United States (US) [ To establish the extent of disease and needs in an individual diagnosed with PAH deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of PAH deficiency to facilitate medical and personal decision making is recommended. Assess the need for family support and resources including community or online resources such as Individuals in this group need to be evaluated for the medical issues associated with untreated PAH deficiency such as epilepsy, intellectual disability, neurobehavioral/psychiatric manifestations, and movement disorders. These evaluations and their management follow standard medical practice and are not discussed further in this There is no cure for PAH deficiency. However, gene therapy trials are currently under way (see ACMG guidelines recommend lifelong treatment of all individuals with untreated blood Phe concentrations >360 μmol/L [ The mainstay of treatment for individuals with an untreated Phe blood concentration >360 umol/L is lifelong treatment with an age-appropriate Phe-restricted diet. Dietary therapy includes dietary protein restriction and Phe-free protein supplementation with medical foods (amino acid or glycomacropeptide based). In certain individuals, FDA-approved pharmacologic therapies may include the Phe hydroxylase activator/cofactor sapropterin dihydrochloride and/or enzyme substitution therapy (pegvaliase) [ Phenylalanine Hydroxylase Deficiency: Targeted Therapies Lifelong & age appropriate Implementation of Phe-restricted diet for infants requires use of Phe-free metabolic infant formula in combination w/breast milk &/or infant formula. Phe is an essential amino acid; thus, measured amounts of dietary Phe are required to meet daily requirements while maintaining blood Phe concentrations w/in treatment range. Determination of clinical/biochemical responsiveness to sapropterin should be documented prior to implementation of patient-specific treatment plan. As 25%-50% of persons w/PAH deficiency are sapropterin responsive, all persons w/PAH deficiency should be offered the opportunity to determine their sapropterin dihydrochloride responsiveness. Approved for adults in US who have uncontrolled blood Phe concentrations >600 μmol/L on existing mgmt PEGylated recombinant Phe ammonia lyase enzyme administered via subcutaneous injection Requires an induction, titration, & maintenance dosing schedule based on individual's drug tolerance Based on BH4 = tetrahydrobiopterin; PAH = phenylalanine hydroxylase; Phe = phenylalanine Although genotype could be predictive of sapropterin dihydrochloride responsiveness, to date genotype-phenotype correlations are imperfect. Thus, all individuals with PAH deficiency (except those with biallelic null Supportive treatment should be provided for individuals with PAH deficiency and their parents/caregivers. Treatment for affected individuals of all ages, which can be difficult, is enhanced with the teaching and support of an experienced health care team consisting of physicians, metabolic dietitians, genetic counselors, social workers, nurses, nurse practitioners, and psychologists [ Regular individualized screening for early identification of manifestations of PAH deficiency is recommended (see Individuals with PAH deficiency should be monitored closely with screening testing for developmental delay/intellectual disability. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country and may not be indicated for individuals with PAH deficiency without apparent developmental concerns. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children might qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. As PAH deficiency is a lifelong disorder with varying age-related implications, smooth transition of care of affected individuals from a pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because most centers in the US do not have metabolic physicians who specialize in adult care, the primary metabolic care provider is likely to remain unchanged. However, transition of other specialty services can still be transitioned to adult-oriented providers, and older teenagers and young adults can be taught the skills needed to identify the services provided by adult medical care providers. In the US, two formal transition curricula have been developed: The Cristine Trahms Program for Phenylketonuria Boston Children's Hospital A transitional care process has been developed in Italy in which adult internal medicine specialists initially see individuals with PAH deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers [ As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential. Offspring of women with PAH deficiency who have received appropriate treatment throughout childhood and adolescence and during pregnancy have normal physical development and essentially normal intellectual and behavioral development. However, if the woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome, including malformations and intellectual disability, since Phe is a potent teratogen (see Clinical Description, The Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ Maintain maternal blood Phe concentration at 120-360 µmol/L during pregnancy. Maternal blood Phe concentration should be monitored in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PAH deficiency. In unplanned pregnancies, measure maternal blood Phe concentration immediately. If elevated, reduce the blood Phe concentration using dietary management or pharmacologic therapy. Monitor dietary intake of pregnant women with PAH deficiency at every clinic visit to ensure that dietary nutrients are adequate with the proper proportion of protein, fat, and carbohydrates. Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at appropriate gestational ages. Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ Provide coordinated care, including monitoring of blood Phe concentrations of mother and infant as needed, implementation of Phe-restricted diet if the infant has PAH deficiency, and follow-up echocardiogram in infants if indicated. Dietary management, sapropterin dihydrochloride, and/or pegvaliase should be continued for the mother to maintain blood Phe concentrations in the recommended range. Monitoring of the mother for postpartum mental health issues and ability to breastfeed and follow the Phe-restricted diet is recommended [ Breastfeeding may be pursued if the infant does not have PAH deficiency. Phenylalanine Hydroxylase Deficiency: Recommended Biochemical Monitoring Plasma amino acids: monthly to every 3 mos Complete blood count: once Albumin: once Prealbumin: once Ferritin: once 25-hydroxyvitamin D: once Plasma amino acids: each clinic visit Complete blood count: yearly Albumin: every 6-12 mos Prealbumin: every 6-12 mos Ferritin: yearly 25-hydroxyvitamin D: yearly Age 1-7 yrs: monthly to every 6 mos Age 8-18 yrs: every 6-12 mos Based on Phe = phenylalanine Aspartame, an artificial sweetener that is often added to soft drinks, foods, and some medications, is metabolized in the gastrointestinal tract into Phe and aspartate. Persons with PAH deficiency should either avoid products containing aspartame or calculate total Phe intake when using such products in order to adapt diet components accordingly [ Note: Some medications (such as antibiotics) contain aspartame. Depending on the condition being treated, antibiotic treatment might need to be altered if no other alternatives are readily available. The initial newborn screening (NBS) measurement of blood Phe concentration is collected when the newborn is on a normal formula / breast milk diet. In most circumstances, the results of NBS blood Phe concentration will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with an out-of-range NBS result. Note that molecular genetic testing in this circumstance is most informative if the familial Measure blood Phe concentrations; Perform molecular genetic testing if the See Multiple modalities are now in clinical trials or being prepared for clinical trial, including gene therapy ( Search • Lifelong & age appropriate • Implementation of Phe-restricted diet for infants requires use of Phe-free metabolic infant formula in combination w/breast milk &/or infant formula. • Phe is an essential amino acid; thus, measured amounts of dietary Phe are required to meet daily requirements while maintaining blood Phe concentrations w/in treatment range. • Determination of clinical/biochemical responsiveness to sapropterin should be documented prior to implementation of patient-specific treatment plan. • As 25%-50% of persons w/PAH deficiency are sapropterin responsive, all persons w/PAH deficiency should be offered the opportunity to determine their sapropterin dihydrochloride responsiveness. • Approved for adults in US who have uncontrolled blood Phe concentrations >600 μmol/L on existing mgmt • PEGylated recombinant Phe ammonia lyase enzyme administered via subcutaneous injection • Requires an induction, titration, & maintenance dosing schedule based on individual's drug tolerance • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • The Cristine Trahms Program for Phenylketonuria • Boston Children's Hospital • Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus • Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. • Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ • Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. • There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ • Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ • Plasma amino acids: monthly to every 3 mos • Complete blood count: once • Albumin: once • Prealbumin: once • Ferritin: once • 25-hydroxyvitamin D: once • Plasma amino acids: each clinic visit • Complete blood count: yearly • Albumin: every 6-12 mos • Prealbumin: every 6-12 mos • Ferritin: yearly • 25-hydroxyvitamin D: yearly • Age 1-7 yrs: monthly to every 6 mos • Age 8-18 yrs: every 6-12 mos • Measure blood Phe concentrations; • Perform molecular genetic testing if the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PAH deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of PAH deficiency to facilitate medical and personal decision making is recommended. Assess the need for family support and resources including community or online resources such as Individuals in this group need to be evaluated for the medical issues associated with untreated PAH deficiency such as epilepsy, intellectual disability, neurobehavioral/psychiatric manifestations, and movement disorders. These evaluations and their management follow standard medical practice and are not discussed further in this ## Treatment of Manifestations There is no cure for PAH deficiency. However, gene therapy trials are currently under way (see ACMG guidelines recommend lifelong treatment of all individuals with untreated blood Phe concentrations >360 μmol/L [ The mainstay of treatment for individuals with an untreated Phe blood concentration >360 umol/L is lifelong treatment with an age-appropriate Phe-restricted diet. Dietary therapy includes dietary protein restriction and Phe-free protein supplementation with medical foods (amino acid or glycomacropeptide based). In certain individuals, FDA-approved pharmacologic therapies may include the Phe hydroxylase activator/cofactor sapropterin dihydrochloride and/or enzyme substitution therapy (pegvaliase) [ Phenylalanine Hydroxylase Deficiency: Targeted Therapies Lifelong & age appropriate Implementation of Phe-restricted diet for infants requires use of Phe-free metabolic infant formula in combination w/breast milk &/or infant formula. Phe is an essential amino acid; thus, measured amounts of dietary Phe are required to meet daily requirements while maintaining blood Phe concentrations w/in treatment range. Determination of clinical/biochemical responsiveness to sapropterin should be documented prior to implementation of patient-specific treatment plan. As 25%-50% of persons w/PAH deficiency are sapropterin responsive, all persons w/PAH deficiency should be offered the opportunity to determine their sapropterin dihydrochloride responsiveness. Approved for adults in US who have uncontrolled blood Phe concentrations >600 μmol/L on existing mgmt PEGylated recombinant Phe ammonia lyase enzyme administered via subcutaneous injection Requires an induction, titration, & maintenance dosing schedule based on individual's drug tolerance Based on BH4 = tetrahydrobiopterin; PAH = phenylalanine hydroxylase; Phe = phenylalanine Although genotype could be predictive of sapropterin dihydrochloride responsiveness, to date genotype-phenotype correlations are imperfect. Thus, all individuals with PAH deficiency (except those with biallelic null Supportive treatment should be provided for individuals with PAH deficiency and their parents/caregivers. Treatment for affected individuals of all ages, which can be difficult, is enhanced with the teaching and support of an experienced health care team consisting of physicians, metabolic dietitians, genetic counselors, social workers, nurses, nurse practitioners, and psychologists [ Regular individualized screening for early identification of manifestations of PAH deficiency is recommended (see Individuals with PAH deficiency should be monitored closely with screening testing for developmental delay/intellectual disability. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country and may not be indicated for individuals with PAH deficiency without apparent developmental concerns. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children might qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. As PAH deficiency is a lifelong disorder with varying age-related implications, smooth transition of care of affected individuals from a pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because most centers in the US do not have metabolic physicians who specialize in adult care, the primary metabolic care provider is likely to remain unchanged. However, transition of other specialty services can still be transitioned to adult-oriented providers, and older teenagers and young adults can be taught the skills needed to identify the services provided by adult medical care providers. In the US, two formal transition curricula have been developed: The Cristine Trahms Program for Phenylketonuria Boston Children's Hospital A transitional care process has been developed in Italy in which adult internal medicine specialists initially see individuals with PAH deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers [ As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential. Offspring of women with PAH deficiency who have received appropriate treatment throughout childhood and adolescence and during pregnancy have normal physical development and essentially normal intellectual and behavioral development. However, if the woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome, including malformations and intellectual disability, since Phe is a potent teratogen (see Clinical Description, The Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ Maintain maternal blood Phe concentration at 120-360 µmol/L during pregnancy. Maternal blood Phe concentration should be monitored in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PAH deficiency. In unplanned pregnancies, measure maternal blood Phe concentration immediately. If elevated, reduce the blood Phe concentration using dietary management or pharmacologic therapy. Monitor dietary intake of pregnant women with PAH deficiency at every clinic visit to ensure that dietary nutrients are adequate with the proper proportion of protein, fat, and carbohydrates. Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at appropriate gestational ages. Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ Provide coordinated care, including monitoring of blood Phe concentrations of mother and infant as needed, implementation of Phe-restricted diet if the infant has PAH deficiency, and follow-up echocardiogram in infants if indicated. Dietary management, sapropterin dihydrochloride, and/or pegvaliase should be continued for the mother to maintain blood Phe concentrations in the recommended range. Monitoring of the mother for postpartum mental health issues and ability to breastfeed and follow the Phe-restricted diet is recommended [ Breastfeeding may be pursued if the infant does not have PAH deficiency. • Lifelong & age appropriate • Implementation of Phe-restricted diet for infants requires use of Phe-free metabolic infant formula in combination w/breast milk &/or infant formula. • Phe is an essential amino acid; thus, measured amounts of dietary Phe are required to meet daily requirements while maintaining blood Phe concentrations w/in treatment range. • Determination of clinical/biochemical responsiveness to sapropterin should be documented prior to implementation of patient-specific treatment plan. • As 25%-50% of persons w/PAH deficiency are sapropterin responsive, all persons w/PAH deficiency should be offered the opportunity to determine their sapropterin dihydrochloride responsiveness. • Approved for adults in US who have uncontrolled blood Phe concentrations >600 μmol/L on existing mgmt • PEGylated recombinant Phe ammonia lyase enzyme administered via subcutaneous injection • Requires an induction, titration, & maintenance dosing schedule based on individual's drug tolerance • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • The Cristine Trahms Program for Phenylketonuria • Boston Children's Hospital • Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus • Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. • Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ • Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. • There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ • Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ ## Targeted Therapies The mainstay of treatment for individuals with an untreated Phe blood concentration >360 umol/L is lifelong treatment with an age-appropriate Phe-restricted diet. Dietary therapy includes dietary protein restriction and Phe-free protein supplementation with medical foods (amino acid or glycomacropeptide based). In certain individuals, FDA-approved pharmacologic therapies may include the Phe hydroxylase activator/cofactor sapropterin dihydrochloride and/or enzyme substitution therapy (pegvaliase) [ Phenylalanine Hydroxylase Deficiency: Targeted Therapies Lifelong & age appropriate Implementation of Phe-restricted diet for infants requires use of Phe-free metabolic infant formula in combination w/breast milk &/or infant formula. Phe is an essential amino acid; thus, measured amounts of dietary Phe are required to meet daily requirements while maintaining blood Phe concentrations w/in treatment range. Determination of clinical/biochemical responsiveness to sapropterin should be documented prior to implementation of patient-specific treatment plan. As 25%-50% of persons w/PAH deficiency are sapropterin responsive, all persons w/PAH deficiency should be offered the opportunity to determine their sapropterin dihydrochloride responsiveness. Approved for adults in US who have uncontrolled blood Phe concentrations >600 μmol/L on existing mgmt PEGylated recombinant Phe ammonia lyase enzyme administered via subcutaneous injection Requires an induction, titration, & maintenance dosing schedule based on individual's drug tolerance Based on BH4 = tetrahydrobiopterin; PAH = phenylalanine hydroxylase; Phe = phenylalanine Although genotype could be predictive of sapropterin dihydrochloride responsiveness, to date genotype-phenotype correlations are imperfect. Thus, all individuals with PAH deficiency (except those with biallelic null • Lifelong & age appropriate • Implementation of Phe-restricted diet for infants requires use of Phe-free metabolic infant formula in combination w/breast milk &/or infant formula. • Phe is an essential amino acid; thus, measured amounts of dietary Phe are required to meet daily requirements while maintaining blood Phe concentrations w/in treatment range. • Determination of clinical/biochemical responsiveness to sapropterin should be documented prior to implementation of patient-specific treatment plan. • As 25%-50% of persons w/PAH deficiency are sapropterin responsive, all persons w/PAH deficiency should be offered the opportunity to determine their sapropterin dihydrochloride responsiveness. • Approved for adults in US who have uncontrolled blood Phe concentrations >600 μmol/L on existing mgmt • PEGylated recombinant Phe ammonia lyase enzyme administered via subcutaneous injection • Requires an induction, titration, & maintenance dosing schedule based on individual's drug tolerance ## Supportive Care Supportive treatment should be provided for individuals with PAH deficiency and their parents/caregivers. Treatment for affected individuals of all ages, which can be difficult, is enhanced with the teaching and support of an experienced health care team consisting of physicians, metabolic dietitians, genetic counselors, social workers, nurses, nurse practitioners, and psychologists [ Regular individualized screening for early identification of manifestations of PAH deficiency is recommended (see Individuals with PAH deficiency should be monitored closely with screening testing for developmental delay/intellectual disability. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country and may not be indicated for individuals with PAH deficiency without apparent developmental concerns. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children might qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. As PAH deficiency is a lifelong disorder with varying age-related implications, smooth transition of care of affected individuals from a pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because most centers in the US do not have metabolic physicians who specialize in adult care, the primary metabolic care provider is likely to remain unchanged. However, transition of other specialty services can still be transitioned to adult-oriented providers, and older teenagers and young adults can be taught the skills needed to identify the services provided by adult medical care providers. In the US, two formal transition curricula have been developed: The Cristine Trahms Program for Phenylketonuria Boston Children's Hospital A transitional care process has been developed in Italy in which adult internal medicine specialists initially see individuals with PAH deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers [ As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • The Cristine Trahms Program for Phenylketonuria • Boston Children's Hospital ## Individuals with PAH deficiency should be monitored closely with screening testing for developmental delay/intellectual disability. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country and may not be indicated for individuals with PAH deficiency without apparent developmental concerns. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) should be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Children might qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## As PAH deficiency is a lifelong disorder with varying age-related implications, smooth transition of care of affected individuals from a pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because most centers in the US do not have metabolic physicians who specialize in adult care, the primary metabolic care provider is likely to remain unchanged. However, transition of other specialty services can still be transitioned to adult-oriented providers, and older teenagers and young adults can be taught the skills needed to identify the services provided by adult medical care providers. In the US, two formal transition curricula have been developed: The Cristine Trahms Program for Phenylketonuria Boston Children's Hospital A transitional care process has been developed in Italy in which adult internal medicine specialists initially see individuals with PAH deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers [ As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential. • The Cristine Trahms Program for Phenylketonuria • Boston Children's Hospital ## Preconception, Pregnancy, and Postpartum Care Offspring of women with PAH deficiency who have received appropriate treatment throughout childhood and adolescence and during pregnancy have normal physical development and essentially normal intellectual and behavioral development. However, if the woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome, including malformations and intellectual disability, since Phe is a potent teratogen (see Clinical Description, The Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ Maintain maternal blood Phe concentration at 120-360 µmol/L during pregnancy. Maternal blood Phe concentration should be monitored in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PAH deficiency. In unplanned pregnancies, measure maternal blood Phe concentration immediately. If elevated, reduce the blood Phe concentration using dietary management or pharmacologic therapy. Monitor dietary intake of pregnant women with PAH deficiency at every clinic visit to ensure that dietary nutrients are adequate with the proper proportion of protein, fat, and carbohydrates. Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at appropriate gestational ages. Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ Provide coordinated care, including monitoring of blood Phe concentrations of mother and infant as needed, implementation of Phe-restricted diet if the infant has PAH deficiency, and follow-up echocardiogram in infants if indicated. Dietary management, sapropterin dihydrochloride, and/or pegvaliase should be continued for the mother to maintain blood Phe concentrations in the recommended range. Monitoring of the mother for postpartum mental health issues and ability to breastfeed and follow the Phe-restricted diet is recommended [ Breastfeeding may be pursued if the infant does not have PAH deficiency. • Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus • Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. • Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ • Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. • There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ • Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ ## The Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ • Genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus • Achievement and maintenance of maternal blood Phe concentration at <360 µmol/L for three months prior to conception. Note: Maternal Phe concentrations tend to decrease in the third trimester of pregnancy, presumably due to increased protein accretion in the developing fetus. • Some evidence suggests that poorly treated or untreated maternal PAH deficiency during pregnancy can result in an increased risk of miscarriage [ ## Maintain maternal blood Phe concentration at 120-360 µmol/L during pregnancy. Maternal blood Phe concentration should be monitored in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PAH deficiency. In unplanned pregnancies, measure maternal blood Phe concentration immediately. If elevated, reduce the blood Phe concentration using dietary management or pharmacologic therapy. Monitor dietary intake of pregnant women with PAH deficiency at every clinic visit to ensure that dietary nutrients are adequate with the proper proportion of protein, fat, and carbohydrates. Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at appropriate gestational ages. Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ • Despite limited data available to date, sapropterin can be continued in addition to dietary therapy due to the risk of elevated maternal blood Phe concentration if discontinued. • There is limited experience with pegvaliase in pregnancy. In a single report, 14 infants (six females and eight males) had no congenital anomalies, and all infants had normal growth parameters [ • Large neutral amino acid (LNAA) treatment should be avoided in pregnant women because (1) its effects on fetal growth and central nervous system development is not well understood and (2) it does not sufficiently lower blood Phe concentration to the range that is safe for fetal development [ ## Provide coordinated care, including monitoring of blood Phe concentrations of mother and infant as needed, implementation of Phe-restricted diet if the infant has PAH deficiency, and follow-up echocardiogram in infants if indicated. Dietary management, sapropterin dihydrochloride, and/or pegvaliase should be continued for the mother to maintain blood Phe concentrations in the recommended range. Monitoring of the mother for postpartum mental health issues and ability to breastfeed and follow the Phe-restricted diet is recommended [ Breastfeeding may be pursued if the infant does not have PAH deficiency. ## Surveillance Phenylalanine Hydroxylase Deficiency: Recommended Biochemical Monitoring Plasma amino acids: monthly to every 3 mos Complete blood count: once Albumin: once Prealbumin: once Ferritin: once 25-hydroxyvitamin D: once Plasma amino acids: each clinic visit Complete blood count: yearly Albumin: every 6-12 mos Prealbumin: every 6-12 mos Ferritin: yearly 25-hydroxyvitamin D: yearly Age 1-7 yrs: monthly to every 6 mos Age 8-18 yrs: every 6-12 mos Based on Phe = phenylalanine • Plasma amino acids: monthly to every 3 mos • Complete blood count: once • Albumin: once • Prealbumin: once • Ferritin: once • 25-hydroxyvitamin D: once • Plasma amino acids: each clinic visit • Complete blood count: yearly • Albumin: every 6-12 mos • Prealbumin: every 6-12 mos • Ferritin: yearly • 25-hydroxyvitamin D: yearly • Age 1-7 yrs: monthly to every 6 mos • Age 8-18 yrs: every 6-12 mos ## Agents/Circumstances to Avoid Aspartame, an artificial sweetener that is often added to soft drinks, foods, and some medications, is metabolized in the gastrointestinal tract into Phe and aspartate. Persons with PAH deficiency should either avoid products containing aspartame or calculate total Phe intake when using such products in order to adapt diet components accordingly [ Note: Some medications (such as antibiotics) contain aspartame. Depending on the condition being treated, antibiotic treatment might need to be altered if no other alternatives are readily available. ## Evaluation of Relatives at Risk The initial newborn screening (NBS) measurement of blood Phe concentration is collected when the newborn is on a normal formula / breast milk diet. In most circumstances, the results of NBS blood Phe concentration will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with an out-of-range NBS result. Note that molecular genetic testing in this circumstance is most informative if the familial Measure blood Phe concentrations; Perform molecular genetic testing if the See • Measure blood Phe concentrations; • Perform molecular genetic testing if the ## Therapies Under Investigation Multiple modalities are now in clinical trials or being prepared for clinical trial, including gene therapy ( Search ## Genetic Counseling Phenylalanine hydroxylase (PAH) deficiency is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Significant intrafamilial variability has been observed in PAH deficiency; thus, the clinical phenotype observed in the proband might not be consistent with or predicative of the clinical phenotype in affected sibs [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Children born of one parent with PAH deficiency and one parent with two normal If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected. If the mother is the affected parent, maternal phenylketonuria (MPKU) syndrome is a critical issue (see Clinical Description, See Management, Young women with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (e.g., MPKU syndrome) when they reach childbearing age (see Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Partners of an individual affected with PAH deficiency or known to be a carrier of a The ACMG includes PAH deficiency among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [ Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Significant intrafamilial variability has been observed in PAH deficiency; thus, the clinical phenotype observed in the proband might not be consistent with or predicative of the clinical phenotype in affected sibs [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Children born of one parent with PAH deficiency and one parent with two normal • If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected. • If the mother is the affected parent, maternal phenylketonuria (MPKU) syndrome is a critical issue (see Clinical Description, • Young women with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (e.g., MPKU syndrome) when they reach childbearing age (see Management, • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Partners of an individual affected with PAH deficiency or known to be a carrier of a • The ACMG includes PAH deficiency among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [ ## Mode of Inheritance Phenylalanine hydroxylase (PAH) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Significant intrafamilial variability has been observed in PAH deficiency; thus, the clinical phenotype observed in the proband might not be consistent with or predicative of the clinical phenotype in affected sibs [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Children born of one parent with PAH deficiency and one parent with two normal If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected. If the mother is the affected parent, maternal phenylketonuria (MPKU) syndrome is a critical issue (see Clinical Description, • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Significant intrafamilial variability has been observed in PAH deficiency; thus, the clinical phenotype observed in the proband might not be consistent with or predicative of the clinical phenotype in affected sibs [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Children born of one parent with PAH deficiency and one parent with two normal • If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected. • If the mother is the affected parent, maternal phenylketonuria (MPKU) syndrome is a critical issue (see Clinical Description, ## Carrier Detection ## Related Genetic Counseling Issues See Management, Young women with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (e.g., MPKU syndrome) when they reach childbearing age (see Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Partners of an individual affected with PAH deficiency or known to be a carrier of a The ACMG includes PAH deficiency among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [ • Young women with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (e.g., MPKU syndrome) when they reach childbearing age (see Management, • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Partners of an individual affected with PAH deficiency or known to be a carrier of a • The ACMG includes PAH deficiency among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [ ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom Canada United Kingdom United Kingdom Health Resources & Services Administration • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • Canada • • • • • • • • • United Kingdom • • • United Kingdom • • • • • Health Resources & Services Administration • ## Molecular Genetics Phenylalanine Hydroxylase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Phenylalanine Hydroxylase Deficiency ( Phenylalanine hydroxylase (PAH) is the rate-limiting step in the conversion of phenylalanine (Phe) to tyrosine (Tyr), a reaction that requires the cofactor tetrahydrobiopterin (BH4). PAH deficiency is an inborn error of Phe metabolism caused by biallelic ## Molecular Pathogenesis Phenylalanine hydroxylase (PAH) is the rate-limiting step in the conversion of phenylalanine (Phe) to tyrosine (Tyr), a reaction that requires the cofactor tetrahydrobiopterin (BH4). PAH deficiency is an inborn error of Phe metabolism caused by biallelic ## Chapter Notes Georgianne Arnold, MD (2025-present)Carol L Greene, MD, FAAP, FACMG; University of Maryland School of Medicine (2016-2025)John J Mitchell, MD; McGill University, Montreal (2005-2016) Debra S Regier, MD, PhD, FAAP, FACMG; Children's National Medical Center (2016-present)Shannon Ryan, MSc; Montreal Children's Hospital (2000-2005)Charles R Scriver, MD; Montreal Children's Hospital (2000-2013)Jerry Vockley, MD, PhD (2025-present) 13 March 2025 (bp) Comprehensive update posted live 20 October 2016 (ma) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 4 May 2010 (me) Comprehensive update posted live 29 March 2007 (me) Comprehensive update posted live 8 July 2004 (me) Comprehensive update posted live 13 August 2002 (me) Comprehensive update posted live 10 January 2000 (me) Review posted live 16 July 1999 (dsr) Original submission • 13 March 2025 (bp) Comprehensive update posted live • 20 October 2016 (ma) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 4 May 2010 (me) Comprehensive update posted live • 29 March 2007 (me) Comprehensive update posted live • 8 July 2004 (me) Comprehensive update posted live • 13 August 2002 (me) Comprehensive update posted live • 10 January 2000 (me) Review posted live • 16 July 1999 (dsr) Original submission ## Author History Georgianne Arnold, MD (2025-present)Carol L Greene, MD, FAAP, FACMG; University of Maryland School of Medicine (2016-2025)John J Mitchell, MD; McGill University, Montreal (2005-2016) Debra S Regier, MD, PhD, FAAP, FACMG; Children's National Medical Center (2016-present)Shannon Ryan, MSc; Montreal Children's Hospital (2000-2005)Charles R Scriver, MD; Montreal Children's Hospital (2000-2013)Jerry Vockley, MD, PhD (2025-present) ## Revision History 13 March 2025 (bp) Comprehensive update posted live 20 October 2016 (ma) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 4 May 2010 (me) Comprehensive update posted live 29 March 2007 (me) Comprehensive update posted live 8 July 2004 (me) Comprehensive update posted live 13 August 2002 (me) Comprehensive update posted live 10 January 2000 (me) Review posted live 16 July 1999 (dsr) Original submission • 13 March 2025 (bp) Comprehensive update posted live • 20 October 2016 (ma) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 4 May 2010 (me) Comprehensive update posted live • 29 March 2007 (me) Comprehensive update posted live • 8 July 2004 (me) Comprehensive update posted live • 13 August 2002 (me) Comprehensive update posted live • 10 January 2000 (me) Review posted live • 16 July 1999 (dsr) Original submission ## Key Sections in This ## References Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. The Canadian Guide to Clinical Preventive Health Care. Available Committee on Genetics. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria). American College of Obstetricians and Gynecologists Committee Opinion April 2020. Number 802. Available Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121-31. [ Smith WE, Berry SA, Bloom K, Brown C, Burton BK, Demarest OM, Jenkins GP, Malinowski J, McBride KL, Mroczkowski HJ, Scharfe C, Vockley J; ACMG Board of Directors. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27:101289. [ van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12:162. [ Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. [ • Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. The Canadian Guide to Clinical Preventive Health Care. Available • Committee on Genetics. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria). American College of Obstetricians and Gynecologists Committee Opinion April 2020. Number 802. Available • Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121-31. [ • Smith WE, Berry SA, Bloom K, Brown C, Burton BK, Demarest OM, Jenkins GP, Malinowski J, McBride KL, Mroczkowski HJ, Scharfe C, Vockley J; ACMG Board of Directors. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27:101289. [ • van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12:162. [ • Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. [ ## Published Guidelines / Consensus Statements Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. The Canadian Guide to Clinical Preventive Health Care. Available Committee on Genetics. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria). American College of Obstetricians and Gynecologists Committee Opinion April 2020. Number 802. Available Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121-31. [ Smith WE, Berry SA, Bloom K, Brown C, Burton BK, Demarest OM, Jenkins GP, Malinowski J, McBride KL, Mroczkowski HJ, Scharfe C, Vockley J; ACMG Board of Directors. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27:101289. [ van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12:162. [ Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. [ • Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. The Canadian Guide to Clinical Preventive Health Care. Available • Committee on Genetics. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria). American College of Obstetricians and Gynecologists Committee Opinion April 2020. Number 802. Available • Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121-31. [ • Smith WE, Berry SA, Bloom K, Brown C, Burton BK, Demarest OM, Jenkins GP, Malinowski J, McBride KL, Mroczkowski HJ, Scharfe C, Vockley J; ACMG Board of Directors. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27:101289. [ • van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12:162. [ • Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. [ ## Literature Cited	[]	10/1/2000	13/3/2025	5/1/2017	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
plosl	plosl	[ "Nasu-Hakola Disease", "PLOSL", "Nasu-Hakola Disease", "PLOSL", "Triggering receptor expressed on myeloid cells 2", "TYRO protein tyrosine kinase-binding protein", "TREM2", "TYROBP", "Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy" ]	Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy	Juha Paloneva, Taina Autti, Panu Hakola, Matti J Haltia	Summary Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. The clinical course of PLOSL can be divided into four stages: The The In the The Death usually occurs before age 50 years. The diagnosis of PLOSL can be established in a proband with radiologically demonstrable polycystic osseous lesions, frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. Identification of biallelic pathogenic variants in PLOSL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus clinical diagnostic criteria for polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) have been published. PLOSL The clinical diagnosis of PLOSL can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Sequence analysis of each gene is performed first. If only one or no pathogenic variant is found, deletion/duplication analysis is performed next. For an introduction to multigene panels click When the diagnosis of PLOSL has not been considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, Molecular Genetic Testing Used in Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Most affected individuals tested to date are homozygous for their pathogenic variant [ No data on detection rate of gene-targeted deletion/duplication analysis are available. Pathogenic variants in All Finnish individuals with PLOSL are homozygous for deletion of exons 1-4 (c.-2897_277-1227del5265) • Sequence analysis of each gene is performed first. • If only one or no pathogenic variant is found, deletion/duplication analysis is performed next. ## Suggestive Findings PLOSL ## Establishing the Diagnosis The clinical diagnosis of PLOSL can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Sequence analysis of each gene is performed first. If only one or no pathogenic variant is found, deletion/duplication analysis is performed next. For an introduction to multigene panels click When the diagnosis of PLOSL has not been considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, Molecular Genetic Testing Used in Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Most affected individuals tested to date are homozygous for their pathogenic variant [ No data on detection rate of gene-targeted deletion/duplication analysis are available. Pathogenic variants in All Finnish individuals with PLOSL are homozygous for deletion of exons 1-4 (c.-2897_277-1227del5265) • Sequence analysis of each gene is performed first. • If only one or no pathogenic variant is found, deletion/duplication analysis is performed next. ## Option 1 Sequence analysis of each gene is performed first. If only one or no pathogenic variant is found, deletion/duplication analysis is performed next. For an introduction to multigene panels click • Sequence analysis of each gene is performed first. • If only one or no pathogenic variant is found, deletion/duplication analysis is performed next. ## Option 2 When the diagnosis of PLOSL has not been considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, Molecular Genetic Testing Used in Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Most affected individuals tested to date are homozygous for their pathogenic variant [ No data on detection rate of gene-targeted deletion/duplication analysis are available. Pathogenic variants in All Finnish individuals with PLOSL are homozygous for deletion of exons 1-4 (c.-2897_277-1227del5265) ## Clinical Characteristics The clinical course of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) can be divided into four stages: latent, osseous, early neurologic, and late neurologic [ Progressive signs of upper motor neuron involvement (spasticity, extensor plantar reflexes) are noticed. With advancing disease, lack of initiative and activity conceal the aforementioned symptoms [ Memory disturbances begin at approximately the same age as the personality changes, and are best detectable by psychometric tests [ Other disturbances of higher cortical function, such as motor aphasia, agraphia, acalculia, and apraxia, appear only at the last stage of the disease. Affected individuals may develop postural dyspraxia: they walk or sit in peculiar skewed postures. Involuntary athetotic or choreatic movements or myoclonic twitches are common. Individuals who reach their mid-thirties frequently experience epileptic seizures. In some individuals, impotence or lack of libido and urinary incontinence are among the first symptoms [ Histologic examination reveals scattered neurons showing features of central chromatolysis. Intraneuronal or glial pathologic inclusions have not been observed [ Individuals with homozygous pathogenic variants in Some Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy may be abbreviated as PLOSL. The first affected individuals were described in the 1960s independently by Järvi and Hakola in Finland and Nasu in Japan. In the early literature, PLOSL was also known as membranous lipodystrophy. This term is outdated and should not be used. The prevalence of PLOSL is highest in Finland due to a ## Clinical Description The clinical course of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) can be divided into four stages: latent, osseous, early neurologic, and late neurologic [ Progressive signs of upper motor neuron involvement (spasticity, extensor plantar reflexes) are noticed. With advancing disease, lack of initiative and activity conceal the aforementioned symptoms [ Memory disturbances begin at approximately the same age as the personality changes, and are best detectable by psychometric tests [ Other disturbances of higher cortical function, such as motor aphasia, agraphia, acalculia, and apraxia, appear only at the last stage of the disease. Affected individuals may develop postural dyspraxia: they walk or sit in peculiar skewed postures. Involuntary athetotic or choreatic movements or myoclonic twitches are common. Individuals who reach their mid-thirties frequently experience epileptic seizures. In some individuals, impotence or lack of libido and urinary incontinence are among the first symptoms [ Histologic examination reveals scattered neurons showing features of central chromatolysis. Intraneuronal or glial pathologic inclusions have not been observed [ ## Genotype-Phenotype Correlations Individuals with homozygous pathogenic variants in Some ## Nomenclature Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy may be abbreviated as PLOSL. The first affected individuals were described in the 1960s independently by Järvi and Hakola in Finland and Nasu in Japan. In the early literature, PLOSL was also known as membranous lipodystrophy. This term is outdated and should not be used. ## Prevalence The prevalence of PLOSL is highest in Finland due to a ## Genetically Related (Allelic) Disorders No disorders other than those discussed in this CNS = central nervous system ## Differential Diagnosis The combination of frontal-type dementia beginning in the fourth decade and radiologically demonstrable polycystic osseous lesions makes it easy to clinically distinguish polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) from the established forms of familial and nonfamilial frontotemporal dementia (e.g., Pick disease, nonspecific frontal lobe degeneration, ## Management No clinical practice guidelines for polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) have been published. To establish the extent of disease and needs in an individual diagnosed with PLOSL, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy To determine extent of osseous manifestations A plain radiograph must be taken if skeletal pain ↑ due to risk of pathologic fracture. CNS = central nervous system; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Only symptomatic treatment is available. Treatment of Manifestations in Individuals with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy Insufficient data available Not helpful in 1 report [ The interval of surveillance for bone lesions, neurologic, and psychiatric manifestations must be determined individually. Recommended Surveillance for Individuals with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy See Search Calcium substitution alone has been shown to be ineffective in preventing the development of the osseous manifestations. The effect of bisphosphonates has not been studied. It has been speculated that nonsteroidal anti-inflammatory drugs could slow the progression of PLOSL; however, clinical trials have not been performed. A single individual with PLOSL improved temporarily when taking donepezil [D Hemelsoet, personal observation]. Clinical trials in a series of individuals with PLOSL have not been reported. • To determine extent of osseous manifestations • A plain radiograph must be taken if skeletal pain ↑ due to risk of pathologic fracture. • Insufficient data available • Not helpful in 1 report [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PLOSL, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy To determine extent of osseous manifestations A plain radiograph must be taken if skeletal pain ↑ due to risk of pathologic fracture. CNS = central nervous system; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • To determine extent of osseous manifestations • A plain radiograph must be taken if skeletal pain ↑ due to risk of pathologic fracture. ## Treatment of Manifestations Only symptomatic treatment is available. Treatment of Manifestations in Individuals with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy Insufficient data available Not helpful in 1 report [ • Insufficient data available • Not helpful in 1 report [ ## Surveillance The interval of surveillance for bone lesions, neurologic, and psychiatric manifestations must be determined individually. Recommended Surveillance for Individuals with Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other Calcium substitution alone has been shown to be ineffective in preventing the development of the osseous manifestations. The effect of bisphosphonates has not been studied. It has been speculated that nonsteroidal anti-inflammatory drugs could slow the progression of PLOSL; however, clinical trials have not been performed. A single individual with PLOSL improved temporarily when taking donepezil [D Hemelsoet, personal observation]. Clinical trials in a series of individuals with PLOSL have not been reported. ## Genetic Counseling Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a PLOSL-related pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a PLOSL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Sibs who are younger than age 40 years are at risk for PLOSL. Polycystic osseous lesions in radiographs of the hands and feet of an at-risk adult suggest the diagnosis. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has PLOSL or is a carrier, offspring will be obligate heterozygotes for a Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is very low except in genetic isolates (see Carrier testing for at-risk relatives requires prior identification of the PLOSL-related pathogenic variants in the family. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers. Predictive testing for at-risk relatives is possible once the PLOSL-related pathogenic variants have been identified in an affected family member. Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of PLOSL, it is appropriate to consider testing of symptomatic individuals regardless of age. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a PLOSL-related pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a PLOSL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Note: Sibs who are younger than age 40 years are at risk for PLOSL. Polycystic osseous lesions in radiographs of the hands and feet of an at-risk adult suggest the diagnosis. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has PLOSL or is a carrier, offspring will be obligate heterozygotes for a • Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is very low except in genetic isolates (see • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers. • Predictive testing for at-risk relatives is possible once the PLOSL-related pathogenic variants have been identified in an affected family member. • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors ## Mode of Inheritance Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a PLOSL-related pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a PLOSL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Sibs who are younger than age 40 years are at risk for PLOSL. Polycystic osseous lesions in radiographs of the hands and feet of an at-risk adult suggest the diagnosis. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has PLOSL or is a carrier, offspring will be obligate heterozygotes for a Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is very low except in genetic isolates (see • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a PLOSL-related pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a PLOSL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Note: Sibs who are younger than age 40 years are at risk for PLOSL. Polycystic osseous lesions in radiographs of the hands and feet of an at-risk adult suggest the diagnosis. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has PLOSL or is a carrier, offspring will be obligate heterozygotes for a • Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is very low except in genetic isolates (see ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the PLOSL-related pathogenic variants in the family. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers. Predictive testing for at-risk relatives is possible once the PLOSL-related pathogenic variants have been identified in an affected family member. Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of PLOSL, it is appropriate to consider testing of symptomatic individuals regardless of age. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being affected or carriers. • Predictive testing for at-risk relatives is possible once the PLOSL-related pathogenic variants have been identified in an affected family member. • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy ( TYROBP is a transmembrane adaptor protein that mediates the activation of a wide variety of cells of myeloid and lymphoid origin. On the cell plasma membrane, TYROBP is expressed as a disulfide-bonded homodimer linked to the associated cell surface receptors. Numerous TYROBP-associated cell surface receptors have been reported [ The protein encoded by TREM2 is expressed by a variety of cells of myeloid origin. TREM2 also activates monocyte-derived dendritic cells and is expressed by macrophages [ The intracellular responses underlying the pathogenic mechanisms of PLOSL are poorly understood. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. Because the exon 1-4 deletion is an ## Molecular Pathogenesis TYROBP is a transmembrane adaptor protein that mediates the activation of a wide variety of cells of myeloid and lymphoid origin. On the cell plasma membrane, TYROBP is expressed as a disulfide-bonded homodimer linked to the associated cell surface receptors. Numerous TYROBP-associated cell surface receptors have been reported [ The protein encoded by TREM2 is expressed by a variety of cells of myeloid origin. TREM2 also activates monocyte-derived dendritic cells and is expressed by macrophages [ The intracellular responses underlying the pathogenic mechanisms of PLOSL are poorly understood. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. Because the exon 1-4 deletion is an ## Chapter Notes 10 December 2020 (sw) Comprehensive update posted live 12 March 2015 (me) Comprehensive update posted live 26 August 2010 (me) Comprehensive update posted live 16 April 2009 (jp) Revision: sequence analysis available on a clinical basis for 1 May 2006 (me) Comprehensive update posted live 15 March 2004 (me) Comprehensive update posted live 24 January 2002 (me) Review posted live 31 October 2001 (jp) Original submission • 10 December 2020 (sw) Comprehensive update posted live • 12 March 2015 (me) Comprehensive update posted live • 26 August 2010 (me) Comprehensive update posted live • 16 April 2009 (jp) Revision: sequence analysis available on a clinical basis for • 1 May 2006 (me) Comprehensive update posted live • 15 March 2004 (me) Comprehensive update posted live • 24 January 2002 (me) Review posted live • 31 October 2001 (jp) Original submission ## Revision History 10 December 2020 (sw) Comprehensive update posted live 12 March 2015 (me) Comprehensive update posted live 26 August 2010 (me) Comprehensive update posted live 16 April 2009 (jp) Revision: sequence analysis available on a clinical basis for 1 May 2006 (me) Comprehensive update posted live 15 March 2004 (me) Comprehensive update posted live 24 January 2002 (me) Review posted live 31 October 2001 (jp) Original submission • 10 December 2020 (sw) Comprehensive update posted live • 12 March 2015 (me) Comprehensive update posted live • 26 August 2010 (me) Comprehensive update posted live • 16 April 2009 (jp) Revision: sequence analysis available on a clinical basis for • 1 May 2006 (me) Comprehensive update posted live • 15 March 2004 (me) Comprehensive update posted live • 24 January 2002 (me) Review posted live • 31 October 2001 (jp) Original submission ## References Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Published Guidelines / Consensus Statements Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available ## Literature Cited A radiograph of the hand of a person with PLOSL demonstrates multiple cyst-like lesions and loss of bone trabeculae. A radiograph shows a well-demarcated cyst-like lesion (arrow) in the talus of a person with PLOSL, age 28 years. T T Brain MRI. High-intensity lesions in the bilateral periventricular white matter on an axial FLAIR image (TR: 8000 ms, TE: 120 ms) Contents of a cyst-like bone lesion. Microscopically, the lesions contain (C) convoluted lipid membrane structures filled with amorphous lipid substance and (F) fat. (B) Bone trabeculae are partially preserved. Scale bar corresponds to 250 μm (Van Gieson).	[ "N Aoki, K Tsuchiya, T Togo, Z Kobayashi, H Uchikado, O Katsuse, K Suzuki, H Fujishiro, T Arai, E Iseki, M Anno, K Kosaka, H Akiyama, Y Hirayasu. Gray matter lesions in Nasu-Hakola disease: a report on three autopsy cases.. Neuropathology. 2011;31:135-43", "M Arıkan, A Yıldırım, G Togral, AB Ekmekçi. Extremity manifestations and surgical treatment for Nasu Hakola disease.. Case Rep Orthop. 2014;2014", "V Bock, A Botturi, P Gaviani, E Lamperti, C Maccagnano, L Piccio, A Silvani, A. Salmaggi. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of the literature.. J Neurol Sci. 2013;326:115-9", "S Carmona, K Zahs, E Wu, K Dakin, J Bras, R Guerreiro. The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders.. Lancet Neurology 2018;17:721-30", "M Cella, C Buonsanti, C Strader, T Kondo, A Salmaggi, M Colonna. Impaired differentiation of osteoclasts in TREM-2-deficient individuals.. J Exp Med 2003;198:645-51", "E Chouery, V Delague, A Bergougnoux, S Koussa, JL Serre, A Mégarbané. Mutations in TREM2 lead to pure early-onset dementia without bone cysts.. Hum Mutat 2008;29:E194-E204", "E Dardiotis, V Siokas, E Pantazi, M Dardioti, D Rikos, G Xiromerisiou, A Markou, D Papadimitriou, M Speletas, GM Hadjigeorgiou. A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature.. Neurobiol Aging. 2017;53:194.e13-194.e22", "RJ Guerreiro, E Lohmann, JM Brás, JR Gibbs, JD Rohrer, N Gurunlian, B Dursun, B Bilgic, H Hanagasi, H Gurvit, M Emre, A Singleton, J Hardy. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.. JAMA Neurol. 2013;70:78-84", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "T Ilonen, P Hakola, M Vanhanen, J Tiihonen. Rorschach assessment of personality functioning in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.. Acta Neuropsychiatr. 2012;24:236-44", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "H Kalimo, P Sourander, O Järvi, P Hakola. Vascular changes and blood-brain barrier damage in the pathogenesis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (membranous lipodystrophy).. Acta Neurol Scand 1994;89:353-61", "I Kitajima, M Kuriyama, F Usuki, S Izumo, M Osame, T Suganuma, F Murata, K Nagamatsu. Nasu-Hakola disease (membranous lipodystrophy). Clinical, histopathological and biochemical studies of three cases.. J Neurol Sci 1989;91:35-52", "HH Klünemann, BH Ridha, L Magy, JR Wherrett, DM Hemelsoet, RW Keen, JL De Bleecker, MN Rossor, J Marienhagen, HE Klein, L Peltonen, J Paloneva. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.. Neurology 2005;64:1502-7", "K Kobayashi, E Kobayashi, K Miyazu, F Muramori, S Hiramatsu, T Aoki, I Nakamura, Y Koshino. Hypothalamic haemorrhage and thalamus degeneration in a case of Nasu-Hakola disease with hallucinatory symptoms and central hypothermia.. Neuropathol Appl Neurobiol 2000;26:98-101", "T Kondo, K Takahashi, N Kohara, Y Takahashi, S Hayashi, H Takahashi, H Matsuo, M Yamazaki, K Inoue, K Miyamoto, T Yamamura. Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms.. Neurology 2002;59:1105-7", "H Konishi, H. Kiyama. Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases.. Front Cell Neurosci. 2018;12:206", "R Kuroda, J Satoh, T Yamamura, T Anezaki, T Terada, K Yamazaki, T Obi, K Mizoguchi. A novel compound heterozygous mutation in the DAP12 gene in a patient with Nasu-Hakola disease.. J Neurol Sci 2007;252:88-91", "LL Lanier. DAP10- and DAP12-associated receptors in innate immunity.. Immunol Rev. 2009;227:150-60", "I Le Ber, A De Septenville, R Guerreiro, J Bras, A Camuzat, P Caroppo, S Lattante, P Couarch, E Kabashi, K Bouya-Ahmed, B Dubois, A Brice. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.. Neurobiol Aging. 2014;35:2419.e23-5", "P Mäkelä, O Järví, P Hakola, P Virtama. Radiologic bone changes of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.. Skeletal Radiol 1982;8:51-4", "T Nasu, Y Tsukahara, K Terayama. A lipid metabolic disease-\"membranous lipodystrophy\"-an autopsy case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues.. Acta Pathol Jpn 1973;23:539-58", "OK Nwawka, R Schneider, M Bansal, DN Mintz, J Lane. Membranous lipodystrophy: skeletal findings on CT and MRI.. Skeletal Radiol 2014;43:1449-55", "MM Painter, Y Atagi, CC Liu, R Rademakers, H Xu, JD Fryer, G Bu. TREM2 in CNS homeostasis and neurodegenerative disease.. Mol Neurodegener. 2015;10:43", "J Paloneva, T Autti, R Raininko, J Partanen, O Salonen, M Puranen, P Hakola, M Haltia. CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts.. Neurology 2001;56:1552-8", "J Paloneva, M Kestilä, J Wu, A Salminen, T Böhling, V Ruotsalainen, P Hakola, AB Bakker, JH Phillips, P Pekkarinen, LL Lanier, T Timonen, L Peltonen. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.. Nat Genet 2000;25:357-61", "J Paloneva, J Mandelin, A Kiialainen, T Bohling, J Prudlo, P Hakola, M Haltia, YT Konttinen, L Peltonen. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.. J Exp Med 2003;198:669-75", "J Paloneva, T Manninen, G Christman, K Hovanes, J Mandelin, R Adolfsson, M Bianchin, T Bird, R Miranda, A Salmaggi, L Tranebjaerg, Y Konttinen, L Peltonen. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype.. Am J Hum Genet 2002;71:656-62", "P Pekkarinen, I Hovatta, P Hakola, O Järvi, M Kestilä, U Lenkkeri, R Adolfsson, G Holmgren, PO Nylander, L Tranebjaerg, JD Terwilliger, J Lönnqvist, L Peltonen. Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13.. Am J Hum Genet 1998;62:362-72", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "JI Satoh, M Yanaizu, Y Tosaki, K Sakai, Y Kino. Targeted sequencing approach to identify genetic mutations in Nasu-Hakola disease.. Intractable Rare Dis Res. 2016;5:269-274", "E Solje, P Hartikainen, M Valori, R Vanninen, J Tiihonen, P Hakola, P Tienari, A Remes. The C9ORF72 expansion does not affect the phenotype in Nasu-Hkola disease with the DAP12 mutation.. Neurobiology of aging 2014;35:1780.e13-1780.e17", "T Takeshita, T Kaminaga, T Tatsumi, Y Hatanaka, S Furui. Regional cerebral blood flow in a patient with Nasu-Hakola disease.. Ann Nucl Med 2005;19:309-12", "JC Thrash, BE Torbett, MJ Carson. Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu-Hakola disease.. Neurochem Res. 2009;34:38-45", "L Tranebjaerg, H Schrader, J Paloneva. Polycystic lipomembranous osteodysplasia. Tidsskr Nor Laegeforen 2000;120:3196", "M Vanhanen, P Hakola, T Ilonen, J Tiihonen. Word list learning in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.. Dement Geriatr Cogn Dis Extra. 2013;3:10-5", "JC Williamson, AJ Larner. Behavioral variant frontotemporal dementia-like syndrome with novel heterozygous TREM2 frameshift mutation.. Alzheimer Dis Assoc Disord. 2019;33:75-76", "K Yamazaki, Y Yoshino, Y Mori, S Ochi, T Yoshida, T Ishimaru, S Ueno. A case of Nasu-Hakola disease without fractures or consanguinity diagnosed using exome sequencing and treated with sodium valproate.. Clin Psychopharmacol Neurosci. 2015;13:324-6" ]	24/1/2002	10/12/2020	16/4/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
plpbp-def	plpbp-def	[ "PLPHP Deficiency", "PROSC Deficiency", "Pyridoxal 5'-Phosphate Homeostasis Protein Deficiency", "Pyridoxal 5'-Phosphate-Binding Protein Deficiency", "PDE-PLPBP", "PLPHP Deficiency", "PROSC Deficiency", "Pyridoxal 5'-Phosphate Homeostasis Protein Deficiency", "Pyridoxal 5'-Phosphate-Binding Protein Deficiency", "PDE-PLPBP", "Pyridoxal phosphate homeostasis protein", "PLPBP", "PLPBP Deficiency" ]	PLPBP Deficiency	Hilal Al-Shekaili, Jolita Ciapaite, Clara van Karnebeek, Izabella Pena	Summary PLPBP deficiency is a treatable form of vitamin B The diagnosis of PLPBP deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in When prenatal testing has not been performed on a pregnancy at risk, prompt diagnostic evaluation of the newborn is essential. While results of molecular genetic testing are pending, the options for management are either: (1) treatment with PN or PLP (whichever was effective in the affected sib); or (2) clinical and EEG monitoring with initiation of PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy. PLPBP deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus clinical diagnostic criteria for PLPBP deficiency have been published. PLPBP deficiency should be suspected in individuals with the following clinical findings, imaging findings, clinical response to a standardized vitamin B Difficult-to-treat seizures irrespective of a history of fetal distress Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) Infants with a history of fetal distress and microcephaly Individuals with a history of partial or complete response of seizures to pyridoxine (PN) or pyridoxal 5'-phosphate (PLP) Seizure recurrence following discontinuation of vitamin B Developmental delay and/or intellectual disability Mitochondrial encephalopathy-like presentation with lactic acidemia Movement disorder (opisthotonos, oculogyric crises) at age two months (one child) [ Epileptic seizures (different types) starting at age one to 14 months partially responsive to anti-seizure medications (five individuals) [ Epileptic spasms without hypsarrhythmia at age four months (one individual) [ The following brain MRI findings have been noted in individuals with PLPBP deficiency [ White matter abnormalities (T Cortical atrophy and simplified cortical gyral pattern Periventricular cysts Thinning of the corpus callosum (particularly of the posterior corpus callosum) A standardized vitamin B Note: The classic approach to confirm the clinical diagnosis of the different forms of pyridoxine-dependent epilepsy (PDE) was based on withdrawal of anti-seizure medications, followed by withdrawal of daily vitamin B Stages of a standardized vitamin B Based on Note: (1) Because the first administration of either PN or PLP may lead to apnea or respiratory arrest, the vitamin B Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: (1) Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. (2) Families segregating pathogenic variants associated with autosomal recessive epileptic encephalopathy may have a history of infertility and miscarriage [ The diagnosis of PLPBP deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see For an introduction to multigene panels click When the diagnosis of PLPBP deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PLPBP Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All variants reported to date have been detected by sequence analysis [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Difficult-to-treat seizures irrespective of a history of fetal distress • Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) • Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) • Infants with a history of fetal distress and microcephaly • Individuals with a history of partial or complete response of seizures to pyridoxine (PN) or pyridoxal 5'-phosphate (PLP) • Seizure recurrence following discontinuation of vitamin B • Developmental delay and/or intellectual disability • Mitochondrial encephalopathy-like presentation with lactic acidemia • Movement disorder (opisthotonos, oculogyric crises) at age two months (one child) [ • Epileptic seizures (different types) starting at age one to 14 months partially responsive to anti-seizure medications (five individuals) [ • Epileptic spasms without hypsarrhythmia at age four months (one individual) [ • White matter abnormalities (T • Cortical atrophy and simplified cortical gyral pattern • Periventricular cysts • Thinning of the corpus callosum (particularly of the posterior corpus callosum) ## Suggestive Findings PLPBP deficiency should be suspected in individuals with the following clinical findings, imaging findings, clinical response to a standardized vitamin B Difficult-to-treat seizures irrespective of a history of fetal distress Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) Infants with a history of fetal distress and microcephaly Individuals with a history of partial or complete response of seizures to pyridoxine (PN) or pyridoxal 5'-phosphate (PLP) Seizure recurrence following discontinuation of vitamin B Developmental delay and/or intellectual disability Mitochondrial encephalopathy-like presentation with lactic acidemia Movement disorder (opisthotonos, oculogyric crises) at age two months (one child) [ Epileptic seizures (different types) starting at age one to 14 months partially responsive to anti-seizure medications (five individuals) [ Epileptic spasms without hypsarrhythmia at age four months (one individual) [ The following brain MRI findings have been noted in individuals with PLPBP deficiency [ White matter abnormalities (T Cortical atrophy and simplified cortical gyral pattern Periventricular cysts Thinning of the corpus callosum (particularly of the posterior corpus callosum) A standardized vitamin B Note: The classic approach to confirm the clinical diagnosis of the different forms of pyridoxine-dependent epilepsy (PDE) was based on withdrawal of anti-seizure medications, followed by withdrawal of daily vitamin B Stages of a standardized vitamin B Based on Note: (1) Because the first administration of either PN or PLP may lead to apnea or respiratory arrest, the vitamin B Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: (1) Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. (2) Families segregating pathogenic variants associated with autosomal recessive epileptic encephalopathy may have a history of infertility and miscarriage [ • Difficult-to-treat seizures irrespective of a history of fetal distress • Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) • Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) • Infants with a history of fetal distress and microcephaly • Individuals with a history of partial or complete response of seizures to pyridoxine (PN) or pyridoxal 5'-phosphate (PLP) • Seizure recurrence following discontinuation of vitamin B • Developmental delay and/or intellectual disability • Mitochondrial encephalopathy-like presentation with lactic acidemia • Movement disorder (opisthotonos, oculogyric crises) at age two months (one child) [ • Epileptic seizures (different types) starting at age one to 14 months partially responsive to anti-seizure medications (five individuals) [ • Epileptic spasms without hypsarrhythmia at age four months (one individual) [ • White matter abnormalities (T • Cortical atrophy and simplified cortical gyral pattern • Periventricular cysts • Thinning of the corpus callosum (particularly of the posterior corpus callosum) ## Clinical Findings Difficult-to-treat seizures irrespective of a history of fetal distress Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) Infants with a history of fetal distress and microcephaly Individuals with a history of partial or complete response of seizures to pyridoxine (PN) or pyridoxal 5'-phosphate (PLP) Seizure recurrence following discontinuation of vitamin B Developmental delay and/or intellectual disability Mitochondrial encephalopathy-like presentation with lactic acidemia Movement disorder (opisthotonos, oculogyric crises) at age two months (one child) [ Epileptic seizures (different types) starting at age one to 14 months partially responsive to anti-seizure medications (five individuals) [ Epileptic spasms without hypsarrhythmia at age four months (one individual) [ • Difficult-to-treat seizures irrespective of a history of fetal distress • Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) • Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) • Infants with a history of fetal distress and microcephaly • Individuals with a history of partial or complete response of seizures to pyridoxine (PN) or pyridoxal 5'-phosphate (PLP) • Seizure recurrence following discontinuation of vitamin B • Developmental delay and/or intellectual disability • Mitochondrial encephalopathy-like presentation with lactic acidemia • Movement disorder (opisthotonos, oculogyric crises) at age two months (one child) [ • Epileptic seizures (different types) starting at age one to 14 months partially responsive to anti-seizure medications (five individuals) [ • Epileptic spasms without hypsarrhythmia at age four months (one individual) [ ## Imaging Findings The following brain MRI findings have been noted in individuals with PLPBP deficiency [ White matter abnormalities (T Cortical atrophy and simplified cortical gyral pattern Periventricular cysts Thinning of the corpus callosum (particularly of the posterior corpus callosum) • White matter abnormalities (T • Cortical atrophy and simplified cortical gyral pattern • Periventricular cysts • Thinning of the corpus callosum (particularly of the posterior corpus callosum) ## Standardized Vitamin B A standardized vitamin B Note: The classic approach to confirm the clinical diagnosis of the different forms of pyridoxine-dependent epilepsy (PDE) was based on withdrawal of anti-seizure medications, followed by withdrawal of daily vitamin B Stages of a standardized vitamin B Based on Note: (1) Because the first administration of either PN or PLP may lead to apnea or respiratory arrest, the vitamin B ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: (1) Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. (2) Families segregating pathogenic variants associated with autosomal recessive epileptic encephalopathy may have a history of infertility and miscarriage [ ## Establishing the Diagnosis The diagnosis of PLPBP deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see For an introduction to multigene panels click When the diagnosis of PLPBP deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PLPBP Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All variants reported to date have been detected by sequence analysis [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of PLPBP deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PLPBP Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All variants reported to date have been detected by sequence analysis [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics PLPBP deficiency, first identified in 2016, causes a rare, treatable form of vitamin B To date, 56 individuals have been identified with biallelic pathogenic variants in In PLPBP deficiency, seizures that have not been responsive – or only partly responsive – to anti-seizure medications (ASMs) show an immediate positive response to vitamin B Classic PLPBP deficiency is defined as neonatal onset (i.e., within the first 28 days after birth). Birth is often at term; however, preterm to late preterm birth is reported. Perinatal distress, reported in some instances, included abnormal intrauterine movements and fetal distress, suggesting fetal seizures [ The various types of seizures included tonic, clonic, generalized tonic-clonic, myoclonic, lip smacking, and/or grimacing. Initial EEG recordings vary from normal to abnormal, including burst suppression, reduced background activity, focal discharges, and multifocal spikes. In most instances, seizures that were nonresponsive or only partially responsive to ASMs responded well to PN or PLP. In a few instances, seizure control improved with discontinuation of PN and initiation of PLP [ Withdrawal of PN or PLP (either incidentally or for diagnostic purposes before establishing the diagnosis with molecular genetic testing) led to reoccurrence of seizures, highlighting vitamin B Breakthrough seizures during illness/fever are fairly common. Head circumference at birth varies widely from low (<10%) to normal. While progressive microcephaly is common, it is not the rule [ Some individuals had minor dysmorphic features [ In one individual with an early-onset seizure disorder (at age 15 days), PLPBP deficiency was not diagnosed until age 16 years. His seizures were relatively well controlled with ASMs; he had a mild learning disability. Prior to the diagnosis of PLPBP deficiency and initiation of PN treatment, he experienced excessive seizure clusters and intermittent states of anxiety, suggesting that these may be typical features of untreated PLPBP deficiency in adolescents [ Late-onset PLPBP deficiency is defined as onset after the neonatal period (i.e., after age 28 days). To date six individuals (14% of affected individuals) have been reported with late-onset PLPBP deficiency, five with seizures [ At age two months, the child without seizures presented with a movement disorder (opisthotonos, oculogyric crisis), findings that resembled At age four months, a girl presented with paroxysmal episodes of abnormal multidirectional eye-head movements, followed at age five months by almost daily epileptic spasms without hypsarrhythmia [ At age 14 months, a boy with normal development and a normal brain MRI presented with recurring prolonged myoclonic seizures, after which speech regression was observed [ At age three months, a boy presented with focal and generalized tonic seizures and no neurologic abnormalities [ Summary of Nonspecific Biochemical Findings Reported in PLPBP Deficiency Based on the review in CSF = cerebrospinal fluid Unless otherwise noted, these results are from samples obtained before initiation of vitamin B Refers to number of individuals with specific finding / total number of individuals in whom the analyte was measured Since the number of individuals with PLPBP deficiency is small, it is difficult to establish true genotype-phenotype correlations. Nonetheless, the following observations about vitamin B Truncating Missense Mild-to-moderate phenotypes may be associated with missense variants that decrease, but do not abolish, PLP binding or protein stability. Currently, there are no data on the prevalence of PLPBP deficiency. To date, a total of 56 individuals with PLPBP deficiency have been reported in more than 15 publications [ • Head circumference at birth varies widely from low (<10%) to normal. While progressive microcephaly is common, it is not the rule [ • Some individuals had minor dysmorphic features [ • In one individual with an early-onset seizure disorder (at age 15 days), PLPBP deficiency was not diagnosed until age 16 years. His seizures were relatively well controlled with ASMs; he had a mild learning disability. Prior to the diagnosis of PLPBP deficiency and initiation of PN treatment, he experienced excessive seizure clusters and intermittent states of anxiety, suggesting that these may be typical features of untreated PLPBP deficiency in adolescents [ • At age two months, the child without seizures presented with a movement disorder (opisthotonos, oculogyric crisis), findings that resembled • At age four months, a girl presented with paroxysmal episodes of abnormal multidirectional eye-head movements, followed at age five months by almost daily epileptic spasms without hypsarrhythmia [ • At age 14 months, a boy with normal development and a normal brain MRI presented with recurring prolonged myoclonic seizures, after which speech regression was observed [ • At age three months, a boy presented with focal and generalized tonic seizures and no neurologic abnormalities [ • Truncating • Missense ## Clinical Description PLPBP deficiency, first identified in 2016, causes a rare, treatable form of vitamin B To date, 56 individuals have been identified with biallelic pathogenic variants in In PLPBP deficiency, seizures that have not been responsive – or only partly responsive – to anti-seizure medications (ASMs) show an immediate positive response to vitamin B Classic PLPBP deficiency is defined as neonatal onset (i.e., within the first 28 days after birth). Birth is often at term; however, preterm to late preterm birth is reported. Perinatal distress, reported in some instances, included abnormal intrauterine movements and fetal distress, suggesting fetal seizures [ The various types of seizures included tonic, clonic, generalized tonic-clonic, myoclonic, lip smacking, and/or grimacing. Initial EEG recordings vary from normal to abnormal, including burst suppression, reduced background activity, focal discharges, and multifocal spikes. In most instances, seizures that were nonresponsive or only partially responsive to ASMs responded well to PN or PLP. In a few instances, seizure control improved with discontinuation of PN and initiation of PLP [ Withdrawal of PN or PLP (either incidentally or for diagnostic purposes before establishing the diagnosis with molecular genetic testing) led to reoccurrence of seizures, highlighting vitamin B Breakthrough seizures during illness/fever are fairly common. Head circumference at birth varies widely from low (<10%) to normal. While progressive microcephaly is common, it is not the rule [ Some individuals had minor dysmorphic features [ In one individual with an early-onset seizure disorder (at age 15 days), PLPBP deficiency was not diagnosed until age 16 years. His seizures were relatively well controlled with ASMs; he had a mild learning disability. Prior to the diagnosis of PLPBP deficiency and initiation of PN treatment, he experienced excessive seizure clusters and intermittent states of anxiety, suggesting that these may be typical features of untreated PLPBP deficiency in adolescents [ Late-onset PLPBP deficiency is defined as onset after the neonatal period (i.e., after age 28 days). To date six individuals (14% of affected individuals) have been reported with late-onset PLPBP deficiency, five with seizures [ At age two months, the child without seizures presented with a movement disorder (opisthotonos, oculogyric crisis), findings that resembled At age four months, a girl presented with paroxysmal episodes of abnormal multidirectional eye-head movements, followed at age five months by almost daily epileptic spasms without hypsarrhythmia [ At age 14 months, a boy with normal development and a normal brain MRI presented with recurring prolonged myoclonic seizures, after which speech regression was observed [ At age three months, a boy presented with focal and generalized tonic seizures and no neurologic abnormalities [ Summary of Nonspecific Biochemical Findings Reported in PLPBP Deficiency Based on the review in CSF = cerebrospinal fluid Unless otherwise noted, these results are from samples obtained before initiation of vitamin B Refers to number of individuals with specific finding / total number of individuals in whom the analyte was measured • Head circumference at birth varies widely from low (<10%) to normal. While progressive microcephaly is common, it is not the rule [ • Some individuals had minor dysmorphic features [ • In one individual with an early-onset seizure disorder (at age 15 days), PLPBP deficiency was not diagnosed until age 16 years. His seizures were relatively well controlled with ASMs; he had a mild learning disability. Prior to the diagnosis of PLPBP deficiency and initiation of PN treatment, he experienced excessive seizure clusters and intermittent states of anxiety, suggesting that these may be typical features of untreated PLPBP deficiency in adolescents [ • At age two months, the child without seizures presented with a movement disorder (opisthotonos, oculogyric crisis), findings that resembled • At age four months, a girl presented with paroxysmal episodes of abnormal multidirectional eye-head movements, followed at age five months by almost daily epileptic spasms without hypsarrhythmia [ • At age 14 months, a boy with normal development and a normal brain MRI presented with recurring prolonged myoclonic seizures, after which speech regression was observed [ • At age three months, a boy presented with focal and generalized tonic seizures and no neurologic abnormalities [ ## Classic PLPBP Deficiency Classic PLPBP deficiency is defined as neonatal onset (i.e., within the first 28 days after birth). Birth is often at term; however, preterm to late preterm birth is reported. Perinatal distress, reported in some instances, included abnormal intrauterine movements and fetal distress, suggesting fetal seizures [ The various types of seizures included tonic, clonic, generalized tonic-clonic, myoclonic, lip smacking, and/or grimacing. Initial EEG recordings vary from normal to abnormal, including burst suppression, reduced background activity, focal discharges, and multifocal spikes. In most instances, seizures that were nonresponsive or only partially responsive to ASMs responded well to PN or PLP. In a few instances, seizure control improved with discontinuation of PN and initiation of PLP [ Withdrawal of PN or PLP (either incidentally or for diagnostic purposes before establishing the diagnosis with molecular genetic testing) led to reoccurrence of seizures, highlighting vitamin B Breakthrough seizures during illness/fever are fairly common. Head circumference at birth varies widely from low (<10%) to normal. While progressive microcephaly is common, it is not the rule [ Some individuals had minor dysmorphic features [ In one individual with an early-onset seizure disorder (at age 15 days), PLPBP deficiency was not diagnosed until age 16 years. His seizures were relatively well controlled with ASMs; he had a mild learning disability. Prior to the diagnosis of PLPBP deficiency and initiation of PN treatment, he experienced excessive seizure clusters and intermittent states of anxiety, suggesting that these may be typical features of untreated PLPBP deficiency in adolescents [ • Head circumference at birth varies widely from low (<10%) to normal. While progressive microcephaly is common, it is not the rule [ • Some individuals had minor dysmorphic features [ • In one individual with an early-onset seizure disorder (at age 15 days), PLPBP deficiency was not diagnosed until age 16 years. His seizures were relatively well controlled with ASMs; he had a mild learning disability. Prior to the diagnosis of PLPBP deficiency and initiation of PN treatment, he experienced excessive seizure clusters and intermittent states of anxiety, suggesting that these may be typical features of untreated PLPBP deficiency in adolescents [ ## Late-Onset PLPBP Deficiency Late-onset PLPBP deficiency is defined as onset after the neonatal period (i.e., after age 28 days). To date six individuals (14% of affected individuals) have been reported with late-onset PLPBP deficiency, five with seizures [ At age two months, the child without seizures presented with a movement disorder (opisthotonos, oculogyric crisis), findings that resembled At age four months, a girl presented with paroxysmal episodes of abnormal multidirectional eye-head movements, followed at age five months by almost daily epileptic spasms without hypsarrhythmia [ At age 14 months, a boy with normal development and a normal brain MRI presented with recurring prolonged myoclonic seizures, after which speech regression was observed [ At age three months, a boy presented with focal and generalized tonic seizures and no neurologic abnormalities [ • At age two months, the child without seizures presented with a movement disorder (opisthotonos, oculogyric crisis), findings that resembled • At age four months, a girl presented with paroxysmal episodes of abnormal multidirectional eye-head movements, followed at age five months by almost daily epileptic spasms without hypsarrhythmia [ • At age 14 months, a boy with normal development and a normal brain MRI presented with recurring prolonged myoclonic seizures, after which speech regression was observed [ • At age three months, a boy presented with focal and generalized tonic seizures and no neurologic abnormalities [ ## Other Summary of Nonspecific Biochemical Findings Reported in PLPBP Deficiency Based on the review in CSF = cerebrospinal fluid Unless otherwise noted, these results are from samples obtained before initiation of vitamin B Refers to number of individuals with specific finding / total number of individuals in whom the analyte was measured ## Genotype-Phenotype Correlations Since the number of individuals with PLPBP deficiency is small, it is difficult to establish true genotype-phenotype correlations. Nonetheless, the following observations about vitamin B Truncating Missense Mild-to-moderate phenotypes may be associated with missense variants that decrease, but do not abolish, PLP binding or protein stability. • Truncating • Missense ## Nomenclature ## Prevalence Currently, there are no data on the prevalence of PLPBP deficiency. To date, a total of 56 individuals with PLPBP deficiency have been reported in more than 15 publications [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis In addition to other vitamin B Early targeted therapy with PN or PLP is critical in individuals with a vitamin B Prematurity has been reported in the vitamin B See Other Vitamin B ↑ levels of α-AASA irrespective of treatment w/PN or PLP May also have ↑ levels of pipecolic acid Low PLP levels in plasma & CSF prior to vitamin B Although most newborns have szs soon after birth, some have late-onset szs (i.e., age >2 mos or as late as adolescence). ID is common, w/more favorable outcomes observed in those w/late-onset szs. ↓ CSF & plasma levels of PLP when measured prior to administration of PN or PLP ↑ CSF glycine ↑ urinary vanillactic acid. ↑ plasma PM, ↑ PM:PA ratio. The vast majority of infants w/classic PNPO deficiency have szs before age 2 wks, w/30% presenting on day 1 of life. As w/other forms of vitamin B Motor delay has been reported, likely due to long periods of poor sz control before introduction of PLP/PN treatment. ~50% of persons develop szs. PN leads to cessation &/or prevention of szs (esp during infection) Szs usually manifest after neonatal period, may occur w/febrile infections, & may respond to common ASMs. Persons may have ID or normal intellectual ability. Clinical signs may be recognized between birth & age 6 mos & resemble rickets. Prior to availability of enzyme replacement therapy, ~50% succumbed to respiratory failure caused by undermineralization of ribs. Intractable szs may precede biochemical or radiographic manifestations of rickets. Early-onset metabolic epileptic encephalopathy Severely impaired intellectual development w/absent speech & spastic tetraplegia Microcephaly, cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, & white matter abnormalities. May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy Szs are tonic & often asymmetric. α-AASA = alpha-aminoadipic semialdehyde; AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; P5C = pyrroline-5-carboxylate; PA = pyridoxic acid; PLP = pyridoxal 5'-phosphate; PM = pyridoxamine; PN = pyridoxine; sz = seizure; XL = X-linked Epilepsies that respond to treatment with vitamin B See Mills et al, "Vitamin B6 Metabolism and Inborn Errors," in Epilepsies that may respond to treatment with vitamin B Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. • ↑ levels of α-AASA irrespective of treatment w/PN or PLP • May also have ↑ levels of pipecolic acid • Low PLP levels in plasma & CSF prior to vitamin B • Although most newborns have szs soon after birth, some have late-onset szs (i.e., age >2 mos or as late as adolescence). • ID is common, w/more favorable outcomes observed in those w/late-onset szs. • ↓ CSF & plasma levels of PLP when measured prior to administration of PN or PLP • ↑ CSF glycine • ↑ urinary vanillactic acid. • ↑ plasma PM, ↑ PM:PA ratio. • The vast majority of infants w/classic PNPO deficiency have szs before age 2 wks, w/30% presenting on day 1 of life. • As w/other forms of vitamin B • Motor delay has been reported, likely due to long periods of poor sz control before introduction of PLP/PN treatment. • ~50% of persons develop szs. • PN leads to cessation &/or prevention of szs (esp during infection) • Szs usually manifest after neonatal period, may occur w/febrile infections, & may respond to common ASMs. • Persons may have ID or normal intellectual ability. • Clinical signs may be recognized between birth & age 6 mos & resemble rickets. • Prior to availability of enzyme replacement therapy, ~50% succumbed to respiratory failure caused by undermineralization of ribs. • Intractable szs may precede biochemical or radiographic manifestations of rickets. • Early-onset metabolic epileptic encephalopathy • Severely impaired intellectual development w/absent speech & spastic tetraplegia • Microcephaly, cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, & white matter abnormalities. • May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy • Szs are tonic & often asymmetric. ## Vitamin B Prematurity has been reported in the vitamin B See Other Vitamin B ↑ levels of α-AASA irrespective of treatment w/PN or PLP May also have ↑ levels of pipecolic acid Low PLP levels in plasma & CSF prior to vitamin B Although most newborns have szs soon after birth, some have late-onset szs (i.e., age >2 mos or as late as adolescence). ID is common, w/more favorable outcomes observed in those w/late-onset szs. ↓ CSF & plasma levels of PLP when measured prior to administration of PN or PLP ↑ CSF glycine ↑ urinary vanillactic acid. ↑ plasma PM, ↑ PM:PA ratio. The vast majority of infants w/classic PNPO deficiency have szs before age 2 wks, w/30% presenting on day 1 of life. As w/other forms of vitamin B Motor delay has been reported, likely due to long periods of poor sz control before introduction of PLP/PN treatment. ~50% of persons develop szs. PN leads to cessation &/or prevention of szs (esp during infection) Szs usually manifest after neonatal period, may occur w/febrile infections, & may respond to common ASMs. Persons may have ID or normal intellectual ability. Clinical signs may be recognized between birth & age 6 mos & resemble rickets. Prior to availability of enzyme replacement therapy, ~50% succumbed to respiratory failure caused by undermineralization of ribs. Intractable szs may precede biochemical or radiographic manifestations of rickets. Early-onset metabolic epileptic encephalopathy Severely impaired intellectual development w/absent speech & spastic tetraplegia Microcephaly, cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, & white matter abnormalities. May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy Szs are tonic & often asymmetric. α-AASA = alpha-aminoadipic semialdehyde; AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; P5C = pyrroline-5-carboxylate; PA = pyridoxic acid; PLP = pyridoxal 5'-phosphate; PM = pyridoxamine; PN = pyridoxine; sz = seizure; XL = X-linked Epilepsies that respond to treatment with vitamin B See Mills et al, "Vitamin B6 Metabolism and Inborn Errors," in Epilepsies that may respond to treatment with vitamin B Perinatal and infantile hypophosphatasia are typically inherited in an autosomal recessive manner. • ↑ levels of α-AASA irrespective of treatment w/PN or PLP • May also have ↑ levels of pipecolic acid • Low PLP levels in plasma & CSF prior to vitamin B • Although most newborns have szs soon after birth, some have late-onset szs (i.e., age >2 mos or as late as adolescence). • ID is common, w/more favorable outcomes observed in those w/late-onset szs. • ↓ CSF & plasma levels of PLP when measured prior to administration of PN or PLP • ↑ CSF glycine • ↑ urinary vanillactic acid. • ↑ plasma PM, ↑ PM:PA ratio. • The vast majority of infants w/classic PNPO deficiency have szs before age 2 wks, w/30% presenting on day 1 of life. • As w/other forms of vitamin B • Motor delay has been reported, likely due to long periods of poor sz control before introduction of PLP/PN treatment. • ~50% of persons develop szs. • PN leads to cessation &/or prevention of szs (esp during infection) • Szs usually manifest after neonatal period, may occur w/febrile infections, & may respond to common ASMs. • Persons may have ID or normal intellectual ability. • Clinical signs may be recognized between birth & age 6 mos & resemble rickets. • Prior to availability of enzyme replacement therapy, ~50% succumbed to respiratory failure caused by undermineralization of ribs. • Intractable szs may precede biochemical or radiographic manifestations of rickets. • Early-onset metabolic epileptic encephalopathy • Severely impaired intellectual development w/absent speech & spastic tetraplegia • Microcephaly, cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, & white matter abnormalities. • May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy • Szs are tonic & often asymmetric. ## Management No clinical practice guidelines for PLPBP deficiency have been published. To establish the extent of disease and needs in an individual diagnosed with PLPBP deficiency, the following evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Full neurologic examination, including evaluation of eye movements and muscle tone (for hypotonia or rigidity) and description of seizure semiology EEG, including sleep and wake cycles (preferably with a recording time of two hours) Physical examination, including measurement of weight, length, and head circumference Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PLPBP deficiency in order to facilitate medical and personal decision making To support the family of an individual diagnosed with PLPBP deficiency, review of the following options is recommended: Use of community or Social work involvement for parental support Home nursing referral (if needed) Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family There is no cure for PLPBP deficiency. Individuals with PLPBP deficiency require pharmacologic treatment with vitamin B PN is the first-line therapy. The majority of individuals have a favorable response to PN: 79% were seizure free and 10% had good seizure control [ When the therapy in about 25% of these previously reported individuals was changed from PN to PLP due either to suspected Recommended Daily Oral Dose of Pyridoxine Data from Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled to a maximum dose of 60 mg/kg/day (in children) or 500 mg/day (in adolescents and adults) for up to three days [ Individuals clinically responsive to PN should receive 30 mg/kg/day of PN intravenously or orally in three to four single doses (up to a total dose of 300 mg/day or, if needed, 500 mg/day) [ Nearly 57% of reported individuals required additional anti-seizure medications (ASMs) during breakthrough seizures (often described with fever) [ PLP is only available as a nonlicensed compound outside of Asia. Recent studies have raised major concerns about the dose accuracy, stability, and safety of food-grade PLP supplements [ Because PLP is a photosensitive compound that can rapidly degrade when in solution (which could reduce its effectiveness and produce unwanted byproducts), it should be dissolved immediately prior to administration to avoid buildup of photochemical degradation products. Another concern is that PLP content in a number of dietary supplements differed from the expected amount, reflecting inconsistencies in PLP dose accuracy. In a recent report, three individuals with PLP-dependent seizures experienced clinical complications (the most serious of which was status epilepticus) due to food supplement quality issues and possible PLP intoxication [ PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ Because of this reported toxicity, it might be reasonable to avoid high doses of PLP by adding ASMs in those individuals who do not become seizure free or who do not stay seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PLPBP deficiency. Bleeding was reported in one boy with PNPO deficiency who also had mild Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP [ D-cycloserine can act as a PN antagonist and increases renal excretion of PN [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. Absence of seizures in an individual treated with PN precludes a change to PLP. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). Supportive care often includes specialists in multiple disciplines, including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to pharmacologic treatment and supportive care, and the emergence of new manifestations, see Recommended Surveillance for Individuals with PLPBP Deficiency 1st yr of life: every 3-6 mos Children & adults: every 3-12 mos 1st yr of life: every 3-6 mos Thereafter: every 6 mos OR not required in those who are seizure free Age <10 yrs: transaminases every 3-6 mos If transaminases are >3x normal, also assess clotting factors Annually (or more frequently as needed) Age >4 yrs: incl elastography Children age <6 yrs: every 4-6 mos Children age >6 yrs: annually PLP = pyridoxal 5'-phosphate; PN = pyridoxine Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbitone) can cause a low plasma concentration of PLP [ PLP interacts with various small molecules. See Targeted Therapies, Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected Note: At least one newborn at risk for Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy See As recurrence risk for couples who have had a child with PLPBP deficiency is 25%, there has been discussion about the utility of empiric supplementation of PN during pregnancies in women carrying an at-risk fetus. In contrast to reports on PN supplementation in pregnancies at risk for Search • Full neurologic examination, including evaluation of eye movements and muscle tone (for hypotonia or rigidity) and description of seizure semiology • EEG, including sleep and wake cycles (preferably with a recording time of two hours) • Physical examination, including measurement of weight, length, and head circumference • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PLPBP deficiency in order to facilitate medical and personal decision making • Use of community or • Social work involvement for parental support • Home nursing referral (if needed) • Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family • Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ • One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • 1st yr of life: every 3-6 mos • Children & adults: every 3-12 mos • 1st yr of life: every 3-6 mos • Thereafter: every 6 mos OR not required in those who are seizure free • Age <10 yrs: transaminases every 3-6 mos • If transaminases are >3x normal, also assess clotting factors • Annually (or more frequently as needed) • Age >4 yrs: incl elastography • Children age <6 yrs: every 4-6 mos • Children age >6 yrs: annually • Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected • Note: At least one newborn at risk for • Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PLPBP deficiency, the following evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Full neurologic examination, including evaluation of eye movements and muscle tone (for hypotonia or rigidity) and description of seizure semiology EEG, including sleep and wake cycles (preferably with a recording time of two hours) Physical examination, including measurement of weight, length, and head circumference Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PLPBP deficiency in order to facilitate medical and personal decision making To support the family of an individual diagnosed with PLPBP deficiency, review of the following options is recommended: Use of community or Social work involvement for parental support Home nursing referral (if needed) Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family • Full neurologic examination, including evaluation of eye movements and muscle tone (for hypotonia or rigidity) and description of seizure semiology • EEG, including sleep and wake cycles (preferably with a recording time of two hours) • Physical examination, including measurement of weight, length, and head circumference • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PLPBP deficiency in order to facilitate medical and personal decision making • Use of community or • Social work involvement for parental support • Home nursing referral (if needed) • Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family ## Treatment of Manifestations There is no cure for PLPBP deficiency. Individuals with PLPBP deficiency require pharmacologic treatment with vitamin B PN is the first-line therapy. The majority of individuals have a favorable response to PN: 79% were seizure free and 10% had good seizure control [ When the therapy in about 25% of these previously reported individuals was changed from PN to PLP due either to suspected Recommended Daily Oral Dose of Pyridoxine Data from Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled to a maximum dose of 60 mg/kg/day (in children) or 500 mg/day (in adolescents and adults) for up to three days [ Individuals clinically responsive to PN should receive 30 mg/kg/day of PN intravenously or orally in three to four single doses (up to a total dose of 300 mg/day or, if needed, 500 mg/day) [ Nearly 57% of reported individuals required additional anti-seizure medications (ASMs) during breakthrough seizures (often described with fever) [ PLP is only available as a nonlicensed compound outside of Asia. Recent studies have raised major concerns about the dose accuracy, stability, and safety of food-grade PLP supplements [ Because PLP is a photosensitive compound that can rapidly degrade when in solution (which could reduce its effectiveness and produce unwanted byproducts), it should be dissolved immediately prior to administration to avoid buildup of photochemical degradation products. Another concern is that PLP content in a number of dietary supplements differed from the expected amount, reflecting inconsistencies in PLP dose accuracy. In a recent report, three individuals with PLP-dependent seizures experienced clinical complications (the most serious of which was status epilepticus) due to food supplement quality issues and possible PLP intoxication [ PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ Because of this reported toxicity, it might be reasonable to avoid high doses of PLP by adding ASMs in those individuals who do not become seizure free or who do not stay seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PLPBP deficiency. Bleeding was reported in one boy with PNPO deficiency who also had mild Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP [ D-cycloserine can act as a PN antagonist and increases renal excretion of PN [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. Absence of seizures in an individual treated with PN precludes a change to PLP. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). Supportive care often includes specialists in multiple disciplines, including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ • One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Targeted Therapies Individuals with PLPBP deficiency require pharmacologic treatment with vitamin B PN is the first-line therapy. The majority of individuals have a favorable response to PN: 79% were seizure free and 10% had good seizure control [ When the therapy in about 25% of these previously reported individuals was changed from PN to PLP due either to suspected Recommended Daily Oral Dose of Pyridoxine Data from Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled to a maximum dose of 60 mg/kg/day (in children) or 500 mg/day (in adolescents and adults) for up to three days [ Individuals clinically responsive to PN should receive 30 mg/kg/day of PN intravenously or orally in three to four single doses (up to a total dose of 300 mg/day or, if needed, 500 mg/day) [ Nearly 57% of reported individuals required additional anti-seizure medications (ASMs) during breakthrough seizures (often described with fever) [ PLP is only available as a nonlicensed compound outside of Asia. Recent studies have raised major concerns about the dose accuracy, stability, and safety of food-grade PLP supplements [ Because PLP is a photosensitive compound that can rapidly degrade when in solution (which could reduce its effectiveness and produce unwanted byproducts), it should be dissolved immediately prior to administration to avoid buildup of photochemical degradation products. Another concern is that PLP content in a number of dietary supplements differed from the expected amount, reflecting inconsistencies in PLP dose accuracy. In a recent report, three individuals with PLP-dependent seizures experienced clinical complications (the most serious of which was status epilepticus) due to food supplement quality issues and possible PLP intoxication [ PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ Because of this reported toxicity, it might be reasonable to avoid high doses of PLP by adding ASMs in those individuals who do not become seizure free or who do not stay seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PLPBP deficiency. Bleeding was reported in one boy with PNPO deficiency who also had mild Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP [ D-cycloserine can act as a PN antagonist and increases renal excretion of PN [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. Absence of seizures in an individual treated with PN precludes a change to PLP. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). • Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ • One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ ## Recommended Daily Oral Dose of Pyridoxine Data from Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled to a maximum dose of 60 mg/kg/day (in children) or 500 mg/day (in adolescents and adults) for up to three days [ Individuals clinically responsive to PN should receive 30 mg/kg/day of PN intravenously or orally in three to four single doses (up to a total dose of 300 mg/day or, if needed, 500 mg/day) [ Nearly 57% of reported individuals required additional anti-seizure medications (ASMs) during breakthrough seizures (often described with fever) [ ## PLP is only available as a nonlicensed compound outside of Asia. Recent studies have raised major concerns about the dose accuracy, stability, and safety of food-grade PLP supplements [ Because PLP is a photosensitive compound that can rapidly degrade when in solution (which could reduce its effectiveness and produce unwanted byproducts), it should be dissolved immediately prior to administration to avoid buildup of photochemical degradation products. Another concern is that PLP content in a number of dietary supplements differed from the expected amount, reflecting inconsistencies in PLP dose accuracy. In a recent report, three individuals with PLP-dependent seizures experienced clinical complications (the most serious of which was status epilepticus) due to food supplement quality issues and possible PLP intoxication [ PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ Because of this reported toxicity, it might be reasonable to avoid high doses of PLP by adding ASMs in those individuals who do not become seizure free or who do not stay seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PLPBP deficiency. Bleeding was reported in one boy with PNPO deficiency who also had mild • Two individuals with unstable epilepsy had liver cirrhosis at ages four years and eight years, respectively, following long-term use of PLP in doses ranging from 50-100 mg/kg/day [ • One individual age 15 years underwent liver transplantation because of hepatocellular carcinoma [ ## Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP [ D-cycloserine can act as a PN antagonist and increases renal excretion of PN [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PLPBP deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ ## Absence of seizures in an individual treated with PN precludes a change to PLP. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). ## Supportive Care Supportive care often includes specialists in multiple disciplines, including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## ## Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to pharmacologic treatment and supportive care, and the emergence of new manifestations, see Recommended Surveillance for Individuals with PLPBP Deficiency 1st yr of life: every 3-6 mos Children & adults: every 3-12 mos 1st yr of life: every 3-6 mos Thereafter: every 6 mos OR not required in those who are seizure free Age <10 yrs: transaminases every 3-6 mos If transaminases are >3x normal, also assess clotting factors Annually (or more frequently as needed) Age >4 yrs: incl elastography Children age <6 yrs: every 4-6 mos Children age >6 yrs: annually PLP = pyridoxal 5'-phosphate; PN = pyridoxine • 1st yr of life: every 3-6 mos • Children & adults: every 3-12 mos • 1st yr of life: every 3-6 mos • Thereafter: every 6 mos OR not required in those who are seizure free • Age <10 yrs: transaminases every 3-6 mos • If transaminases are >3x normal, also assess clotting factors • Annually (or more frequently as needed) • Age >4 yrs: incl elastography • Children age <6 yrs: every 4-6 mos • Children age >6 yrs: annually ## Agents/Circumstances to Avoid Several ASMs (such as carbamazepine, valproate, phenytoin, and phenobarbitone) can cause a low plasma concentration of PLP [ PLP interacts with various small molecules. See Targeted Therapies, ## Evaluation of Relatives at Risk Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected Note: At least one newborn at risk for Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy See • Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected • Note: At least one newborn at risk for • Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy ## Pregnancy Management As recurrence risk for couples who have had a child with PLPBP deficiency is 25%, there has been discussion about the utility of empiric supplementation of PN during pregnancies in women carrying an at-risk fetus. In contrast to reports on PN supplementation in pregnancies at risk for ## Therapies Under Investigation Search ## Genetic Counseling PLPBP deficiency is inherited in an autosomal recessive manner. The families of probands with PLPBP deficiency are often consanguineous. The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has PLPBP deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in If an individual with PLPBP deficiency has children with an individual who is heterozygous for a Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has PLPBP deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • If an individual with PLPBP deficiency has children with an individual who is heterozygous for a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance PLPBP deficiency is inherited in an autosomal recessive manner. The families of probands with PLPBP deficiency are often consanguineous. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has PLPBP deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in If an individual with PLPBP deficiency has children with an individual who is heterozygous for a • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has PLPBP deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • If an individual with PLPBP deficiency has children with an individual who is heterozygous for a ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources PDE Consortium • • • • • • PDE Consortium • ## Molecular Genetics PLPBP Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PLPBP Deficiency ( PLPBP belongs to a highly conserved family of proteins known to bind PLP, but their function in humans as well as other species is not understood. Because biochemical analysis of samples from individuals with PLPBP deficiency showed a widely deranged vitamin B Notable Variants listed in the table have been provided by the authors. Other proven or predicted loss-of-function variants including splicing and truncating variants can be associated with severe phenotypes and/or early mortality [ Other missense variants that decrease but do not abolish PLP binding or protein stability are expected to cause mild-to-moderate phenotypes. ## Molecular Pathogenesis PLPBP belongs to a highly conserved family of proteins known to bind PLP, but their function in humans as well as other species is not understood. Because biochemical analysis of samples from individuals with PLPBP deficiency showed a widely deranged vitamin B Notable Variants listed in the table have been provided by the authors. Other proven or predicted loss-of-function variants including splicing and truncating variants can be associated with severe phenotypes and/or early mortality [ Other missense variants that decrease but do not abolish PLP binding or protein stability are expected to cause mild-to-moderate phenotypes. ## Chapter Notes Prof Clara van Karnebeek is actively involved in clinical research regarding individuals with PLPBP deficiency. She would be happy to communicate with persons who have any questions regarding diagnosis of PLPBP deficiency or other considerations. Contact Drs Izabella Pena and/or Jolita Ciapaite to inquire about review of Prof van Karnebeek is also interested in hearing from clinicians treating families affected by a pyridoxine-dependent epilepsy in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. We are grateful to the patients and families for collaborating and teaching us about this metabolic epilepsy. 16 February 2023 (bp) Review posted live 8 July 2022 (ip) Original submission • 16 February 2023 (bp) Review posted live • 8 July 2022 (ip) Original submission ## Author Notes Prof Clara van Karnebeek is actively involved in clinical research regarding individuals with PLPBP deficiency. She would be happy to communicate with persons who have any questions regarding diagnosis of PLPBP deficiency or other considerations. Contact Drs Izabella Pena and/or Jolita Ciapaite to inquire about review of Prof van Karnebeek is also interested in hearing from clinicians treating families affected by a pyridoxine-dependent epilepsy in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. ## Acknowledgments We are grateful to the patients and families for collaborating and teaching us about this metabolic epilepsy. ## Revision History 16 February 2023 (bp) Review posted live 8 July 2022 (ip) Original submission • 16 February 2023 (bp) Review posted live • 8 July 2022 (ip) Original submission ## Key Sections in this ## References ## Literature Cited	[]	16/2/2023			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pmd	pmd	[ "Spastic Paraplegia 2 (SPG2)", "Pelizaeus-Merzbacher Disease (PMD)", "PLP1 Null Syndrome", "Hypomyelination of Early Myelinating Structures (HEMS)", "Myelin proteolipid protein", "PLP1", "PLP1-Related Disorders" ]		Nicole I Wolf, Rosalina ML van Spaendonk, Grace M Hobson	Summary The diagnosis of a	Pelizaeus-Merzbacher disease Hypomyelination of early myelinating structures Spastic paraplegia 2 For synonyms and outdated names see For other genetic causes of these phenotypes, see • Pelizaeus-Merzbacher disease • Hypomyelination of early myelinating structures • Spastic paraplegia 2 ## Diagnosis For the purposes of this No consensus clinical diagnostic criteria for A Suggestive clinical findings include: Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment Progression to severe spasticity and ataxia Spastic paraparesis with or without CNS involvement Spastic urinary bladder Note: Because the bulk of myelination normally occurs during the first two years of life, the T Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of a Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B. For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by motor and cognitive impairment, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The majority of gene dosage changes are tandem duplications occurring in Xq22, which include all of Whole-gene deletions of Depending on the method used, larger deletion or duplication events may be detected. Position effect of a duplication identified by FISH that was near but did not include Sequence analysis which should include analysis of intron 3B detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click An inversion of the X chromosome with a breakpoint 70 kb upstream of • Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment • Progression to severe spasticity and ataxia • Spastic paraparesis with or without CNS involvement • Spastic urinary bladder • Note: Because the bulk of myelination normally occurs during the first two years of life, the T • Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B. • For an introduction to multigene panels click ## Suggestive Findings A Suggestive clinical findings include: Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment Progression to severe spasticity and ataxia Spastic paraparesis with or without CNS involvement Spastic urinary bladder Note: Because the bulk of myelination normally occurs during the first two years of life, the T Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. • Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment • Progression to severe spasticity and ataxia • Spastic paraparesis with or without CNS involvement • Spastic urinary bladder • Note: Because the bulk of myelination normally occurs during the first two years of life, the T ## Clinical Findings Suggestive clinical findings include: Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment Progression to severe spasticity and ataxia Spastic paraparesis with or without CNS involvement Spastic urinary bladder • Infantile or early childhood onset of nystagmus, hypotonia, and cognitive impairment • Progression to severe spasticity and ataxia • Spastic paraparesis with or without CNS involvement • Spastic urinary bladder ## Imaging Findings Note: Because the bulk of myelination normally occurs during the first two years of life, the T • Note: Because the bulk of myelination normally occurs during the first two years of life, the T ## Family History Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of a Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B. For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by motor and cognitive impairment, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The majority of gene dosage changes are tandem duplications occurring in Xq22, which include all of Whole-gene deletions of Depending on the method used, larger deletion or duplication events may be detected. Position effect of a duplication identified by FISH that was near but did not include Sequence analysis which should include analysis of intron 3B detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click An inversion of the X chromosome with a breakpoint 70 kb upstream of • Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of a Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B. For an introduction to multigene panels click • Note: In individuals with HEMS, sequence analysis of intron 3 should be performed if no pathogenic variant is identified in exon 3B. • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by motor and cognitive impairment, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The majority of gene dosage changes are tandem duplications occurring in Xq22, which include all of Whole-gene deletions of Depending on the method used, larger deletion or duplication events may be detected. Position effect of a duplication identified by FISH that was near but did not include Sequence analysis which should include analysis of intron 3B detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click An inversion of the X chromosome with a breakpoint 70 kb upstream of ## Clinical Characteristics Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia 2 (SPG2) are at opposite ends of a clinical spectrum of disease caused by pathogenic variants in Spectrum of HEMS = hypomyelination of early myelinating structures; PMD = Pelizaeus-Merzbacher disease; SPG = spastic paraplegia Spastic urinary bladder Later, children with severe PMD may have short stature and poor weight gain. Hypotonia later evolves into spasticity of the extremities that is usually quite severe. Children do not walk or develop effective use of the upper limbs. Verbal expression is severely limited, but comprehension may be significant. Swallowing difficulties may require feeding tube placement. Affected children may die during infancy or childhood, usually of aspiration; with attentive care, they may live into the third decade or longer. Cognitive abilities are usually mildly to moderately impaired but exceed those of the more severely affected children; language and speech usually develop. Extrapyramidal abnormalities, such as dystonic posturing and athetosis, may occur. Survival into the sixth or seventh decade has been observed. Males with SPG2 have reproduced; males with the PMD phenotype have not. Visual, auditory, and somatosensory evoked potential testing show normal-to-near-normal latencies of the peripheral component of the respective sensory modality, but severely prolonged or absent central latencies. This does not indicate profound deafness, and hearing is usually clinically normal [ Except in individuals with Women with a The risk to heterozygous females of developing neurologic signs is greatest in families in which affected males have a The following explanation is offered: Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [ Manifesting heterozygotes are usually not index cases, but rather are identified in the course of evaluating the relatives of an affected male. Females with PMD have been described. This is thought to be due to unfavorable X inactivation in the brain [ Some genotype-phenotype correlations exist. Most individuals with The most severe phenotypes are typically caused by missense variants (especially nonconservative amino acid substitutions) and other SPG2 is most often caused by conservative amino acid substitutions in presumably less critical regions of the protein. The locations of these pathogenic variants do not provide a clear correlation between amino acid position and clinical phenotype. However, pathogenic variants in the Individuals with null Peripheral neuropathy as well as a relatively mild CNS manifestations result from pathogenic variants that affect only the Pelizaeus-Merzbacher disease is also known as sudanophilic or orthochromatic leukodystrophy. SPG2 may also be referred to as HSP- HEMS (hypomyelination of early myelinating structures) is a subtype of SPG2 (i.e., complicated SPG2) with characteristic MRI abnormalities [ Proteolipid protein 1 was previously called proteolipid protein. After discovery of a similar gene that is predominantly expressed in gut, numerical designation was added. Note also that the older literature usually begins numbering of the amino acids with the glycine encoded by codon 2, since the initiation methionine is cleaved post-translationally. In the US population, the prevalence of PMD due to all causes is estimated at 1:200,000 to 1:500,000. In a survey of leukodystrophies in Germany, the incidence of PMD was approximately 0.13:100,000 live births [ • Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated • Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [ ## Clinical Description Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia 2 (SPG2) are at opposite ends of a clinical spectrum of disease caused by pathogenic variants in Spectrum of HEMS = hypomyelination of early myelinating structures; PMD = Pelizaeus-Merzbacher disease; SPG = spastic paraplegia Spastic urinary bladder Later, children with severe PMD may have short stature and poor weight gain. Hypotonia later evolves into spasticity of the extremities that is usually quite severe. Children do not walk or develop effective use of the upper limbs. Verbal expression is severely limited, but comprehension may be significant. Swallowing difficulties may require feeding tube placement. Affected children may die during infancy or childhood, usually of aspiration; with attentive care, they may live into the third decade or longer. Cognitive abilities are usually mildly to moderately impaired but exceed those of the more severely affected children; language and speech usually develop. Extrapyramidal abnormalities, such as dystonic posturing and athetosis, may occur. Survival into the sixth or seventh decade has been observed. Males with SPG2 have reproduced; males with the PMD phenotype have not. Visual, auditory, and somatosensory evoked potential testing show normal-to-near-normal latencies of the peripheral component of the respective sensory modality, but severely prolonged or absent central latencies. This does not indicate profound deafness, and hearing is usually clinically normal [ Except in individuals with Women with a The risk to heterozygous females of developing neurologic signs is greatest in families in which affected males have a The following explanation is offered: Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [ Manifesting heterozygotes are usually not index cases, but rather are identified in the course of evaluating the relatives of an affected male. Females with PMD have been described. This is thought to be due to unfavorable X inactivation in the brain [ • Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated • Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [ ## Males Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia 2 (SPG2) are at opposite ends of a clinical spectrum of disease caused by pathogenic variants in Spectrum of HEMS = hypomyelination of early myelinating structures; PMD = Pelizaeus-Merzbacher disease; SPG = spastic paraplegia Spastic urinary bladder Later, children with severe PMD may have short stature and poor weight gain. Hypotonia later evolves into spasticity of the extremities that is usually quite severe. Children do not walk or develop effective use of the upper limbs. Verbal expression is severely limited, but comprehension may be significant. Swallowing difficulties may require feeding tube placement. Affected children may die during infancy or childhood, usually of aspiration; with attentive care, they may live into the third decade or longer. Cognitive abilities are usually mildly to moderately impaired but exceed those of the more severely affected children; language and speech usually develop. Extrapyramidal abnormalities, such as dystonic posturing and athetosis, may occur. Survival into the sixth or seventh decade has been observed. Males with SPG2 have reproduced; males with the PMD phenotype have not. ## Neurophysiologic Studies Visual, auditory, and somatosensory evoked potential testing show normal-to-near-normal latencies of the peripheral component of the respective sensory modality, but severely prolonged or absent central latencies. This does not indicate profound deafness, and hearing is usually clinically normal [ Except in individuals with ## Heterozygous Females Women with a The risk to heterozygous females of developing neurologic signs is greatest in families in which affected males have a The following explanation is offered: Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [ Manifesting heterozygotes are usually not index cases, but rather are identified in the course of evaluating the relatives of an affected male. Females with PMD have been described. This is thought to be due to unfavorable X inactivation in the brain [ • Alleles associated with a severe phenotype cause apoptosis (cell death) of oligodendrocytes (the cells that make myelin in the CNS) during early childhood. In heterozygous females, the oligodendrocytes that express the mutated • Alleles associated with a mild phenotype in males do not cause apoptosis of oligodendrocytes. In heterozygous females, abnormal oligodendrocytes persist and can cause neurologic signs [ ## Genotype-Phenotype Correlations Some genotype-phenotype correlations exist. Most individuals with The most severe phenotypes are typically caused by missense variants (especially nonconservative amino acid substitutions) and other SPG2 is most often caused by conservative amino acid substitutions in presumably less critical regions of the protein. The locations of these pathogenic variants do not provide a clear correlation between amino acid position and clinical phenotype. However, pathogenic variants in the Individuals with null Peripheral neuropathy as well as a relatively mild CNS manifestations result from pathogenic variants that affect only the ## Penetrance ## Nomenclature Pelizaeus-Merzbacher disease is also known as sudanophilic or orthochromatic leukodystrophy. SPG2 may also be referred to as HSP- HEMS (hypomyelination of early myelinating structures) is a subtype of SPG2 (i.e., complicated SPG2) with characteristic MRI abnormalities [ Proteolipid protein 1 was previously called proteolipid protein. After discovery of a similar gene that is predominantly expressed in gut, numerical designation was added. Note also that the older literature usually begins numbering of the amino acids with the glycine encoded by codon 2, since the initiation methionine is cleaved post-translationally. ## Prevalence In the US population, the prevalence of PMD due to all causes is estimated at 1:200,000 to 1:500,000. In a survey of leukodystrophies in Germany, the incidence of PMD was approximately 0.13:100,000 live births [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Individuals with The combination of nystagmus within the first two years of life, initial hypotonia, and abnormal white matter changes on the brain MRI (e.g., abnormal signal in the posterior limbs of the internal capsule, the middle, and superior cerebellar peduncles and the medial and lateral lemnisci, all of which should be myelinated in a normal newborn) should suggest the diagnosis of PMD, especially if the family history is consistent with an X-linked disorder. Hypomyelination occurs in several disorders with clinical phenotypes distinct from PMD. Approximately 20% of males with clinical findings consistent with a Genes of Interest in the Differential Diagnosis of Pelizaeus-Merzbacher Disease Nystagmus Spasticity DD Hypomyelination Spasticity/ataxia Nystagmus Hypomyelination DD Dystonia Spasticity Spasticity/ataxia Nystagmus Hypomyelination Milder manifestations, may not be recognized until adulthood Syndactyly Ocular abnormalities Dysmorphic features Spasticity/ataxia Nystagmus Hypomyelination Epilepsy is frequent More pronounced hypomyelination in subcortical white matter Prominent brain stem involvement Resembles severe PMD Hypomyelination Acquired microcephaly Severe epilepsy Spasticity/ataxia Nystagmus Demyelinating peripheral neuropathy Hypomyelination Congenital cataract Areas w/both T Nystagmus DD Balance problems Mild spasticity Spasticity/ataxia Nystagmus Hypotonia Hypomyelination Severe early dystonia Early-onset (transitory) respiratory failure Spasticity Nystagmus Hypomyelination DD Ataxia Hypomyelination Ataxia Hypomyelination Myopia (no nystagmus) Hypodontia Hypogonadotropic hypogonadism Early cerebellar atrophy Better myelination of posterior limb of the internal capsule, ventrolateral thalamus & optic radiation Nystagmus DD Hypomyelination Skin lesions Epilepsy Spasticity/ataxia Nystagmus Hypomyelination No specific distinguishing features In severely affected children, microcephaly & early epileptic encephalopathy Neonatal hypotonia Nystagmus Severe DD High serum T3 concentration; low serum reverse T3 concentration MRI shows (severely) delayed myelination, but not hypomyelination ± hypotonia, nystagmus, DD In severely affected children, diffusely abnormal myelination w/uniformly hyperintense white matter on T Seizures are more common than in PMD, but children w/Salla disease are more likely to show improvement MRI shows thin corpus callosum early on Peripheral congenital hypomyelinating neuropathy Waardenburg-Hirschsprung syndrome Nystagmus Hypomyelination Mild DD Nystagmus Spasticity, Nystagmus (not invariable) Can present w/pure hypomyelination AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; PCWH = peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease; PMD = Pelizaeus-Merzbacher disease; XL = X-linked To date, more than 80 genetic types of hereditary spastic paraplegia have been defined. See • Nystagmus • Spasticity • DD • Hypomyelination • Spasticity/ataxia • Nystagmus • Hypomyelination • DD • Dystonia • Spasticity • Spasticity/ataxia • Nystagmus • Hypomyelination • Milder manifestations, may not be recognized until adulthood • Syndactyly • Ocular abnormalities • Dysmorphic features • Spasticity/ataxia • Nystagmus • Hypomyelination • Epilepsy is frequent • More pronounced hypomyelination in subcortical white matter • Prominent brain stem involvement • Resembles severe PMD • Hypomyelination • Acquired microcephaly • Severe epilepsy • Spasticity/ataxia • Nystagmus • Demyelinating peripheral neuropathy • Hypomyelination • Congenital cataract • Areas w/both T • Nystagmus • DD • Balance problems • Mild spasticity • Spasticity/ataxia • Nystagmus • Hypotonia • Hypomyelination • Severe early dystonia • Early-onset (transitory) respiratory failure • Spasticity • Nystagmus • Hypomyelination • DD • Ataxia • Hypomyelination • Ataxia • Hypomyelination • Myopia (no nystagmus) • Hypodontia • Hypogonadotropic hypogonadism • Early cerebellar atrophy • Better myelination of posterior limb of the internal capsule, ventrolateral thalamus & optic radiation • Nystagmus • DD • Hypomyelination • Skin lesions • Epilepsy • Spasticity/ataxia • Nystagmus • Hypomyelination • No specific distinguishing features • In severely affected children, microcephaly & early epileptic encephalopathy • Neonatal hypotonia • Nystagmus • Severe DD • High serum T3 concentration; low serum reverse T3 concentration • MRI shows (severely) delayed myelination, but not hypomyelination • ± hypotonia, nystagmus, DD • In severely affected children, diffusely abnormal myelination w/uniformly hyperintense white matter on T • Seizures are more common than in PMD, but children w/Salla disease are more likely to show improvement • MRI shows thin corpus callosum early on • Peripheral congenital hypomyelinating neuropathy • Waardenburg-Hirschsprung syndrome • Nystagmus • Hypomyelination • Mild DD • Nystagmus • Spasticity, • Nystagmus (not invariable) • Can present w/pure hypomyelination ## Pelizaeus-Merzbacher Disease (PMD) The combination of nystagmus within the first two years of life, initial hypotonia, and abnormal white matter changes on the brain MRI (e.g., abnormal signal in the posterior limbs of the internal capsule, the middle, and superior cerebellar peduncles and the medial and lateral lemnisci, all of which should be myelinated in a normal newborn) should suggest the diagnosis of PMD, especially if the family history is consistent with an X-linked disorder. Hypomyelination occurs in several disorders with clinical phenotypes distinct from PMD. Approximately 20% of males with clinical findings consistent with a Genes of Interest in the Differential Diagnosis of Pelizaeus-Merzbacher Disease Nystagmus Spasticity DD Hypomyelination Spasticity/ataxia Nystagmus Hypomyelination DD Dystonia Spasticity Spasticity/ataxia Nystagmus Hypomyelination Milder manifestations, may not be recognized until adulthood Syndactyly Ocular abnormalities Dysmorphic features Spasticity/ataxia Nystagmus Hypomyelination Epilepsy is frequent More pronounced hypomyelination in subcortical white matter Prominent brain stem involvement Resembles severe PMD Hypomyelination Acquired microcephaly Severe epilepsy Spasticity/ataxia Nystagmus Demyelinating peripheral neuropathy Hypomyelination Congenital cataract Areas w/both T Nystagmus DD Balance problems Mild spasticity Spasticity/ataxia Nystagmus Hypotonia Hypomyelination Severe early dystonia Early-onset (transitory) respiratory failure Spasticity Nystagmus Hypomyelination DD Ataxia Hypomyelination Ataxia Hypomyelination Myopia (no nystagmus) Hypodontia Hypogonadotropic hypogonadism Early cerebellar atrophy Better myelination of posterior limb of the internal capsule, ventrolateral thalamus & optic radiation Nystagmus DD Hypomyelination Skin lesions Epilepsy Spasticity/ataxia Nystagmus Hypomyelination No specific distinguishing features In severely affected children, microcephaly & early epileptic encephalopathy Neonatal hypotonia Nystagmus Severe DD High serum T3 concentration; low serum reverse T3 concentration MRI shows (severely) delayed myelination, but not hypomyelination ± hypotonia, nystagmus, DD In severely affected children, diffusely abnormal myelination w/uniformly hyperintense white matter on T Seizures are more common than in PMD, but children w/Salla disease are more likely to show improvement MRI shows thin corpus callosum early on Peripheral congenital hypomyelinating neuropathy Waardenburg-Hirschsprung syndrome Nystagmus Hypomyelination Mild DD Nystagmus Spasticity, Nystagmus (not invariable) Can present w/pure hypomyelination AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; PCWH = peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease; PMD = Pelizaeus-Merzbacher disease; XL = X-linked • Nystagmus • Spasticity • DD • Hypomyelination • Spasticity/ataxia • Nystagmus • Hypomyelination • DD • Dystonia • Spasticity • Spasticity/ataxia • Nystagmus • Hypomyelination • Milder manifestations, may not be recognized until adulthood • Syndactyly • Ocular abnormalities • Dysmorphic features • Spasticity/ataxia • Nystagmus • Hypomyelination • Epilepsy is frequent • More pronounced hypomyelination in subcortical white matter • Prominent brain stem involvement • Resembles severe PMD • Hypomyelination • Acquired microcephaly • Severe epilepsy • Spasticity/ataxia • Nystagmus • Demyelinating peripheral neuropathy • Hypomyelination • Congenital cataract • Areas w/both T • Nystagmus • DD • Balance problems • Mild spasticity • Spasticity/ataxia • Nystagmus • Hypotonia • Hypomyelination • Severe early dystonia • Early-onset (transitory) respiratory failure • Spasticity • Nystagmus • Hypomyelination • DD • Ataxia • Hypomyelination • Ataxia • Hypomyelination • Myopia (no nystagmus) • Hypodontia • Hypogonadotropic hypogonadism • Early cerebellar atrophy • Better myelination of posterior limb of the internal capsule, ventrolateral thalamus & optic radiation • Nystagmus • DD • Hypomyelination • Skin lesions • Epilepsy • Spasticity/ataxia • Nystagmus • Hypomyelination • No specific distinguishing features • In severely affected children, microcephaly & early epileptic encephalopathy • Neonatal hypotonia • Nystagmus • Severe DD • High serum T3 concentration; low serum reverse T3 concentration • MRI shows (severely) delayed myelination, but not hypomyelination • ± hypotonia, nystagmus, DD • In severely affected children, diffusely abnormal myelination w/uniformly hyperintense white matter on T • Seizures are more common than in PMD, but children w/Salla disease are more likely to show improvement • MRI shows thin corpus callosum early on • Peripheral congenital hypomyelinating neuropathy • Waardenburg-Hirschsprung syndrome • Nystagmus • Hypomyelination • Mild DD • Nystagmus • Spasticity, • Nystagmus (not invariable) • Can present w/pure hypomyelination ## Spastic Paraplegia 2 (SPG2) To date, more than 80 genetic types of hereditary spastic paraplegia have been defined. See ## Management No clinical practice guidelines for To establish the extent of disease and needs of an individual diagnosed with a To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Brain MRI to determine severity of myelination abnormalities Brain MRS in older children & adults to ascertain atrophy To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Scoliosis, contractures, joint dislocations Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; MOI = mode of inheritance; MRS = magnetic resonance spectroscopy; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care to improve quality of life, maximize function, and reduce complications is recommended. A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care (see Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls Anti-spasticity medications such as baclofen (including intrathecal administration), diazepam, & tizanidine may be helpful, especially in combination w/PT, exercise, orthotics, & other assistive devices. Surgery may be required to release severe joint contractures Many ASMs may be effective; seizures generally respond to anti-seizure medication such as carbamazepine. Education of parents/caregivers PT to maintain mobility & function Exercise as prescribed by PT OT to optimize ADL Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs) OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats) Avoid excessive alcohol intake. Treatment as per orthopedics Corrective surgery as needed for severe scoliosis that results in pulmonary compromise or discomfort, esp w/position changes. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed to increase autonomy (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Measurement of growth parameters Evaluation of nutritional status & safety of oral intake Orthopedic assessment of scoliosis, contractures, & frequency of joint dislocations Physical medicine, OT/PT assessment of mobility, self-help skills OT = occupational therapy; PT = physical therapy Elevated body temperature, as with fever, may cause neurologic manifestations to transiently worsen. See CNS stem cells were transplanted into brains of individuals with PMD in a US FDA-approved Phase I trial [ Pharmacologic agents that lower expression of Search • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Brain MRI to determine severity of myelination abnormalities • Brain MRS in older children & adults to ascertain atrophy • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Scoliosis, contractures, joint dislocations • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • Anti-spasticity medications such as baclofen (including intrathecal administration), diazepam, & tizanidine may be helpful, especially in combination w/PT, exercise, orthotics, & other assistive devices. • Surgery may be required to release severe joint contractures • Many ASMs may be effective; seizures generally respond to anti-seizure medication such as carbamazepine. • Education of parents/caregivers • PT to maintain mobility & function • Exercise as prescribed by PT • OT to optimize ADL • Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs) • OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats) • Avoid excessive alcohol intake. • Treatment as per orthopedics • Corrective surgery as needed for severe scoliosis that results in pulmonary compromise or discomfort, esp w/position changes. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed to increase autonomy (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measurement of growth parameters • Evaluation of nutritional status & safety of oral intake • Orthopedic assessment of scoliosis, contractures, & frequency of joint dislocations • Physical medicine, OT/PT assessment of mobility, self-help skills ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with a To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. Brain MRI to determine severity of myelination abnormalities Brain MRS in older children & adults to ascertain atrophy To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Scoliosis, contractures, joint dislocations Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; MOI = mode of inheritance; MRS = magnetic resonance spectroscopy; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Brain MRI to determine severity of myelination abnormalities • Brain MRS in older children & adults to ascertain atrophy • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Scoliosis, contractures, joint dislocations • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. A multidisciplinary team comprising specialists in neurology, physical medicine, orthopedics, pulmonary medicine, and gastroenterology is optimal for care (see Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls Anti-spasticity medications such as baclofen (including intrathecal administration), diazepam, & tizanidine may be helpful, especially in combination w/PT, exercise, orthotics, & other assistive devices. Surgery may be required to release severe joint contractures Many ASMs may be effective; seizures generally respond to anti-seizure medication such as carbamazepine. Education of parents/caregivers PT to maintain mobility & function Exercise as prescribed by PT OT to optimize ADL Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs) OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats) Avoid excessive alcohol intake. Treatment as per orthopedics Corrective surgery as needed for severe scoliosis that results in pulmonary compromise or discomfort, esp w/position changes. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed to increase autonomy (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • Anti-spasticity medications such as baclofen (including intrathecal administration), diazepam, & tizanidine may be helpful, especially in combination w/PT, exercise, orthotics, & other assistive devices. • Surgery may be required to release severe joint contractures • Many ASMs may be effective; seizures generally respond to anti-seizure medication such as carbamazepine. • Education of parents/caregivers • PT to maintain mobility & function • Exercise as prescribed by PT • OT to optimize ADL • Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs) • OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats) • Avoid excessive alcohol intake. • Treatment as per orthopedics • Corrective surgery as needed for severe scoliosis that results in pulmonary compromise or discomfort, esp w/position changes. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed to increase autonomy (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed to increase autonomy (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed to increase autonomy (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended. Measurement of growth parameters Evaluation of nutritional status & safety of oral intake Orthopedic assessment of scoliosis, contractures, & frequency of joint dislocations Physical medicine, OT/PT assessment of mobility, self-help skills OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Evaluation of nutritional status & safety of oral intake • Orthopedic assessment of scoliosis, contractures, & frequency of joint dislocations • Physical medicine, OT/PT assessment of mobility, self-help skills ## Agents/Circumstances to Avoid Elevated body temperature, as with fever, may cause neurologic manifestations to transiently worsen. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation CNS stem cells were transplanted into brains of individuals with PMD in a US FDA-approved Phase I trial [ Pharmacologic agents that lower expression of Search ## Genetic Counseling The The father of an affected male will not have the disorder nor will he be hemizygous for the In the majority of families (including those in which a male proband is the only family member known to be affected), the mother of the proband is heterozygous for a In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a The minority of affected males have the disorder as the result of a Molecular genetic testing of the mother for the If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ If the proband represents a simplex case and if the Males with classic PMD do not reproduce. Males with SPG2 may be able to father children. Affected males transmit the All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: None of their sons. Identification of female heterozygotes requires prior identification of the Note: (1) Females who are heterozygous for this X-linked disorder are usually neurologically normal but may manifest mild-to-moderate signs of the disease. (2) Molecular genetic testing may be able to identify the family member in whom a The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In the majority of families (including those in which a male proband is the only family member known to be affected), the mother of the proband is heterozygous for a • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • The minority of affected males have the disorder as the result of a • The minority of affected males have the disorder as the result of a • Molecular genetic testing of the mother for the • The minority of affected males have the disorder as the result of a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ • Males with classic PMD do not reproduce. • Males with SPG2 may be able to father children. Affected males transmit the • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: • None of their sons. • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: • None of their sons. • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: • None of their sons. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. ## Mode of Inheritance The ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In the majority of families (including those in which a male proband is the only family member known to be affected), the mother of the proband is heterozygous for a In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a The minority of affected males have the disorder as the result of a Molecular genetic testing of the mother for the If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ If the proband represents a simplex case and if the Males with classic PMD do not reproduce. Males with SPG2 may be able to father children. Affected males transmit the All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: None of their sons. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In the majority of families (including those in which a male proband is the only family member known to be affected), the mother of the proband is heterozygous for a • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • The minority of affected males have the disorder as the result of a • The minority of affected males have the disorder as the result of a • Molecular genetic testing of the mother for the • The minority of affected males have the disorder as the result of a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ • If the proband represents a simplex case and if the • Males who inherit the pathogenic variant will be affected. Significant intrafamilial clinical variability is uncommon in • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or manifest mild-to-moderate signs of the disorder. Female sibs are more likely to develop neurologic signs if the phenotype in affected males is relatively mild [ • Males with classic PMD do not reproduce. • Males with SPG2 may be able to father children. Affected males transmit the • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: • None of their sons. • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: • None of their sons. • All of their daughters, who may be asymptomatic or manifest mild-to-moderate signs of the disease. Note: • None of their sons. ## Heterozygote Detection Identification of female heterozygotes requires prior identification of the Note: (1) Females who are heterozygous for this X-linked disorder are usually neurologically normal but may manifest mild-to-moderate signs of the disease. (2) Molecular genetic testing may be able to identify the family member in whom a ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Australia • • • • • • Australia • • • • • ## Molecular Genetics PLP1-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PLP1-Related Disorders ( PLP1, but not DM20, has been shown to form dimers at an intracellular cysteine residue [ Pathogenic missense variants cause misfolding of PLP1 or DM20. These misfolded proteins are retained in the endoplasmic reticulum (ER), failing to be incorporated into the cell membrane where they activate the unfolded protein response [ Deletion of Variants in the HEMS = hypomyelination of early myelinating structures Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis PLP1, but not DM20, has been shown to form dimers at an intracellular cysteine residue [ Pathogenic missense variants cause misfolding of PLP1 or DM20. These misfolded proteins are retained in the endoplasmic reticulum (ER), failing to be incorporated into the cell membrane where they activate the unfolded protein response [ Deletion of Variants in the HEMS = hypomyelination of early myelinating structures Variants listed in the table have been provided by the authors. ## Chapter Notes The authors are grateful to the Pelizaeus-Merzbacher disease Foundation, the Children's Research Center of Michigan, the Nemours Foundation, the NIH, and affected individuals and families of those with Pelizaeus-Merzbacher disease. James Y Garbern, MD, PhD; University of Rochester Medical Center (1999-2011)Grace M Hobson, PhD (2006-present)John Kamholz, MD, PhD; University of Iowa Hospitals & Clinics (2013-2025)Karen Krajewski, MS; Wayne State University School of Medicine/Detroit Medical Center (2006-2010)Rosalina ML van Spaendonk, PhD (2019-present)Nicole I Wolf, MD, PhD (2019-present) James Y Garbern was a specialist in leukodystrophies and hereditary neurologic disorders and an internationally recognized expert on PMD. Dr Garbern died in November 2011. 12 June 2025 (sw) Comprehensive update posted live 19 December 2019 (sw) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 16 March 2010 (me) Comprehensive update posted live 15 September 2006 (me) Comprehensive update posted live 11 June 2004 (me) Comprehensive update posted live 20 March 2002 (me) Comprehensive update posted live 15 June 1999 (me) Review posted live 28 January 1999 (jg) Original submission • 12 June 2025 (sw) Comprehensive update posted live • 19 December 2019 (sw) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 16 March 2010 (me) Comprehensive update posted live • 15 September 2006 (me) Comprehensive update posted live • 11 June 2004 (me) Comprehensive update posted live • 20 March 2002 (me) Comprehensive update posted live • 15 June 1999 (me) Review posted live • 28 January 1999 (jg) Original submission ## Author History James Y Garbern, MD, PhD; University of Rochester Medical Center (1999-2011)Grace M Hobson, PhD (2006-present)John Kamholz, MD, PhD; University of Iowa Hospitals & Clinics (2013-2025)Karen Krajewski, MS; Wayne State University School of Medicine/Detroit Medical Center (2006-2010)Rosalina ML van Spaendonk, PhD (2019-present)Nicole I Wolf, MD, PhD (2019-present) James Y Garbern was a specialist in leukodystrophies and hereditary neurologic disorders and an internationally recognized expert on PMD. Dr Garbern died in November 2011. ## Revision History 12 June 2025 (sw) Comprehensive update posted live 19 December 2019 (sw) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 16 March 2010 (me) Comprehensive update posted live 15 September 2006 (me) Comprehensive update posted live 11 June 2004 (me) Comprehensive update posted live 20 March 2002 (me) Comprehensive update posted live 15 June 1999 (me) Review posted live 28 January 1999 (jg) Original submission • 12 June 2025 (sw) Comprehensive update posted live • 19 December 2019 (sw) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 16 March 2010 (me) Comprehensive update posted live • 15 September 2006 (me) Comprehensive update posted live • 11 June 2004 (me) Comprehensive update posted live • 20 March 2002 (me) Comprehensive update posted live • 15 June 1999 (me) Review posted live • 28 January 1999 (jg) Original submission ## References ## Literature Cited	[]	15/6/1999	12/6/2025	7/10/2004	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pmld1	pmld1	[ "Hypomyelinating Leukodystrophy 2 (HLD2)", "PMLD1", "PMLD1", "Hypomyelinating Leukodystrophy 2 (HLD2)", "Gap junction gamma-2 protein", "GJC2", "Pelizaeus-Merzbacher-Like Disease 1" ]	Pelizaeus-Merzbacher-Like Disease 1	Norah Nahhas, Alex Conant, Jennifer Orthmann-Murphy, Adeline Vanderver, Grace Hobson	Summary Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents during the neonatal or early-infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time the hypotonia typically evolves into spasticity that affects the ability to walk and communicate. Cerebellar signs (gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia) frequently manifest during childhood. Some individuals develop extrapyramidal movement abnormalities (choreoathetosis and dystonia). Hearing loss and optic atrophy are observed in rare cases. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Most individuals have normal cognitive skills or mild intellectual disability – which, however, can be difficult to evaluate in the context of profound motor impairment. The diagnosis of PMLD1 is established in a proband with suggestive clinical and neuroimaging findings and identification of biallelic pathogenic variants in PMLD1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the	## Diagnosis Pelizaeus-Merzbacher-like disease 1 (PMLD1) Nystagmus that typically presents during the neonatal period or early infancy Mainly motor developmental delay and central hypotonia during infancy Signs of upper motor neuron dysfunction (including spasticity, brisk deep tendon reflexes, and Babinski sign) usually affecting the lower limbs more than the upper limbs Gait ataxia and other cerebellar signs Mild choreiform movements and dystonia of the extremities that can become severe and disabling Dysarthria and swallowing dysfunction Diffuse homogeneous hyperintense T Involvement of the corticospinal tracts with abnormal T Thin corpus callosum in older children Brain atrophy and ventricular dilatation as a consequence of white matter loss without specific cerebellar atrophy [ Relative preservation of deep gray nuclei and the thalami The diagnosis of PMLD1 Molecular genetic testing approaches can include a combination of Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotype of PMLD1 is broad, children with the distinctive findings described in When the clinical findings and brain MRI findings suggest the diagnosis of a PMLD1, molecular genetic testing approaches can include Note: Two variants in the noncoding exon 1, For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited leukodystrophies, molecular genetic testing approaches can include a combination of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pelizaeus-Merzbacher-Like Disease 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Twenty-two of 51 reported affected individuals had pathogenic variants in the noncoding exon 1 of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Nystagmus that typically presents during the neonatal period or early infancy • Mainly motor developmental delay and central hypotonia during infancy • Signs of upper motor neuron dysfunction (including spasticity, brisk deep tendon reflexes, and Babinski sign) usually affecting the lower limbs more than the upper limbs • Gait ataxia and other cerebellar signs • Mild choreiform movements and dystonia of the extremities that can become severe and disabling • Dysarthria and swallowing dysfunction • Diffuse homogeneous hyperintense T • Involvement of the corticospinal tracts with abnormal T • Thin corpus callosum in older children • Brain atrophy and ventricular dilatation as a consequence of white matter loss without specific cerebellar atrophy [ • Relative preservation of deep gray nuclei and the thalami • Note: Two variants in the noncoding exon 1, • For an introduction to multigene panels click ## Suggestive Findings Pelizaeus-Merzbacher-like disease 1 (PMLD1) Nystagmus that typically presents during the neonatal period or early infancy Mainly motor developmental delay and central hypotonia during infancy Signs of upper motor neuron dysfunction (including spasticity, brisk deep tendon reflexes, and Babinski sign) usually affecting the lower limbs more than the upper limbs Gait ataxia and other cerebellar signs Mild choreiform movements and dystonia of the extremities that can become severe and disabling Dysarthria and swallowing dysfunction Diffuse homogeneous hyperintense T Involvement of the corticospinal tracts with abnormal T Thin corpus callosum in older children Brain atrophy and ventricular dilatation as a consequence of white matter loss without specific cerebellar atrophy [ Relative preservation of deep gray nuclei and the thalami • Nystagmus that typically presents during the neonatal period or early infancy • Mainly motor developmental delay and central hypotonia during infancy • Signs of upper motor neuron dysfunction (including spasticity, brisk deep tendon reflexes, and Babinski sign) usually affecting the lower limbs more than the upper limbs • Gait ataxia and other cerebellar signs • Mild choreiform movements and dystonia of the extremities that can become severe and disabling • Dysarthria and swallowing dysfunction • Diffuse homogeneous hyperintense T • Involvement of the corticospinal tracts with abnormal T • Thin corpus callosum in older children • Brain atrophy and ventricular dilatation as a consequence of white matter loss without specific cerebellar atrophy [ • Relative preservation of deep gray nuclei and the thalami ## Establishing the Diagnosis The diagnosis of PMLD1 Molecular genetic testing approaches can include a combination of Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotype of PMLD1 is broad, children with the distinctive findings described in When the clinical findings and brain MRI findings suggest the diagnosis of a PMLD1, molecular genetic testing approaches can include Note: Two variants in the noncoding exon 1, For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited leukodystrophies, molecular genetic testing approaches can include a combination of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pelizaeus-Merzbacher-Like Disease 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Twenty-two of 51 reported affected individuals had pathogenic variants in the noncoding exon 1 of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Note: Two variants in the noncoding exon 1, • For an introduction to multigene panels click ## Option 1 When the clinical findings and brain MRI findings suggest the diagnosis of a PMLD1, molecular genetic testing approaches can include Note: Two variants in the noncoding exon 1, For an introduction to multigene panels click • Note: Two variants in the noncoding exon 1, • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited leukodystrophies, molecular genetic testing approaches can include a combination of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Pelizaeus-Merzbacher-Like Disease 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Twenty-two of 51 reported affected individuals had pathogenic variants in the noncoding exon 1 of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents in the neonatal period or early infancy with nystagmus, often complicated by hypotonia and developmental delay. Over time the hypotonia may evolve into spasticity, and extrapyramidal movement abnormalities may emerge. Older children often manifest significant motor impairments that can also effect communication. Cognition is relatively preserved. The following detailed description of clinical manifestations is based on findings in individuals with a molecularly proven diagnosis [ Nystagmus (either rotatory or horizontal) appears in early infancy and is not present in all individuals. During later infancy, signs of central hypotonia and delayed acquisition of motor milestones become more apparent, with most children having speech delay and dysarthria as well. Over time, progressive pyramidal tract involvement (manifest as spasticity, brisk deep tendon reflexes, and bilateral Babinski signs) affects the ability to walk. The lower limbs are often more involved than in the upper limbs. Most affected children become wheelchair dependent in their first decade. Cerebellar signs including gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia frequently manifest during childhood. Some develop extrapyramidal movement disorders (choreoathetosis and dystonia), which may contribute to the functional disability. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Cognitive function is relatively preserved: Most individuals have normal cognitive skills or mild intellectual disability that may be difficult to evaluate in the context of profound motor impairment. Dysarthria may severely impair communication in adolescents and young adults. Other less common findings: Seizures that are typically infrequent and responsive to antiepileptic drugs Sensorineural hearing loss [ Optic atrophy [ Onset is typically in infancy. Although connatal onset is thought to be very rare, one neonate with congenital nystagmus and severe neurologic impairment has been reported [ The following can be normal or delayed: Visual evoked potentials Brain stem auditory evoked potential Somatosensory evoked potential Nerve conduction studies [ Electromyogram is usually normal. Electroencephalography shows nonspecific findings or occasionally (multi)focal epileptiform activity. No genotype-phenotype correlations have been observed with recurrent pathogenic variants. The disease prevalence is not known. • Seizures that are typically infrequent and responsive to antiepileptic drugs • Sensorineural hearing loss [ • Optic atrophy [ • Visual evoked potentials • Brain stem auditory evoked potential • Somatosensory evoked potential • Nerve conduction studies [ ## Clinical Description Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents in the neonatal period or early infancy with nystagmus, often complicated by hypotonia and developmental delay. Over time the hypotonia may evolve into spasticity, and extrapyramidal movement abnormalities may emerge. Older children often manifest significant motor impairments that can also effect communication. Cognition is relatively preserved. The following detailed description of clinical manifestations is based on findings in individuals with a molecularly proven diagnosis [ Nystagmus (either rotatory or horizontal) appears in early infancy and is not present in all individuals. During later infancy, signs of central hypotonia and delayed acquisition of motor milestones become more apparent, with most children having speech delay and dysarthria as well. Over time, progressive pyramidal tract involvement (manifest as spasticity, brisk deep tendon reflexes, and bilateral Babinski signs) affects the ability to walk. The lower limbs are often more involved than in the upper limbs. Most affected children become wheelchair dependent in their first decade. Cerebellar signs including gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia frequently manifest during childhood. Some develop extrapyramidal movement disorders (choreoathetosis and dystonia), which may contribute to the functional disability. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Cognitive function is relatively preserved: Most individuals have normal cognitive skills or mild intellectual disability that may be difficult to evaluate in the context of profound motor impairment. Dysarthria may severely impair communication in adolescents and young adults. Other less common findings: Seizures that are typically infrequent and responsive to antiepileptic drugs Sensorineural hearing loss [ Optic atrophy [ Onset is typically in infancy. Although connatal onset is thought to be very rare, one neonate with congenital nystagmus and severe neurologic impairment has been reported [ The following can be normal or delayed: Visual evoked potentials Brain stem auditory evoked potential Somatosensory evoked potential Nerve conduction studies [ Electromyogram is usually normal. Electroencephalography shows nonspecific findings or occasionally (multi)focal epileptiform activity. • Seizures that are typically infrequent and responsive to antiepileptic drugs • Sensorineural hearing loss [ • Optic atrophy [ • Visual evoked potentials • Brain stem auditory evoked potential • Somatosensory evoked potential • Nerve conduction studies [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been observed with recurrent pathogenic variants. ## Prevalence The disease prevalence is not known. ## Genetically Related (Allelic) Disorders Allelic Disorders AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance See hyperlinked Heterozygous Three individuals with adulthood-onset isolated spastic paraplegia [ One individual with subtle changes on brain MRI and subclinical leukodystrophy (episodes of loss of consciousness associated with loss of bowel and bladder control) [ ## Differential Diagnosis ## Management To establish the extent of disease and needs in an individual diagnosed with Pelizaeus-Merzbacher-like disease 1 (PMLD1), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of Pelizaeus-Merzbacher-Like Disease 1 There is no curative treatment for PMLD1; measures that can be taken to improve the individual's quality of life are summarized in Treatment of Manifestations in Individuals with Pelizaeus-Merzbacher-Like Disease 1 Prevention of Secondary Complications in Individuals with Pelizaeus-Merzbacher-Like Disease 1 Recommended Surveillance for Individuals with Pelizaeus-Merzbacher-Like Disease 1 See Search ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Pelizaeus-Merzbacher-like disease 1 (PMLD1), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of Pelizaeus-Merzbacher-Like Disease 1 ## Treatment of Manifestations There is no curative treatment for PMLD1; measures that can be taken to improve the individual's quality of life are summarized in Treatment of Manifestations in Individuals with Pelizaeus-Merzbacher-Like Disease 1 ## Prevention of Secondary Complications Prevention of Secondary Complications in Individuals with Pelizaeus-Merzbacher-Like Disease 1 ## Surveillance Recommended Surveillance for Individuals with Pelizaeus-Merzbacher-Like Disease 1 ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Pelizaeus-Merzbacher-like disease 1 (PMLD1) is inherited in an autosomal recessive manner. The parents of an affected child are typically obligate heterozygotes (carriers of one Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the • The parents of an affected child are typically obligate heterozygotes (carriers of one • Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance Pelizaeus-Merzbacher-like disease 1 (PMLD1) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are typically obligate heterozygotes (carriers of one Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are typically obligate heterozygotes (carriers of one • Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources No specific resources for Pelizaeus-Merzbacher-Like Disease 1 have been identified by ## Molecular Genetics Pelizaeus-Merzbacher-Like Disease 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Pelizaeus-Merzbacher-Like Disease 1 ( NA = not applicable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Connexins form complex intercellular channels called gap junctions between adjacent cell membranes [ Gap junctions enable the transfer of ions and small molecules between adjacent cells. The function of oligodendrocyte/astrocyte coupling in particular is unknown but appears to be critical for proper myelin formation and maintenance. Mice that do not express Cx47 have a normal phenotype, but have evidence of disrupted myelin (vacuole formation) on pathology. Mice deficient for both oligodendrocyte connexins (Cx47 and Cx32) exhibit a severe phenotype, characterized by seizures, tremor, and development of widespread vacuolated myelin on pathology [ In a mouse model system, ## References ## Literature Cited ## Chapter Notes 17 January 2019 (av) Revision: 21 December 2017 (bp) Review posted live 26 July 2016 (av) Original submission • 17 January 2019 (av) Revision: • 21 December 2017 (bp) Review posted live • 26 July 2016 (av) Original submission ## Revision History 17 January 2019 (av) Revision: 21 December 2017 (bp) Review posted live 26 July 2016 (av) Original submission • 17 January 2019 (av) Revision: • 21 December 2017 (bp) Review posted live • 26 July 2016 (av) Original submission MRI in a male age 36 months with molecularly confirmed PMLD1. Note the diffuse T	[ "CK Abrams, SS Scherer, R Flores-Obando, MM Freidin, S Wong, E Lamantea, L Farina, V Scaioli, D Pareyson, E Salsano. 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Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity.. J Neurosci 2006;26:10984-91", "E Meyer, MA Kurian, NV Morgan, A McNeill, S Pasha, L Tee, R Younis, A Norman, MS van der Knaap, E Wassmer, RC Trembath, L Brueton, ER Maher. Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease.. Mol Genet Metab 2011;104:637-43", "B Odermatt, K Wellershaus, A Wallraff, G Seifert, J Degen, C Euwens, B Fuss, H Büssow, K Schilling, C Steinhäuser, K Willecke. Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.. J Neurosci 2003;23:4549-59", "JL Orthmann-Murphy, M Freidin, E Fischer, SS Scherer, CK Abrams. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins.. 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Two novel gap junction protein alpha 12 gene mutations in two Chinese patients with Pelizaeus-Merzbacher-like disease.. Brain Dev 2010;32:236-43", "SK Wasseff, SS Scherer. Cx32 and Cx47 mediate oligodendrocyte:astrocyte and oligodendrocyte:oligodendrocyte gap junction coupling.. Neurobiol Dis 2011;42:506-13", "K Willecke, J Eiberger, J Degen, D Eckardt, A Romualdi, M Güldenagel, U Deutsch, G Söhl. Structural and functional diversity of connexin genes in the mouse and human genome.. Biol Chem 2002;383:725-37", "NI Wolf, M Cundall, P Rutland, E Rosser, R Surtees, S Benton, WK Chong, S Malcolm, F Ebinger, M Bitner-Glindzicz, KJ Woodward. Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.. Neurogenetics 2007;8:39-44", "S Zittel, M Nickel, NI Wolf, G Uyanik, D Gläser, C Ganos, C Gerloff, A Münchau, A Kohlschütter. \"Pelizaeus-Merzbacher-like disease\" presenting as complicated hereditary spastic paraplegia.. 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pnknd	pnknd	[ "Paroxysmal Dystonic Choreoathetosis", "Paroxysmal Nonkinesigenic Dyskinesia", "PNKD", "PNKD", "Paroxysmal Dystonic Choreoathetosis", "Paroxysmal Nonkinesigenic Dyskinesia", "Probable thioesterase PNKD", "PNKD", "Familial Paroxysmal Nonkinesigenic Dyskinesia" ]	Familial Paroxysmal Nonkinesigenic Dyskinesia	Roberto Erro	Summary Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are typically precipitated by coffee, tea, or alcohol; they can also be triggered by excitement, stress, or fatigue, or can be spontaneous. Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day. Attack frequency, duration, severity, and combinations of symptoms vary within and among families. Age of onset is typically in childhood or early teens but can be as late as age 50 years. The clinical diagnosis of familial PNKD is suspected in a proband who presents with attacks of dystonia, chorea, and/or ballismus typically provoked by alcohol or caffeine. Identification of a heterozygous pathogenic variant in Familial PNKD is inherited in an autosomal dominant manner. To date, all reported individuals with familial PNKD have inherited PNKD from an affected parent. Offspring of an affected individual have a 50% chance of inheriting the	## Diagnosis Familial paroxysmal nonkinesigenic dyskinesia (PNKD) Attacks: Of dystonia, chorea, and/or ballismus, with onset during infancy That can be provoked by alcohol or caffeine Not typically triggered by sudden movement or sustained exercise Lasting several minutes to hours Rarely occurring more than once per day No loss of consciousness during an attack Poor response to pharmacologic treatment (although clonazepam or diazepam can be effective) Normal: Interictal neurologic examination Brain MRI EEG Family history consistent with autosomal dominant inheritance The diagnosis of familial PNKD is Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PNKD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of PNKD, molecular genetic testing approaches can include Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving For an introduction to multigene panels click When the diagnosis of PNKD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic Dyskinesia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No multiexon or whole-gene deletions or duplications have been reported in families with PNKD (see • Attacks: • Of dystonia, chorea, and/or ballismus, with onset during infancy • That can be provoked by alcohol or caffeine • Not typically triggered by sudden movement or sustained exercise • Lasting several minutes to hours • Rarely occurring more than once per day • Of dystonia, chorea, and/or ballismus, with onset during infancy • That can be provoked by alcohol or caffeine • Not typically triggered by sudden movement or sustained exercise • Lasting several minutes to hours • Rarely occurring more than once per day • No loss of consciousness during an attack • Poor response to pharmacologic treatment (although clonazepam or diazepam can be effective) • Normal: • Interictal neurologic examination • Brain MRI • EEG • Interictal neurologic examination • Brain MRI • EEG • Family history consistent with autosomal dominant inheritance • Of dystonia, chorea, and/or ballismus, with onset during infancy • That can be provoked by alcohol or caffeine • Not typically triggered by sudden movement or sustained exercise • Lasting several minutes to hours • Rarely occurring more than once per day • Interictal neurologic examination • Brain MRI • EEG • Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving • For an introduction to multigene panels click ## Suggestive Findings Familial paroxysmal nonkinesigenic dyskinesia (PNKD) Attacks: Of dystonia, chorea, and/or ballismus, with onset during infancy That can be provoked by alcohol or caffeine Not typically triggered by sudden movement or sustained exercise Lasting several minutes to hours Rarely occurring more than once per day No loss of consciousness during an attack Poor response to pharmacologic treatment (although clonazepam or diazepam can be effective) Normal: Interictal neurologic examination Brain MRI EEG Family history consistent with autosomal dominant inheritance • Attacks: • Of dystonia, chorea, and/or ballismus, with onset during infancy • That can be provoked by alcohol or caffeine • Not typically triggered by sudden movement or sustained exercise • Lasting several minutes to hours • Rarely occurring more than once per day • Of dystonia, chorea, and/or ballismus, with onset during infancy • That can be provoked by alcohol or caffeine • Not typically triggered by sudden movement or sustained exercise • Lasting several minutes to hours • Rarely occurring more than once per day • No loss of consciousness during an attack • Poor response to pharmacologic treatment (although clonazepam or diazepam can be effective) • Normal: • Interictal neurologic examination • Brain MRI • EEG • Interictal neurologic examination • Brain MRI • EEG • Family history consistent with autosomal dominant inheritance • Of dystonia, chorea, and/or ballismus, with onset during infancy • That can be provoked by alcohol or caffeine • Not typically triggered by sudden movement or sustained exercise • Lasting several minutes to hours • Rarely occurring more than once per day • Interictal neurologic examination • Brain MRI • EEG ## Establishing the Diagnosis The diagnosis of familial PNKD is Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PNKD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of PNKD, molecular genetic testing approaches can include Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving For an introduction to multigene panels click When the diagnosis of PNKD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic Dyskinesia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No multiexon or whole-gene deletions or duplications have been reported in families with PNKD (see • Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of PNKD, molecular genetic testing approaches can include Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving For an introduction to multigene panels click • Note: The usefulness of deletion/duplication analysis is unknown as no deletions or duplications involving • For an introduction to multigene panels click ## Option 2 When the diagnosis of PNKD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Paroxysmal Nonkinesigenic Dyskinesia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No multiexon or whole-gene deletions or duplications have been reported in families with PNKD (see ## Clinical Characteristics Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are often precipitated by caffeinated beverages but can also be spontaneous or triggered by excitement, stress, fatigue, and very rarely by sudden movements or prolonged exercise [ The clinical description of this disorder is based on the following citations, unless otherwise noted: Age of onset is typically in infancy or childhood but can in rare cases be as late as age 50 years. The attacks predominantly involve dystonic posturing with some choreic and ballistic movements. Individuals often experience an aura-like sensation preceding the attacks. Attacks are never associated with a loss of consciousness and never occur during sleep. Attacks can occur as frequently as once or twice per day or as infrequently as once or twice per year. Although attacks can rarely be as short as 30 seconds, more frequently they last five minutes to six hours. In 50%-60% of individuals with familial PNKD, the frequency of attacks diminishes with age. Expressivity is variable within and among families. Varying degrees of severity in symptoms occur; attacks involving respiratory muscles are potentially life threatening [ Unlike familial paroxysmal kinesigenic dyskinesia (PKD), familial PNKD is not typically associated with seizures. When PNKD co-occurs with epilepsy, other genetic disorders should be considered (see There are currently no known genotype-phenotype correlations. Familial PNKD is classified as paroxysmal dyskinesia [ A study by Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours Normal neurologic examination results between attacks, and exclusion of secondary causes Onset of attacks in infancy or early childhood Precipitation of attacks by caffeine and alcohol consumption Family history of movement disorder meeting all preceding criteria Familial paroxysmal choreoathetosis Paroxysmal dystonic choreoathetosis DYT8 DYT- Familial PNKD is extremely rare; exact prevalence is unknown. • A study by • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks, and exclusion of secondary causes • Onset of attacks in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks, and exclusion of secondary causes • Onset of attacks in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks, and exclusion of secondary causes • Onset of attacks in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all preceding criteria • Familial paroxysmal choreoathetosis • Paroxysmal dystonic choreoathetosis • DYT8 • DYT- ## Clinical Description Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by unilateral or bilateral involuntary movements. Attacks are often precipitated by caffeinated beverages but can also be spontaneous or triggered by excitement, stress, fatigue, and very rarely by sudden movements or prolonged exercise [ The clinical description of this disorder is based on the following citations, unless otherwise noted: Age of onset is typically in infancy or childhood but can in rare cases be as late as age 50 years. The attacks predominantly involve dystonic posturing with some choreic and ballistic movements. Individuals often experience an aura-like sensation preceding the attacks. Attacks are never associated with a loss of consciousness and never occur during sleep. Attacks can occur as frequently as once or twice per day or as infrequently as once or twice per year. Although attacks can rarely be as short as 30 seconds, more frequently they last five minutes to six hours. In 50%-60% of individuals with familial PNKD, the frequency of attacks diminishes with age. Expressivity is variable within and among families. Varying degrees of severity in symptoms occur; attacks involving respiratory muscles are potentially life threatening [ Unlike familial paroxysmal kinesigenic dyskinesia (PKD), familial PNKD is not typically associated with seizures. When PNKD co-occurs with epilepsy, other genetic disorders should be considered (see ## Genotype-Phenotype Correlations There are currently no known genotype-phenotype correlations. ## Penetrance ## Nomenclature Familial PNKD is classified as paroxysmal dyskinesia [ A study by Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours Normal neurologic examination results between attacks, and exclusion of secondary causes Onset of attacks in infancy or early childhood Precipitation of attacks by caffeine and alcohol consumption Family history of movement disorder meeting all preceding criteria Familial paroxysmal choreoathetosis Paroxysmal dystonic choreoathetosis DYT8 DYT- • A study by • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks, and exclusion of secondary causes • Onset of attacks in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks, and exclusion of secondary causes • Onset of attacks in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all preceding criteria • Hyperkinetic involuntary movement attacks, with dystonia, chorea, or a combination of these, typically lasting ten minutes to one hour, but potentially up to four hours • Normal neurologic examination results between attacks, and exclusion of secondary causes • Onset of attacks in infancy or early childhood • Precipitation of attacks by caffeine and alcohol consumption • Family history of movement disorder meeting all preceding criteria • Familial paroxysmal choreoathetosis • Paroxysmal dystonic choreoathetosis • DYT8 • DYT- ## Prevalence Familial PNKD is extremely rare; exact prevalence is unknown. ## Genetically Related (Allelic) Disorders Affected individuals from one family with isolated hemiplegic migraine were reported to have ## Differential Diagnosis Paroxysmal dyskinesias have been reported in individuals with the following disorders (brain MRI examination is important to rule out these etiologies): Basal ganglia lesions caused by multiple sclerosis Tumors Vascular lesions including moyamoya disease Penetrating brain injury (e.g., right frontal) Central pontine myelinolysis Disorders to Consider in the Differential Diagnosis of Familial PNKD Are triggered by sudden movement; Last secs to mins; May occur 100x/day; Do not cause loss of consciousness, & persons have normal ictal EEG. Episodic ataxia; Hemiplegic migraine. Lasts 5-30 mins; Can be part of a complex neurologic syndrome incl epilepsy, DD, ataxia, & spasticity. Incl dystonia, chorea, & ballism Episodes generally occur during non-REM sleep, often evoking arousal followed again by sleep. Persons are able to recall the episodes in the morning. Attacks of PNKD can be triggered by alcohol or coffee. Persons also have epilepsy &/or DD. Non-progressive choreiform movements Severely affected persons can be disabled by the chorea. Paroxysmal attacks of dystonia & chorea often in the form of PED Attacks can be isolated or assoc w/signs & symptoms of Leigh syndrome. AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; PED = paroxysmal exercise-induced dyskinesia; XL = X-linked Heterozygous pathogenic variants in • Basal ganglia lesions caused by multiple sclerosis • Tumors • Vascular lesions including moyamoya disease • Penetrating brain injury (e.g., right frontal) • Central pontine myelinolysis • Are triggered by sudden movement; • Last secs to mins; • May occur 100x/day; • Do not cause loss of consciousness, & persons have normal ictal EEG. • Episodic ataxia; • Hemiplegic migraine. • Lasts 5-30 mins; • Can be part of a complex neurologic syndrome incl epilepsy, DD, ataxia, & spasticity. • Incl dystonia, chorea, & ballism • Episodes generally occur during non-REM sleep, often evoking arousal followed again by sleep. • Persons are able to recall the episodes in the morning. • Attacks of PNKD can be triggered by alcohol or coffee. • Persons also have epilepsy &/or DD. • Non-progressive choreiform movements • Severely affected persons can be disabled by the chorea. • Paroxysmal attacks of dystonia & chorea often in the form of PED • Attacks can be isolated or assoc w/signs & symptoms of Leigh syndrome. ## Inherited Causes of Paroxysmal Dyskinesia Disorders to Consider in the Differential Diagnosis of Familial PNKD Are triggered by sudden movement; Last secs to mins; May occur 100x/day; Do not cause loss of consciousness, & persons have normal ictal EEG. Episodic ataxia; Hemiplegic migraine. Lasts 5-30 mins; Can be part of a complex neurologic syndrome incl epilepsy, DD, ataxia, & spasticity. Incl dystonia, chorea, & ballism Episodes generally occur during non-REM sleep, often evoking arousal followed again by sleep. Persons are able to recall the episodes in the morning. Attacks of PNKD can be triggered by alcohol or coffee. Persons also have epilepsy &/or DD. Non-progressive choreiform movements Severely affected persons can be disabled by the chorea. Paroxysmal attacks of dystonia & chorea often in the form of PED Attacks can be isolated or assoc w/signs & symptoms of Leigh syndrome. AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; PED = paroxysmal exercise-induced dyskinesia; XL = X-linked Heterozygous pathogenic variants in • Are triggered by sudden movement; • Last secs to mins; • May occur 100x/day; • Do not cause loss of consciousness, & persons have normal ictal EEG. • Episodic ataxia; • Hemiplegic migraine. • Lasts 5-30 mins; • Can be part of a complex neurologic syndrome incl epilepsy, DD, ataxia, & spasticity. • Incl dystonia, chorea, & ballism • Episodes generally occur during non-REM sleep, often evoking arousal followed again by sleep. • Persons are able to recall the episodes in the morning. • Attacks of PNKD can be triggered by alcohol or coffee. • Persons also have epilepsy &/or DD. • Non-progressive choreiform movements • Severely affected persons can be disabled by the chorea. • Paroxysmal attacks of dystonia & chorea often in the form of PED • Attacks can be isolated or assoc w/signs & symptoms of Leigh syndrome. ## Management To establish the extent of disease and needs in an individual diagnosed with familial paroxysmal nonkinesigenic dyskinesia (PNKD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Referral to a neurologist for discussion of treatment options Consultation with a clinical geneticist and/or genetic counselor Avoid triggers (e.g., caffeine, alcohol). Response to pharmacologic treatment is poor; however, clonazepam or diazepam can be effective in at least 50% of individuals with PNKD, although response may decrease over time. A child age four years with familial PNKD responded to gabapentin [ Monitor medication requirements and dosage. See Pregnant women who are on anticonvulsant therapy for familial PNKD are advised to take folic acid (5 mg/day). Because of the risk of teratogenic effects related to anticonvulsants, women with mild symptoms related to familial PNKD may consider discontinuing anticonvulsant therapy during pregnancy. See Search • Referral to a neurologist for discussion of treatment options • Consultation with a clinical geneticist and/or genetic counselor • A child age four years with familial PNKD responded to gabapentin [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with familial paroxysmal nonkinesigenic dyskinesia (PNKD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Referral to a neurologist for discussion of treatment options Consultation with a clinical geneticist and/or genetic counselor • Referral to a neurologist for discussion of treatment options • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Avoid triggers (e.g., caffeine, alcohol). Response to pharmacologic treatment is poor; however, clonazepam or diazepam can be effective in at least 50% of individuals with PNKD, although response may decrease over time. A child age four years with familial PNKD responded to gabapentin [ • A child age four years with familial PNKD responded to gabapentin [ ## Surveillance Monitor medication requirements and dosage. ## Evaluation of Relatives at Risk See ## Pregnancy Management Pregnant women who are on anticonvulsant therapy for familial PNKD are advised to take folic acid (5 mg/day). Because of the risk of teratogenic effects related to anticonvulsants, women with mild symptoms related to familial PNKD may consider discontinuing anticonvulsant therapy during pregnancy. See ## Therapies Under Investigation Search ## Genetic Counseling Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is inherited in an autosomal dominant manner. To date, all reported individuals with PNKD have an affected parent. To date, no individuals diagnosed with PNKD have the disorder as the result of a Neurologic assessment and molecular genetic testing are recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Note: Although to date all individuals diagnosed with familial PNKD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. If the parents have been tested for the A parent of the proband has the The If the parents have not been tested for the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • To date, all reported individuals with PNKD have an affected parent. • To date, no individuals diagnosed with PNKD have the disorder as the result of a • Neurologic assessment and molecular genetic testing are recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Note: Although to date all individuals diagnosed with familial PNKD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. • If the parents have been tested for the • A parent of the proband has the • The • A parent of the proband has the • The • If the parents have not been tested for the • A parent of the proband has the • The • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Familial paroxysmal nonkinesigenic dyskinesia (PNKD) is inherited in an autosomal dominant manner. ## Risk to Family Members To date, all reported individuals with PNKD have an affected parent. To date, no individuals diagnosed with PNKD have the disorder as the result of a Neurologic assessment and molecular genetic testing are recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Note: Although to date all individuals diagnosed with familial PNKD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. If the parents have been tested for the A parent of the proband has the The If the parents have not been tested for the • To date, all reported individuals with PNKD have an affected parent. • To date, no individuals diagnosed with PNKD have the disorder as the result of a • Neurologic assessment and molecular genetic testing are recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Note: Although to date all individuals diagnosed with familial PNKD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. • If the parents have been tested for the • A parent of the proband has the • The • A parent of the proband has the • The • If the parents have not been tested for the • A parent of the proband has the • The ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Familial Paroxysmal Nonkinesigenic Dyskinesia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Familial Paroxysmal Nonkinesigenic Dyskinesia ( Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions PNKD binds to Rab3-interacting molecules (RIMs), a group of proteins playing a role in vesicle priming and calcium-dependent neurotransmitter release, suggesting a possible role in synaptic regulation [ Two reported ## References ## Literature Cited ## Chapter Notes Paul Adams, PhD; University of British Columbia (2004-2019)Roberto Erro, MD, PhD (2019-present)Sian Spacey, MD, FRCPC; University of British Columbia (2004-2019) 4 April 2019 (sw) Comprehensive update posted live 3 May 2011 (me) Comprehensive update posted live 26 August 2008 (cg) Comprehensive update posted live 24 June 2005 (ca) Review posted live 2 December 2004 (ss) Original submission • 4 April 2019 (sw) Comprehensive update posted live • 3 May 2011 (me) Comprehensive update posted live • 26 August 2008 (cg) Comprehensive update posted live • 24 June 2005 (ca) Review posted live • 2 December 2004 (ss) Original submission ## Author History Paul Adams, PhD; University of British Columbia (2004-2019)Roberto Erro, MD, PhD (2019-present)Sian Spacey, MD, FRCPC; University of British Columbia (2004-2019) ## Revision History 4 April 2019 (sw) Comprehensive update posted live 3 May 2011 (me) Comprehensive update posted live 26 August 2008 (cg) Comprehensive update posted live 24 June 2005 (ca) Review posted live 2 December 2004 (ss) Original submission • 4 April 2019 (sw) Comprehensive update posted live • 3 May 2011 (me) Comprehensive update posted live • 26 August 2008 (cg) Comprehensive update posted live • 24 June 2005 (ca) Review posted live • 2 December 2004 (ss) Original submission	[ "KP Bhatia. The paroxysmal dyskinesias.. J Neurol 1999;246:149-55", "KP Bhatia. Familial (idiopathic) paroxysmal dyskinesias: an update.. Semin Neurol 2001;21:69-74", "MK Bruno, HY Lee, GW Auburger, A Friedman, JE Nielsen, AE Lang, E Bertini, P Van Bogaert, Y Averyanov, M Hallett, K Gwinn-Hardy, B Sorenson, M Pandolfo, H Kwiecinski, S Servidei, YH Fu, L Ptácek. Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia.. Neurology 2007;68:1782-9", "RS Chudnow, RA Mimbela, DB Owen, ES Roach. Gabapentin for familial paroxysmal dystonic choreoathetosis.. Neurology 1997;49:1441-2", "M Demirkiran, J Jankovic. Paroxysmal dyskinesias: clinical features and classification.. Ann Neurol 1995;38:571-9", "A Djarmati, M Svetel, D Momcilovic, V Kostic, C Klein. Significance of recurrent mutations in the myofibrillogenesis regulator 1 gene.. Arch Neurol 2005;62:1641", "M Engelen, MA Tijssen. Paroxysmal non-kinesigenic dyskinesia in antiphospholipid syndrome.. Mov Disord 2005;20:111-3", "R Erro, KP Bhatia. Unravelling of the paroxysmal dyskinesias.. J Neurol Neurosurg Psychiatry. 2019;90:227-34", "R Erro, KP Bhatia, AJ Espay, P Striano. The epileptic and nonepileptic spectrum of paroxysmal dyskinesias: channelopathies, synaptopathies, and transportopathies.. Mov Disord. 2017;32:310-8", "R Erro, UM Sheerin, KP Bhatia. Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification.. Mov Disord. 2014;29:1108-16", "AR Gardiner, F Jaffer, RC Dale, R Labrum, R Erro, E Meyer, G Xiromerisiou, M Stamelou, M Walker, D Kullmann, T Warner, P Jarman, M Hanna, MA Kurian, KP Bhatia, H Houlden. The clinical and genetic heterogeneity of paroxysmal dyskinesias.. Brain. 2015;138:3567-80", "HY Lee, Y Xu, Y Huang, AH Ahn, GW Auburger, M Pandolfo, H Kwiecinski, DA Grimes, AE Lang, JE Nielsen, Y Averyanov, S Servidei, A Friedman, P Van Bogaert, MJ Abramowicz, MK Bruno, BF Sorensen, L Tang, YH Fu, LJ Ptacek. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.. Hum Mol Genet 2004;13:3161-70", "FH Mahmud, A Linglart, M Bastepe, H Juppner, AN Lteif. Molecular diagnosis of pseudohypoparathyroidism type Ib in a family with presumed paroxysmal dyskinesia.. Pediatrics 2005;115:e242-4", "R Pons, E Cuenca-Leon, E Miravet. Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: report of two Southern European families.. Eur J Paediatr Neurol 2012;16:86-89", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "S Rainier, D Thomas, D Tokarz, L Ming, M Bui, E Plein, X Zhao, R Lemons, R Albin, C Delaney, D Alvarado, JK Fink. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis.. Arch Neurol 2004;61:1025-9", "Y Shen, WP Ge, Y Li, A Hirano, HY Lee, A Rohlmann, M Missler, RW Tsien, LY Jan, YH Fu, LJ Ptáček. Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis.. Proc Natl Acad Sci U S A. 2015;112:2935-41", "Y Shen, HY Lee, J Rawson, S Ojha, P Babbitt, YH Fu, LJ Ptacek. Mutations in PNKD causing paroxysmal dyskinesia alters protein cleavage and stability.. Hum Mol Genet. 2011;20:2322-32", "E Stefanova, A Djarmati, D Momcilovic´. Clinical characteristics of paroxysmal nonkinesigenic dyskinesia in Serbian family with myofibrillogenesis regulator 1 gene mutation.. Mov Disord. 2006;21:2010-2015", "K Szczałuba, M Jurek, E Szczepanik, A Friedman, M Milewski, J Bal, T. Mazurczak. A family with paroxysmal nonkinesigenic dyskinesia: genetic and treatment issues.. Pediatr Neurol. 2009;41:135-8", "TH Yeh, J Lin, S Lai, Y Wu-chou, A Chen. Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family.. J Neurol Sci. 2012;323:80-4", "S Zittel, C Ganos, A Münchau. Fatal paroxysmal non-kinesigenic dyskinesia.. Eur J Neurol. 2015;22:e30-1" ]	24/6/2005	4/4/2019		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pnpla6-dis	pnpla6-dis	[ "Spastic Paraplegia Type 39 (SPG39)", "Boucher-Neuhäuser Syndrome (BNS)", "PNPLA6 Gordon Holmes Syndrome (GHS)", "Oliver-McFarlane Syndrome (OMCS)", "PNPLA6-Related Laurence-Moon Syndrome (LMS)", "Patatin-like phospholipase domain-containing protein 6", "PNPLA6", "PNPLA6 Disorders" ]		Matthis Synofzik, Robert B Hufnagel, Stephan Züchner	Summary The diagnosis of a Ataxia. Continuous training of speech and swallowing, fine-motor skills, gait, and balance Spasticity. Interventions to improve strength and agility and to prevent contractures, such as physical therapy, assistive walking devices and/or ankle-foot orthotics, and drugs to reduce muscle spasticity Chorioretinal dystrophy. Low vision aids when central acuity is reduced; involvement with agencies for the visually impaired, mobility training, and skills for independent living Hypothyroidism. Hormone replacement therapy as soon as identified Growth hormone deficiency. Hormone replacement therapy during childhood and/or adolescence as indicated Hypogonadotropic hypogonadism. Hormone replacement therapy at the expected time of puberty	Boucher-Neuhäuser syndrome (BNS) Oliver-McFarlane syndrome (OMCS) Spastic paraplegia type 39 (SPG39) • Boucher-Neuhäuser syndrome (BNS) • Oliver-McFarlane syndrome (OMCS) • Spastic paraplegia type 39 (SPG39) ## Diagnosis No consensus clinical diagnostic criteria for A Cerebellar ataxia (associated with cerebellar atrophy) starting before age 50 years and Upper motor neuron involvement presenting as spasticity and/or brisk reflexes Chorioretinal dystrophy starting before age 50 years and leading to variable degrees of reduced visual function, including blindness. The diagnosis of chorioretinal dystrophy may be established by ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [ It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. Hypogonadotropic hypogonadism usually manifest in the first two decades of life Other anterior pituitary hormone deficiencies: Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. Peripheral neuropathy (usually of axonal type) manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting Impaired cognitive functioning unrelated to hormone deficiency that may include learning disabilities in children [ Hair anomalies (long eyelashes, bushy eyebrows, premature graying, or scalp alopecia) Cerebellar atrophy in approximately 90% of all affected individuals [ Small pituitary in 20%-30% of all affected individuals [ Thoracic cord atrophy in one individual [ The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. An intragenic duplication of exons 14-20 in • Cerebellar ataxia (associated with cerebellar atrophy) starting before age 50 years and • Upper motor neuron involvement presenting as spasticity and/or brisk reflexes • Chorioretinal dystrophy starting before age 50 years and leading to variable degrees of reduced visual function, including blindness. The diagnosis of chorioretinal dystrophy may be established by ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [ • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. • Hypogonadotropic hypogonadism usually manifest in the first two decades of life • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. • Other anterior pituitary hormone deficiencies: • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. • Peripheral neuropathy (usually of axonal type) manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting • Impaired cognitive functioning unrelated to hormone deficiency that may include learning disabilities in children [ • Hair anomalies (long eyelashes, bushy eyebrows, premature graying, or scalp alopecia) • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. • Cerebellar atrophy in approximately 90% of all affected individuals [ • Small pituitary in 20%-30% of all affected individuals [ • Thoracic cord atrophy in one individual [ ## Suggestive Findings A Cerebellar ataxia (associated with cerebellar atrophy) starting before age 50 years and Upper motor neuron involvement presenting as spasticity and/or brisk reflexes Chorioretinal dystrophy starting before age 50 years and leading to variable degrees of reduced visual function, including blindness. The diagnosis of chorioretinal dystrophy may be established by ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [ It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. Hypogonadotropic hypogonadism usually manifest in the first two decades of life Other anterior pituitary hormone deficiencies: Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. Peripheral neuropathy (usually of axonal type) manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting Impaired cognitive functioning unrelated to hormone deficiency that may include learning disabilities in children [ Hair anomalies (long eyelashes, bushy eyebrows, premature graying, or scalp alopecia) Cerebellar atrophy in approximately 90% of all affected individuals [ Small pituitary in 20%-30% of all affected individuals [ Thoracic cord atrophy in one individual [ • Cerebellar ataxia (associated with cerebellar atrophy) starting before age 50 years and • Upper motor neuron involvement presenting as spasticity and/or brisk reflexes • Chorioretinal dystrophy starting before age 50 years and leading to variable degrees of reduced visual function, including blindness. The diagnosis of chorioretinal dystrophy may be established by ophthalmologic assessment, including visual acuity, visual field testing, fundoscopy, and optic coherence tomography (OCT) [ • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. • Hypogonadotropic hypogonadism usually manifest in the first two decades of life • It is usually characterized by diffuse atrophy of choroidal vessels and retinal pigment epithelium on fundoscopy, leading to complete loss of the choriocapillaris layer and the retinal pigment epithelium [ • OCT can detect thinning of the retina, loss of layered retinal architecture, and effacement of the choriocapillaris and choroidal vessels. • Autofluorescence photographs and fluorescein angiography provide supplementary diagnostic information by revealing hyper- and hypofluorescent regions of abnormal retinal pigment epithelium and the choriocapillaris. • Other anterior pituitary hormone deficiencies: • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. • Peripheral neuropathy (usually of axonal type) manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting • Impaired cognitive functioning unrelated to hormone deficiency that may include learning disabilities in children [ • Hair anomalies (long eyelashes, bushy eyebrows, premature graying, or scalp alopecia) • Thyroid hormone deficiency may start in infancy, childhood, or adolescence. Onset in infancy may result in intellectual disability and poor growth. • Of note, newborn screening for congenital hypothyroidism may detect some newborns with this disorder. • Growth hormone deficiency onset may occur in infancy, childhood, or adolescence and may lead to short stature. • Cerebellar atrophy in approximately 90% of all affected individuals [ • Small pituitary in 20%-30% of all affected individuals [ • Thoracic cord atrophy in one individual [ ## Establishing the Diagnosis The diagnosis of a Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. An intragenic duplication of exons 14-20 in ## Option 1 For an introduction to multigene panels click ## Option 2 If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. An intragenic duplication of exons 14-20 in ## Clinical Characteristics In all affected individuals reported to date, features of the Some of these features can occur in certain combinations, presenting in partly distinct/partly overlapping clusters on the phenotypic continuum of the BNS = Boucher-Neuhäuser syndrome; GHS = Note: The clusters in this table do not constitute distinct phenotypes, as they may overlap in many affected individuals. Given the limited number of individuals reported to date and the lack of longitudinal studies of affected individuals, a more detailed understanding of the natural history of Gait disturbance is due to Dysarthria and dysphagia are recurrent features in Functional impairment due to Progressive Congenital hypothyroidism and growth hormone deficiency can result in global developmental delay, severe cognitive impairment, and short stature. Hypogonadotropic hypogonadism usually becomes manifest during the second decade of life with delayed puberty and lack of secondary sexual characteristics including primary amenorrhea in females, small penis and testes in males, and absent pubic hair and/or breast development. The relationship of white matter lesions and cortical and cerebellar degeneration with cognitive disability has not been explored in No obvious genotype-phenotype correlation exists, as the same Nor does the phenotype appear to depend on either the location of the pathogenic variant or the pathogenic variant type (e.g., missense and frameshift variants) [ In contrast, • Congenital hypothyroidism and growth hormone deficiency can result in global developmental delay, severe cognitive impairment, and short stature. • Hypogonadotropic hypogonadism usually becomes manifest during the second decade of life with delayed puberty and lack of secondary sexual characteristics including primary amenorrhea in females, small penis and testes in males, and absent pubic hair and/or breast development. ## Clinical Description In all affected individuals reported to date, features of the Some of these features can occur in certain combinations, presenting in partly distinct/partly overlapping clusters on the phenotypic continuum of the BNS = Boucher-Neuhäuser syndrome; GHS = Note: The clusters in this table do not constitute distinct phenotypes, as they may overlap in many affected individuals. Given the limited number of individuals reported to date and the lack of longitudinal studies of affected individuals, a more detailed understanding of the natural history of Gait disturbance is due to Dysarthria and dysphagia are recurrent features in Functional impairment due to Progressive Congenital hypothyroidism and growth hormone deficiency can result in global developmental delay, severe cognitive impairment, and short stature. Hypogonadotropic hypogonadism usually becomes manifest during the second decade of life with delayed puberty and lack of secondary sexual characteristics including primary amenorrhea in females, small penis and testes in males, and absent pubic hair and/or breast development. The relationship of white matter lesions and cortical and cerebellar degeneration with cognitive disability has not been explored in • Congenital hypothyroidism and growth hormone deficiency can result in global developmental delay, severe cognitive impairment, and short stature. • Hypogonadotropic hypogonadism usually becomes manifest during the second decade of life with delayed puberty and lack of secondary sexual characteristics including primary amenorrhea in females, small penis and testes in males, and absent pubic hair and/or breast development. ## Genotype-Phenotype Correlations No obvious genotype-phenotype correlation exists, as the same Nor does the phenotype appear to depend on either the location of the pathogenic variant or the pathogenic variant type (e.g., missense and frameshift variants) [ ## Prevalence In contrast, ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders with Ataxia in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; Mat = Maternal; MOI = mode of inheritance; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa; RP = retinitis pigmentosa; SCA = spinocerebellar ataxia Abetalipoproteinemia is caused by biallelic pathogenic variants in Hypocholesterolemia and reduced lipid-soluble vitamins in serum are due to defective intestinal absorption of lipids. Onset of SCA7 in early childhood or infancy has an especially rapid & aggressive course often associated with failure to thrive & regression of motor milestones. Biallelic pathogenic variants in The principal criterion for diagnosis of AVED is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration in the absence of known causes of malabsorption. See also Chorioretinal dystrophy / To date, pathogenic variants of 24 genes account for 70%-80% of individuals with LCA/EOSRD. LCA/EOSRD is typically inherited in an autosomal recessive manner; rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in See also ## Disorders with Ataxia Disorders with Ataxia in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; Mat = Maternal; MOI = mode of inheritance; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa; RP = retinitis pigmentosa; SCA = spinocerebellar ataxia Abetalipoproteinemia is caused by biallelic pathogenic variants in Hypocholesterolemia and reduced lipid-soluble vitamins in serum are due to defective intestinal absorption of lipids. Onset of SCA7 in early childhood or infancy has an especially rapid & aggressive course often associated with failure to thrive & regression of motor milestones. Biallelic pathogenic variants in The principal criterion for diagnosis of AVED is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration in the absence of known causes of malabsorption. See also ## Chorioretinal Dystrophy / Leber Congenital Amaurosis (LCA) / Early-Onset Severe Retinal Dystrophy (EOSRD) Chorioretinal dystrophy / To date, pathogenic variants of 24 genes account for 70%-80% of individuals with LCA/EOSRD. LCA/EOSRD is typically inherited in an autosomal recessive manner; rarely, LCA/EOSRD is inherited in an autosomal dominant manner as a result of a heterozygous pathogenic variant in See also ## Other Types of Disorders ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Recommended Evaluations Following Initial Diagnosis in Individuals with a Nutritional status Aspiration risk Males: for cryptorchidism, micropenis, delayed puberty Females: for hx of primary amenorrhea Community or online resources such as Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; hx = history; LMN = lower motor neuron; MOI= mode of inheritance; OCT= optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; SPRS = Spastic Paraplegia Rating Scale; UMN = upper motor neuron Medical geneticist, certified genetic counselor, certified advanced genetic nurse No disease-modifying drug treatment exists for Management by multidisciplinary specialists including a neurologist, ophthalmologist, endocrinologist, physical, occupational, and speech therapists, and neuropsychologist is recommended. Treatment of Manifestations in Individuals with a PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils, dressing hooks) Consider adaptive devices to maintain / improve independence in mobility (e.g., canes, walkers, motorized chairs). Provide continuous training in the form of active speech, fine-motor, & gait exercises [ Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist Affected individuals require periodic multidisciplinary reevaluations to assess disease progression and modify treatment strategies ( Note that the frequency of recommended surveillance is at the discretion of treating specialists (usually annually or as symptoms change or as medication needs change). Recommended Surveillance for Individuals with a Neurologic assessment for progression of ataxia; UMN or LMN signs Monitor ataxia progression w/standardized scale (SARA). Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia, spasticity, weakness Monitor BMI. Consult nutritionist. Assess need for high-calorie supplementation. OT/PT = occupational therapy / physical therapy; SARA = Scale for the Assessment and Rating of Ataxia Avoid the following: Alcohol Obesity Inactive, sedentary lifestyle Exposure to medications or chemicals that exacerbate neuropathy. See the Charcot-Marie-Tooth Association See Anecdotally, ataxia may sometimes appear for the first time or worsen during pregnancy. Note: While some individuals with ataxia report a worsening of coordination after general anesthesia, no increased risk has been reported specifically with obstetric anesthesia. Spasticity generally does not change significantly with pregnancy. Search • Nutritional status • Aspiration risk • Males: for cryptorchidism, micropenis, delayed puberty • Females: for hx of primary amenorrhea • Community or online resources such as • Social work involvement for parental support; • Home nursing referral. • PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function • OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils, dressing hooks) • Consider adaptive devices to maintain / improve independence in mobility (e.g., canes, walkers, motorized chairs). • Provide continuous training in the form of active speech, fine-motor, & gait exercises [ • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • Neurologic assessment for progression of ataxia; UMN or LMN signs • Monitor ataxia progression w/standardized scale (SARA). • Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia, spasticity, weakness • Monitor BMI. • Consult nutritionist. • Assess need for high-calorie supplementation. • Alcohol • Obesity • Inactive, sedentary lifestyle • Exposure to medications or chemicals that exacerbate neuropathy. See the Charcot-Marie-Tooth Association ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a Recommended Evaluations Following Initial Diagnosis in Individuals with a Nutritional status Aspiration risk Males: for cryptorchidism, micropenis, delayed puberty Females: for hx of primary amenorrhea Community or online resources such as Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; hx = history; LMN = lower motor neuron; MOI= mode of inheritance; OCT= optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; SPRS = Spastic Paraplegia Rating Scale; UMN = upper motor neuron Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Nutritional status • Aspiration risk • Males: for cryptorchidism, micropenis, delayed puberty • Females: for hx of primary amenorrhea • Community or online resources such as • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations No disease-modifying drug treatment exists for Management by multidisciplinary specialists including a neurologist, ophthalmologist, endocrinologist, physical, occupational, and speech therapists, and neuropsychologist is recommended. Treatment of Manifestations in Individuals with a PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils, dressing hooks) Consider adaptive devices to maintain / improve independence in mobility (e.g., canes, walkers, motorized chairs). Provide continuous training in the form of active speech, fine-motor, & gait exercises [ Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist • PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function • OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils, dressing hooks) • Consider adaptive devices to maintain / improve independence in mobility (e.g., canes, walkers, motorized chairs). • Provide continuous training in the form of active speech, fine-motor, & gait exercises [ • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration ## Surveillance Affected individuals require periodic multidisciplinary reevaluations to assess disease progression and modify treatment strategies ( Note that the frequency of recommended surveillance is at the discretion of treating specialists (usually annually or as symptoms change or as medication needs change). Recommended Surveillance for Individuals with a Neurologic assessment for progression of ataxia; UMN or LMN signs Monitor ataxia progression w/standardized scale (SARA). Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia, spasticity, weakness Monitor BMI. Consult nutritionist. Assess need for high-calorie supplementation. OT/PT = occupational therapy / physical therapy; SARA = Scale for the Assessment and Rating of Ataxia • Neurologic assessment for progression of ataxia; UMN or LMN signs • Monitor ataxia progression w/standardized scale (SARA). • Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia, spasticity, weakness • Monitor BMI. • Consult nutritionist. • Assess need for high-calorie supplementation. ## Agents/Circumstances to Avoid Avoid the following: Alcohol Obesity Inactive, sedentary lifestyle Exposure to medications or chemicals that exacerbate neuropathy. See the Charcot-Marie-Tooth Association • Alcohol • Obesity • Inactive, sedentary lifestyle • Exposure to medications or chemicals that exacerbate neuropathy. See the Charcot-Marie-Tooth Association ## Evaluation of Relatives at Risk See ## Pregnancy Management Anecdotally, ataxia may sometimes appear for the first time or worsen during pregnancy. Note: While some individuals with ataxia report a worsening of coordination after general anesthesia, no increased risk has been reported specifically with obstetric anesthesia. Spasticity generally does not change significantly with pregnancy. ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Although affected sibs usually share most of the same Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Although affected sibs usually share most of the same • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Although affected sibs usually share most of the same Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Although affected sibs usually share most of the same • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • United Kingdom • • • • • • • • • • • • ## Molecular Genetics PNPLA6 Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PNPLA6 Disorders ( The most important functional domain is the EST domain, which de-esterifies phosphatidylcholine (a major component of biologic membranes) into its constituent fatty acids and glycerophosphocholine [ Current knowledge suggests that biallelic De-esterify phosphatidylcholine into fatty acids and glycerophosphocholine. (The lack of adequate glycerophosphocholine may disturb development and maintenance of synaptic connections in a variety of neuronal networks.) Catalyze 2-arachidonoyl lysophosphatidylinositol, thus disturbing the metabolism of lipid membranes [ Notable Variants listed in the table have been provided by the authors. • De-esterify phosphatidylcholine into fatty acids and glycerophosphocholine. (The lack of adequate glycerophosphocholine may disturb development and maintenance of synaptic connections in a variety of neuronal networks.) • Catalyze 2-arachidonoyl lysophosphatidylinositol, thus disturbing the metabolism of lipid membranes [ ## Molecular Pathogenesis The most important functional domain is the EST domain, which de-esterifies phosphatidylcholine (a major component of biologic membranes) into its constituent fatty acids and glycerophosphocholine [ Current knowledge suggests that biallelic De-esterify phosphatidylcholine into fatty acids and glycerophosphocholine. (The lack of adequate glycerophosphocholine may disturb development and maintenance of synaptic connections in a variety of neuronal networks.) Catalyze 2-arachidonoyl lysophosphatidylinositol, thus disturbing the metabolism of lipid membranes [ Notable Variants listed in the table have been provided by the authors. • De-esterify phosphatidylcholine into fatty acids and glycerophosphocholine. (The lack of adequate glycerophosphocholine may disturb development and maintenance of synaptic connections in a variety of neuronal networks.) • Catalyze 2-arachidonoyl lysophosphatidylinositol, thus disturbing the metabolism of lipid membranes [ ## Chapter Notes Matthis Synofzik is a professor for translational genomics of neurodegenerative diseases, following the concept to map the full translational pipeline from mapping disease genes via identifying biomarkers to establishing trial-readiness for rare neurologic diseases. Robert B Hufnagel is a physician-scientist specializing in clinical care, molecular diagnostics, and gene discovery for syndromic ocular disorders. Stephan Züchner is professor of human genomics, with a dedicated interest of mapping disease genes and genomic variation that is related to disease. This work was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (Grant 2191-0-0, to MS, U54NS0657, R01NS075764, R01NS072248); National Eye Institute Intramural Funds (ZIAEY000564, ZIAEY000565); the European Joint Program for Rare Diseases via the PROSPAX consortium (DFG No 441409627 to MS and SZ as an associated partner); the Muscular Dystrophy Association; and the Charcot-Marie-Tooth Association. 10 June 2021 (bp) Comprehensive update posted live 11 June 2015 (me) Comprehensive update posted live 9 October 2014 (me) Review posted live 29 May 2014 (ms) Original submission • 10 June 2021 (bp) Comprehensive update posted live • 11 June 2015 (me) Comprehensive update posted live • 9 October 2014 (me) Review posted live • 29 May 2014 (ms) Original submission ## Author Notes Matthis Synofzik is a professor for translational genomics of neurodegenerative diseases, following the concept to map the full translational pipeline from mapping disease genes via identifying biomarkers to establishing trial-readiness for rare neurologic diseases. Robert B Hufnagel is a physician-scientist specializing in clinical care, molecular diagnostics, and gene discovery for syndromic ocular disorders. Stephan Züchner is professor of human genomics, with a dedicated interest of mapping disease genes and genomic variation that is related to disease. ## Acknowledgments This work was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (Grant 2191-0-0, to MS, U54NS0657, R01NS075764, R01NS072248); National Eye Institute Intramural Funds (ZIAEY000564, ZIAEY000565); the European Joint Program for Rare Diseases via the PROSPAX consortium (DFG No 441409627 to MS and SZ as an associated partner); the Muscular Dystrophy Association; and the Charcot-Marie-Tooth Association. ## Revision History 10 June 2021 (bp) Comprehensive update posted live 11 June 2015 (me) Comprehensive update posted live 9 October 2014 (me) Review posted live 29 May 2014 (ms) Original submission • 10 June 2021 (bp) Comprehensive update posted live • 11 June 2015 (me) Comprehensive update posted live • 9 October 2014 (me) Review posted live • 29 May 2014 (ms) Original submission ## References ## Literature Cited	[]	9/10/2014	10/6/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pnpo-def	pnpo-def	[ "Pyridox(am)ine 5'-Phosphate Oxidase Deficiency", "Pyridox(am)ine 5'-Phosphate Oxidase Deficiency", "Pyridoxal 5'-Phosphate (PLP)-Dependent Epilepsy", "Pyridoxine (PN)-Dependent Epilepsy", "Pyridoxine-5'-phosphate oxidase", "PNPO", "PNPO Deficiency" ]	PNPO Deficiency	Barbara Plecko, Philippa Mills	Summary Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures. The diagnosis of PNPO deficiency is established in a proband with suggestive findings (i.e., infantile onset of a wide range of seizure types resistant to common anti-seizure medications and a positive standardized vitamin B PNPO deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	PNPO Deficiency: Included Phenotypes For synonyms and outdated names, see ## Diagnosis No consensus clinical diagnostic criteria for pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency have been published. PNPO deficiency should be suspected in individuals with the following suggestive clinical phenotypes, positive response to a standardized vitamin B Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements Fetal distress before delivery Low APGAR scores Difficult-to-treat seizures irrespective of a history of fetal distress Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) Cryptogenic infantile or epileptic spasms (i.e., an underlying cause is assumed, but not proven) A standardized vitamin B In the 40% of individuals with PNPO deficiency who are pyridoxine (PN) responsive, the majority show cessation of seizures in one to three days; in others amelioration of clinically evident seizures may take several days or may initially be evident on EEG only. In the 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings. Note: PN- and/or PLP-responsive seizures can also be indicative of other vitamin B Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of There is no biomarker for While simultaneous EEG recording is informative, it may not be practical as improvement may take hours to days. Stages of a standardized vitamin B Cerebrospinal fluid and plasma PLP concentrations, in most instances when reported, are below the reference range prior to administration of PN or PLP. See Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: (1) Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. (2) Families with pathogenic variants segregating with autosomal recessive epileptic encephalopathy may have a history of infertility and miscarriage [ The diagnosis of PNPO deficiency The molecular diagnosis of PNPO deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click When the diagnosis of PNPO deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PNPO Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Diagnosis of PNPO deficiency, irrespective of treatment status, can be confirmed by analysis of PNPO enzyme activity in dried blood spots [ • Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements • Fetal distress before delivery • Low APGAR scores • Difficult-to-treat seizures irrespective of a history of fetal distress • Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) • Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) • Cryptogenic infantile or epileptic spasms (i.e., an underlying cause is assumed, but not proven) • In the 40% of individuals with PNPO deficiency who are pyridoxine (PN) responsive, the majority show cessation of seizures in one to three days; in others amelioration of clinically evident seizures may take several days or may initially be evident on EEG only. • In the 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings. • Note: PN- and/or PLP-responsive seizures can also be indicative of other vitamin B • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for • While simultaneous EEG recording is informative, it may not be practical as improvement may take hours to days. • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for ## Suggestive Findings PNPO deficiency should be suspected in individuals with the following suggestive clinical phenotypes, positive response to a standardized vitamin B Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements Fetal distress before delivery Low APGAR scores Difficult-to-treat seizures irrespective of a history of fetal distress Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) Cryptogenic infantile or epileptic spasms (i.e., an underlying cause is assumed, but not proven) A standardized vitamin B In the 40% of individuals with PNPO deficiency who are pyridoxine (PN) responsive, the majority show cessation of seizures in one to three days; in others amelioration of clinically evident seizures may take several days or may initially be evident on EEG only. In the 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings. Note: PN- and/or PLP-responsive seizures can also be indicative of other vitamin B Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of There is no biomarker for While simultaneous EEG recording is informative, it may not be practical as improvement may take hours to days. Stages of a standardized vitamin B Cerebrospinal fluid and plasma PLP concentrations, in most instances when reported, are below the reference range prior to administration of PN or PLP. See Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: (1) Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. (2) Families with pathogenic variants segregating with autosomal recessive epileptic encephalopathy may have a history of infertility and miscarriage [ • Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements • Fetal distress before delivery • Low APGAR scores • Difficult-to-treat seizures irrespective of a history of fetal distress • Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) • Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) • Cryptogenic infantile or epileptic spasms (i.e., an underlying cause is assumed, but not proven) • In the 40% of individuals with PNPO deficiency who are pyridoxine (PN) responsive, the majority show cessation of seizures in one to three days; in others amelioration of clinically evident seizures may take several days or may initially be evident on EEG only. • In the 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings. • Note: PN- and/or PLP-responsive seizures can also be indicative of other vitamin B • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for • While simultaneous EEG recording is informative, it may not be practical as improvement may take hours to days. • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for ## Clinical Findings Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements Fetal distress before delivery Low APGAR scores Difficult-to-treat seizures irrespective of a history of fetal distress Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) Cryptogenic infantile or epileptic spasms (i.e., an underlying cause is assumed, but not proven) • Intrauterine seizures, recognized by mothers as episodic, repetitive rhythmic movements • Fetal distress before delivery • Low APGAR scores • Difficult-to-treat seizures irrespective of a history of fetal distress • Epileptic encephalopathy or signs of encephalopathy (e.g., inconsolable crying, hyperalertness, jitteriness, irritability, dysregulation of muscle tone) • Seizures and neurologic findings (e.g., roving eye movements, hypotonia, dystonia) and/or systemic signs (e.g., respiratory distress, anemia, failure to gain weight, abdominal distention, poor feeding) • Cryptogenic infantile or epileptic spasms (i.e., an underlying cause is assumed, but not proven) ## Standardized Vitamin B A standardized vitamin B In the 40% of individuals with PNPO deficiency who are pyridoxine (PN) responsive, the majority show cessation of seizures in one to three days; in others amelioration of clinically evident seizures may take several days or may initially be evident on EEG only. In the 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings. Note: PN- and/or PLP-responsive seizures can also be indicative of other vitamin B Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of There is no biomarker for While simultaneous EEG recording is informative, it may not be practical as improvement may take hours to days. Stages of a standardized vitamin B • In the 40% of individuals with PNPO deficiency who are pyridoxine (PN) responsive, the majority show cessation of seizures in one to three days; in others amelioration of clinically evident seizures may take several days or may initially be evident on EEG only. • In the 60% of individuals with PNPO deficiency who are pyridoxal 5'-phosphate (PLP) responsive, the majority show cessation of seizures in one to three days, accompanied by improvement of abnormal EEG findings. • Note: PN- and/or PLP-responsive seizures can also be indicative of other vitamin B • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for • While simultaneous EEG recording is informative, it may not be practical as improvement may take hours to days. • Measurement of biomarkers can help to distinguish PNPO deficiency from some of these disorders (e.g., increased plasma and urinary alpha-aminoadipic semialdehyde is indicative of • There is no biomarker for ## Supportive Laboratory Findings Cerebrospinal fluid and plasma PLP concentrations, in most instances when reported, are below the reference range prior to administration of PN or PLP. See ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. Note: (1) Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation. (2) Families with pathogenic variants segregating with autosomal recessive epileptic encephalopathy may have a history of infertility and miscarriage [ ## Establishing the Diagnosis The diagnosis of PNPO deficiency The molecular diagnosis of PNPO deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click When the diagnosis of PNPO deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PNPO Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Diagnosis of PNPO deficiency, irrespective of treatment status, can be confirmed by analysis of PNPO enzyme activity in dried blood spots [ ## Molecular Genetic Testing The molecular diagnosis of PNPO deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click When the diagnosis of PNPO deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PNPO Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## For an introduction to multigene panels click ## When the diagnosis of PNPO deficiency has not been considered because an individual has atypical clinical findings, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PNPO Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## PNPO Enzyme Activity Diagnosis of PNPO deficiency, irrespective of treatment status, can be confirmed by analysis of PNPO enzyme activity in dried blood spots [ ## Clinical Characteristics As of 2022, approximately 90 individuals have been identified with pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency based on the identification of biallelic pathogenic variants in The following description of the phenotypic features of PNPO deficiency is based on these reports [ Note that the clinical presentations of PNPO deficiency, The spectrum of the PNPO deficiency phenotype ranges from classic (i.e., neonatal-onset seizures) to late-onset seizures (i.e., manifesting after the neonatal period), which can be distinguished by age of onset and seizure patterns. In about 10% of pregnancies, rhythmic fetal movements have been reported in the last trimester, suggesting intrauterine seizure onset. In newborns, seizures caused by PNPO deficiency can be confused with seizures associated with birth asphyxia as a result of prematurity (reported in about 64% of infants) and fetal distress (reported in about 15% of infants). Seizures are typically resistant to common anti-seizure medications. Seizure semiology varies from myoclonic to clonic or tonic seizures. To date, epileptic spasms (ES) have been reported in seven infants with classic PNPO deficiency. In four infants ES was the presenting seizure type (within the first 24 hours of life); three infants who had onset of focal seizures before age one month subsequently developed ES and other seizure types (generalized tonic/clonic/tonic-clonic and focal seizures). EEG records on six individuals showed hypsarrhythmia in three, atypical hypsarrhythmia in two, and burst suppression in one; see Affected individuals may show episodes of roving eye, head movements without ictal EEG patterns, and signs of encephalopathy such as hyperalertness and inconsolable crying [ About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures. The observation of older deceased sibs (with manifestations consistent with PNPO deficiency) in families of probands with PNPO deficiency suggests that the mortality rate of untreated PNPO deficiency is high. In the report by In the report of Patient 3 had an afebrile seizure at age five months and gradually developed therapy-resistant epilepsy and developmental delay; Patient 4 had episodic stiffening at age 40 days that increased to daily seizures by age ten months, controlled by a combination of valproate and topiramate. In the report of Patient 1 had focal clonic status epilepticus at age 20 months; Patient 2 had myoclonic atonic as well as generalized tonic-clonic seizures starting at age three years and two months (diagnosed as myoclonic atonic epilepsy with developmental decline); Patient 3 had episodic stiffening (clustering during febrile episodes) starting at age eight months, subsequent mild cognitive impairment, and occasional seizures while on valproic acid monotherapy. In the report of Seventeen individuals had burst suppression patterns prior to the administration of PLP or PN. Seventeen individuals demonstrated a pattern of multifocal or bilateral epileptic discharges. Three individuals had hypsarrhythmia. Four individuals had a normal EEG. Fifteen individuals had normal initial imaging studies; on follow up, three individuals had brain atrophy or delayed myelination. Fifteen individuals had abnormal initial MRIs ranging from increased brain edema, signal intensity of basal ganglia or white matter, delayed myelination, intraventricular hemorrhage or middle cerebral artery infarction to simplified gyral patterns with shallow sulci. No genotype-phenotype correlations have been reported. Nonetheless, the following observations about PN responsiveness may be helpful in guiding clinical management. See Seizures in individuals homozygous for the variant The seizures of four of the seven individuals reported to be homozygous or compound heterozygous for the variant The majority of individuals who are homozygous for the variant Studies suggest that affected individuals with some variants (e.g., Not all individuals homozygous for the variant Intractable seizures for which seizure control is only partially improved with the addition of PN or PLP; or Seizures that do not recur after PN or PLP is withdrawn. * Pyridoxine-dependent epilepsy caused by pathologic variants in As of 2022, approximately 90 individuals have been identified with biallelic pathogenic variants in Variants found commonly in specific populations include the following (see The variant Individuals from the United Arab Emirates and one individual from Qatar were homozygous for The • Patient 3 had an afebrile seizure at age five months and gradually developed therapy-resistant epilepsy and developmental delay; • Patient 4 had episodic stiffening at age 40 days that increased to daily seizures by age ten months, controlled by a combination of valproate and topiramate. • Patient 1 had focal clonic status epilepticus at age 20 months; • Patient 2 had myoclonic atonic as well as generalized tonic-clonic seizures starting at age three years and two months (diagnosed as myoclonic atonic epilepsy with developmental decline); • Patient 3 had episodic stiffening (clustering during febrile episodes) starting at age eight months, subsequent mild cognitive impairment, and occasional seizures while on valproic acid monotherapy. • Seventeen individuals had burst suppression patterns prior to the administration of PLP or PN. • Seventeen individuals demonstrated a pattern of multifocal or bilateral epileptic discharges. • Three individuals had hypsarrhythmia. • Four individuals had a normal EEG. • Fifteen individuals had normal initial imaging studies; on follow up, three individuals had brain atrophy or delayed myelination. • Fifteen individuals had abnormal initial MRIs ranging from increased brain edema, signal intensity of basal ganglia or white matter, delayed myelination, intraventricular hemorrhage or middle cerebral artery infarction to simplified gyral patterns with shallow sulci. • Seizures in individuals homozygous for the variant • The seizures of four of the seven individuals reported to be homozygous or compound heterozygous for the variant • The majority of individuals who are homozygous for the variant • Intractable seizures for which seizure control is only partially improved with the addition of PN or PLP; or • Seizures that do not recur after PN or PLP is withdrawn. • The variant • Individuals from the United Arab Emirates and one individual from Qatar were homozygous for • The ## Clinical Description As of 2022, approximately 90 individuals have been identified with pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency based on the identification of biallelic pathogenic variants in The following description of the phenotypic features of PNPO deficiency is based on these reports [ Note that the clinical presentations of PNPO deficiency, The spectrum of the PNPO deficiency phenotype ranges from classic (i.e., neonatal-onset seizures) to late-onset seizures (i.e., manifesting after the neonatal period), which can be distinguished by age of onset and seizure patterns. In about 10% of pregnancies, rhythmic fetal movements have been reported in the last trimester, suggesting intrauterine seizure onset. In newborns, seizures caused by PNPO deficiency can be confused with seizures associated with birth asphyxia as a result of prematurity (reported in about 64% of infants) and fetal distress (reported in about 15% of infants). Seizures are typically resistant to common anti-seizure medications. Seizure semiology varies from myoclonic to clonic or tonic seizures. To date, epileptic spasms (ES) have been reported in seven infants with classic PNPO deficiency. In four infants ES was the presenting seizure type (within the first 24 hours of life); three infants who had onset of focal seizures before age one month subsequently developed ES and other seizure types (generalized tonic/clonic/tonic-clonic and focal seizures). EEG records on six individuals showed hypsarrhythmia in three, atypical hypsarrhythmia in two, and burst suppression in one; see Affected individuals may show episodes of roving eye, head movements without ictal EEG patterns, and signs of encephalopathy such as hyperalertness and inconsolable crying [ About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures. The observation of older deceased sibs (with manifestations consistent with PNPO deficiency) in families of probands with PNPO deficiency suggests that the mortality rate of untreated PNPO deficiency is high. In the report by In the report of Patient 3 had an afebrile seizure at age five months and gradually developed therapy-resistant epilepsy and developmental delay; Patient 4 had episodic stiffening at age 40 days that increased to daily seizures by age ten months, controlled by a combination of valproate and topiramate. In the report of Patient 1 had focal clonic status epilepticus at age 20 months; Patient 2 had myoclonic atonic as well as generalized tonic-clonic seizures starting at age three years and two months (diagnosed as myoclonic atonic epilepsy with developmental decline); Patient 3 had episodic stiffening (clustering during febrile episodes) starting at age eight months, subsequent mild cognitive impairment, and occasional seizures while on valproic acid monotherapy. In the report of Seventeen individuals had burst suppression patterns prior to the administration of PLP or PN. Seventeen individuals demonstrated a pattern of multifocal or bilateral epileptic discharges. Three individuals had hypsarrhythmia. Four individuals had a normal EEG. Fifteen individuals had normal initial imaging studies; on follow up, three individuals had brain atrophy or delayed myelination. Fifteen individuals had abnormal initial MRIs ranging from increased brain edema, signal intensity of basal ganglia or white matter, delayed myelination, intraventricular hemorrhage or middle cerebral artery infarction to simplified gyral patterns with shallow sulci. • Patient 3 had an afebrile seizure at age five months and gradually developed therapy-resistant epilepsy and developmental delay; • Patient 4 had episodic stiffening at age 40 days that increased to daily seizures by age ten months, controlled by a combination of valproate and topiramate. • Patient 1 had focal clonic status epilepticus at age 20 months; • Patient 2 had myoclonic atonic as well as generalized tonic-clonic seizures starting at age three years and two months (diagnosed as myoclonic atonic epilepsy with developmental decline); • Patient 3 had episodic stiffening (clustering during febrile episodes) starting at age eight months, subsequent mild cognitive impairment, and occasional seizures while on valproic acid monotherapy. • Seventeen individuals had burst suppression patterns prior to the administration of PLP or PN. • Seventeen individuals demonstrated a pattern of multifocal or bilateral epileptic discharges. • Three individuals had hypsarrhythmia. • Four individuals had a normal EEG. • Fifteen individuals had normal initial imaging studies; on follow up, three individuals had brain atrophy or delayed myelination. • Fifteen individuals had abnormal initial MRIs ranging from increased brain edema, signal intensity of basal ganglia or white matter, delayed myelination, intraventricular hemorrhage or middle cerebral artery infarction to simplified gyral patterns with shallow sulci. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been reported. Nonetheless, the following observations about PN responsiveness may be helpful in guiding clinical management. See Seizures in individuals homozygous for the variant The seizures of four of the seven individuals reported to be homozygous or compound heterozygous for the variant The majority of individuals who are homozygous for the variant Studies suggest that affected individuals with some variants (e.g., • Seizures in individuals homozygous for the variant • The seizures of four of the seven individuals reported to be homozygous or compound heterozygous for the variant • The majority of individuals who are homozygous for the variant ## Penetrance Not all individuals homozygous for the variant ## Nomenclature Intractable seizures for which seizure control is only partially improved with the addition of PN or PLP; or Seizures that do not recur after PN or PLP is withdrawn. * Pyridoxine-dependent epilepsy caused by pathologic variants in • Intractable seizures for which seizure control is only partially improved with the addition of PN or PLP; or • Seizures that do not recur after PN or PLP is withdrawn. ## Prevalence As of 2022, approximately 90 individuals have been identified with biallelic pathogenic variants in Variants found commonly in specific populations include the following (see The variant Individuals from the United Arab Emirates and one individual from Qatar were homozygous for The • The variant • Individuals from the United Arab Emirates and one individual from Qatar were homozygous for • The ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis PNPO deficiency must be distinguished from ALDH7A1 deficiency and PLPHP deficiency (also referred to as PLPBP deficiency), as well as other disorders associated with pyridoxine (PN)- and pyridoxal 5'-phosphate (PLP)-responsive seizures (see Selected Disorders of Interest in the Differential Diagnosis of PNPO Deficiency α-AASA = alpha-aminoadipic semialdehyde; ALP = alkaline phosphatase; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; P5C = pyrroline-5-carboxylate; PLP = pyridoxal 5'-phosphate; PN = pyridoxine; sz = seizures Epilepsies that respond to treatment with vitamin B Autosomal recessive mode of inheritance Epilepsies that may respond to treatment with vitamin B Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner. Autosomal dominant mode of inheritance X-linked mode of inheritance ## Other Considerations in the Differential Diagnosis of PNPO Deficiency ## Management No clinical practice guidelines for pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency have been published; however, these are currently being formulated by an international PNPO consortium [Author, personal observation]. To establish the extent of disease and needs in an individual diagnosed with PNPO deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Neurologic examination to evaluate eye movement and muscle tone (for hypotonia or rigidity), and to describe seizure semiology EEG including sleep and wake cycles (preferably with a recording time of two hours) beginning at the time of seizure onset Physical examination including measurement of weight, length, and head circumferenceand evaluation of liver involvement by determination of transaminases, liver function tests, and abdominal ultrasound Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PNPO deficiency in order to facilitate medical and personal decision making Developmental/educational assessment using age-appropriate standardized testing Brain MRI in individuals with abnormal development The two forms of vitamin B Note: Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B Individuals with PNPO deficiency will need lifelong treatment with PLP or PN. PLP is only available as a non-licensed compound outside of Asia. Because PLP is a photosensitive compound that can rapidly degrade when in solution, it should only be dissolved immediately prior to administration to avoid buildup of photochemical degradation products [ In contrast to PN, there is no FDA statement on a safety limit for PLP. PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. While One adolescent underwent liver transplantation at age 15 years because of hepatocellular carcinoma [ Because of this reported toxicity, it may be reasonable to avoid high doses of PLP by adding anti-seizure medications (ASMs) in those patients who do not become seizure free or do not remain seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PNPO deficiency, except in one boy with both PNPO deficiency and mild PN side effects can include sensory (or motor) neuropathy, which is usually reversible with dose reduction. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). Individuals who have become seizure free on vitamin B D-cycloserine can act as a pyridoxine antagonist and increases renal excretion of pyridoxine [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PNPO deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. Supportive care often includes specialists in multiple disciplines, including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with PNPO Deficiency 1st yr of life: every 3-6 mos Children & adults: every 3-12 mos 1st yr of life: every 3-6 mos Thereafter: every 6 mos OR not required in those who are seizure free Age <10 yrs: transaminases & alpha-fetoprotein every 3-6 mos If transaminases are >3x normal, also assess clotting factors Annually (or more frequently as needed) Age >4 yrs: incl elastography Children age <6 yrs: every 4-6 mos Children age >6 yrs: annually PLP = pyridoxal 5'-phosphate Several anti-seizure medications (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP [ Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected. A note of caution: at least one newborn at risk for Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy. As recurrence risk for couples who have had a child with PNPO deficiency is 25%, there has been discussion about the utility of empiric supplementation of PN during pregnancies in women carrying an at-risk fetus. In contrast to reports on PN supplementation in pregnancies at risk for Based on the Search • Neurologic examination to evaluate eye movement and muscle tone (for hypotonia or rigidity), and to describe seizure semiology • EEG including sleep and wake cycles (preferably with a recording time of two hours) beginning at the time of seizure onset • Physical examination including measurement of weight, length, and head circumferenceand evaluation of liver involvement by determination of transaminases, liver function tests, and abdominal ultrasound • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PNPO deficiency in order to facilitate medical and personal decision making • Developmental/educational assessment using age-appropriate standardized testing • Brain MRI in individuals with abnormal development • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PNPO deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • 1st yr of life: every 3-6 mos • Children & adults: every 3-12 mos • 1st yr of life: every 3-6 mos • Thereafter: every 6 mos OR not required in those who are seizure free • Age <10 yrs: transaminases & alpha-fetoprotein every 3-6 mos • If transaminases are >3x normal, also assess clotting factors • Annually (or more frequently as needed) • Age >4 yrs: incl elastography • Children age <6 yrs: every 4-6 mos • Children age >6 yrs: annually • Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected. A note of caution: at least one newborn at risk for • Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PNPO deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Neurologic examination to evaluate eye movement and muscle tone (for hypotonia or rigidity), and to describe seizure semiology EEG including sleep and wake cycles (preferably with a recording time of two hours) beginning at the time of seizure onset Physical examination including measurement of weight, length, and head circumferenceand evaluation of liver involvement by determination of transaminases, liver function tests, and abdominal ultrasound Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PNPO deficiency in order to facilitate medical and personal decision making Developmental/educational assessment using age-appropriate standardized testing Brain MRI in individuals with abnormal development • Neurologic examination to evaluate eye movement and muscle tone (for hypotonia or rigidity), and to describe seizure semiology • EEG including sleep and wake cycles (preferably with a recording time of two hours) beginning at the time of seizure onset • Physical examination including measurement of weight, length, and head circumferenceand evaluation of liver involvement by determination of transaminases, liver function tests, and abdominal ultrasound • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PNPO deficiency in order to facilitate medical and personal decision making • Developmental/educational assessment using age-appropriate standardized testing • Brain MRI in individuals with abnormal development ## Treatment of Manifestations The two forms of vitamin B Note: Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B Individuals with PNPO deficiency will need lifelong treatment with PLP or PN. PLP is only available as a non-licensed compound outside of Asia. Because PLP is a photosensitive compound that can rapidly degrade when in solution, it should only be dissolved immediately prior to administration to avoid buildup of photochemical degradation products [ In contrast to PN, there is no FDA statement on a safety limit for PLP. PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. While One adolescent underwent liver transplantation at age 15 years because of hepatocellular carcinoma [ Because of this reported toxicity, it may be reasonable to avoid high doses of PLP by adding anti-seizure medications (ASMs) in those patients who do not become seizure free or do not remain seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PNPO deficiency, except in one boy with both PNPO deficiency and mild PN side effects can include sensory (or motor) neuropathy, which is usually reversible with dose reduction. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). Individuals who have become seizure free on vitamin B D-cycloserine can act as a pyridoxine antagonist and increases renal excretion of pyridoxine [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PNPO deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. Supportive care often includes specialists in multiple disciplines, including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PNPO deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Targeted Therapy The two forms of vitamin B Note: Because severe apnea and respiratory insufficiency as well as prolonged somnolence can occur with the first administration of either form of vitamin B Individuals with PNPO deficiency will need lifelong treatment with PLP or PN. PLP is only available as a non-licensed compound outside of Asia. Because PLP is a photosensitive compound that can rapidly degrade when in solution, it should only be dissolved immediately prior to administration to avoid buildup of photochemical degradation products [ In contrast to PN, there is no FDA statement on a safety limit for PLP. PLP side effects include possible liver toxicity, which has been observed in a few individuals with PNPO deficiency. While One adolescent underwent liver transplantation at age 15 years because of hepatocellular carcinoma [ Because of this reported toxicity, it may be reasonable to avoid high doses of PLP by adding anti-seizure medications (ASMs) in those patients who do not become seizure free or do not remain seizure free on PLP monotherapy, especially in the presence of elevated transaminases. Likewise, in persons who are PLP dependent who have recurrent seizures, it may be necessary to modify/adjust the dose to weight [Authors, personal experience]. Although PLP inhibits platelet function, no bleeding diathesis has been reported with its use in PNPO deficiency, except in one boy with both PNPO deficiency and mild PN side effects can include sensory (or motor) neuropathy, which is usually reversible with dose reduction. Seizures can recur during febrile episodes and/or with delayed or missed doses. To cover their overnight sleep, some individuals need higher doses in the evening (e.g., 30%-35% of the total daily dose). Individuals who have become seizure free on vitamin B ## Possible Drug Interactions D-cycloserine can act as a pyridoxine antagonist and increases renal excretion of pyridoxine [ PLP interacts with various small molecules: PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B When an individual with PNPO deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B PLP can also react with -SH groups such as that in penicillamine [ PN and presumably also PLP supplementation antagonizes the therapeutic effect of L-dopa. • PLP undergoes a condensation reaction with hydrazines, leading to an increased requirement for vitamin B • When an individual with PNPO deficiency needs treatment with either hydralazine (an antihypertensive medication) or isoniazid (a tuberculostatic drug), the respective dose of PLP or PN may need to be increased. When the actual dose of vitamin B • PLP can also react with -SH groups such as that in penicillamine [ ## Supportive Care Supportive care often includes specialists in multiple disciplines, including neurology, developmental pediatrics, speech-language therapy, physical therapy, and occupational therapy. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## ## Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with PNPO Deficiency 1st yr of life: every 3-6 mos Children & adults: every 3-12 mos 1st yr of life: every 3-6 mos Thereafter: every 6 mos OR not required in those who are seizure free Age <10 yrs: transaminases & alpha-fetoprotein every 3-6 mos If transaminases are >3x normal, also assess clotting factors Annually (or more frequently as needed) Age >4 yrs: incl elastography Children age <6 yrs: every 4-6 mos Children age >6 yrs: annually PLP = pyridoxal 5'-phosphate • 1st yr of life: every 3-6 mos • Children & adults: every 3-12 mos • 1st yr of life: every 3-6 mos • Thereafter: every 6 mos OR not required in those who are seizure free • Age <10 yrs: transaminases & alpha-fetoprotein every 3-6 mos • If transaminases are >3x normal, also assess clotting factors • Annually (or more frequently as needed) • Age >4 yrs: incl elastography • Children age <6 yrs: every 4-6 mos • Children age >6 yrs: annually ## Agents/Circumstances to Avoid Several anti-seizure medications (such as carbamazepine, valproate, phenytoin, and phenobarbital) can cause a low plasma concentration of PLP [ ## Evaluation of Relatives at Risk Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected. A note of caution: at least one newborn at risk for Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy. • Prophylactic treatment with either PN or PLP (whichever was effective in the affected sib) until molecular genetic testing clarifies whether or not the newborn is affected. A note of caution: at least one newborn at risk for • Clinical and EEG monitoring with initiation of treatment with PN or PLP (whichever was effective in the affected sib) at the first sign of seizures or encephalopathy. ## Pregnancy Management As recurrence risk for couples who have had a child with PNPO deficiency is 25%, there has been discussion about the utility of empiric supplementation of PN during pregnancies in women carrying an at-risk fetus. In contrast to reports on PN supplementation in pregnancies at risk for Based on the ## Therapies Under Investigation Search ## Genetic Counseling Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The offspring of an individual with PNPO deficiency will be obligate heterozygotes (carriers) for a pathogenic variant in If an individual with PNPO deficiency has children with an individual who is heterozygous for a Note: The fertility status of adults with PNPO deficiency is not known and there have been no published reports about offspring of affected individuals. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. As the recurrence risk for couples who have a child with PNPO deficiency is 25%, the parents should receive counseling regarding maternal vitamin B It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The offspring of an individual with PNPO deficiency will be obligate heterozygotes (carriers) for a pathogenic variant in • If an individual with PNPO deficiency has children with an individual who is heterozygous for a • Note: The fertility status of adults with PNPO deficiency is not known and there have been no published reports about offspring of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • As the recurrence risk for couples who have a child with PNPO deficiency is 25%, the parents should receive counseling regarding maternal vitamin B • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The offspring of an individual with PNPO deficiency will be obligate heterozygotes (carriers) for a pathogenic variant in If an individual with PNPO deficiency has children with an individual who is heterozygous for a Note: The fertility status of adults with PNPO deficiency is not known and there have been no published reports about offspring of affected individuals. • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The offspring of an individual with PNPO deficiency will be obligate heterozygotes (carriers) for a pathogenic variant in • If an individual with PNPO deficiency has children with an individual who is heterozygous for a • Note: The fertility status of adults with PNPO deficiency is not known and there have been no published reports about offspring of affected individuals. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. As the recurrence risk for couples who have a child with PNPO deficiency is 25%, the parents should receive counseling regarding maternal vitamin B It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • As the recurrence risk for couples who have a child with PNPO deficiency is 25%, the parents should receive counseling regarding maternal vitamin B • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • ## Molecular Genetics PNPO Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PNPO Deficiency ( Vitamin B * Note: The enzyme encoded by Deep intronic variants and intragenic deletions may be missed by sequence analysis that only includes exons and exon/intron boundaries. The effects of variants of uncertain significance can be assessed by analysis of PNPO enzyme activity in dried blood spots [ Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. ## Molecular Pathogenesis Vitamin B * Note: The enzyme encoded by Deep intronic variants and intragenic deletions may be missed by sequence analysis that only includes exons and exon/intron boundaries. The effects of variants of uncertain significance can be assessed by analysis of PNPO enzyme activity in dried blood spots [ Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. ## Chapter Notes Dr Barbara Plecko ( PNPO enzyme analysis is available in the laboratory of Dr Mills. Contact Dr Mills ( Dr Plecko and Dr Mills are also interested in hearing from clinicians treating families affected by vitamin B Dr P Mills is supported by funding from the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. 23 June 2022 (bp) Review posted live 22 November 2021 (bp) Original submission • 23 June 2022 (bp) Review posted live • 22 November 2021 (bp) Original submission ## Author Notes Dr Barbara Plecko ( PNPO enzyme analysis is available in the laboratory of Dr Mills. Contact Dr Mills ( Dr Plecko and Dr Mills are also interested in hearing from clinicians treating families affected by vitamin B ## Acknowledgments Dr P Mills is supported by funding from the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. ## Revision History 23 June 2022 (bp) Review posted live 22 November 2021 (bp) Original submission • 23 June 2022 (bp) Review posted live • 22 November 2021 (bp) Original submission ## Key Sections in this ## References ## Literature Cited	[]	23/6/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
poikiloderma-n	poikiloderma-n	[ "Clericuzio-Type Poikiloderma with Neutropenia", "Clericuzio-Type Poikiloderma with Neutropenia", "U6 snRNA phosphodiesterase 1", "USB1", "Poikiloderma with Neutropenia" ]	Poikiloderma with Neutropenia	Lisa Wang, Carol Clericuzio, Lidia Larizza, Daniela Concolino	Summary Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (appears at ages 6-12 months) followed by post-inflammatory poikiloderma (at age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome, acute myelogenous leukemia, and skin cancer. Other ectodermal findings include thickened nails, nail dystrophy, and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease, and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers. Often the diagnosis of PN can be established in a proband based on clinical findings (post-inflammatory poikiloderma and congenital chronic neutropenia). Unequivocal confirmation of the diagnosis of PN relies on detection of biallelic PN is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Poikiloderma with neutropenia (PN) Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) (See Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis). In the first two years of life, recurrent sinopulmonary infections, often complicated by bronchiectasis Adolescent- and adult-onset non-healing skin ulcers Cellulitis, osteomyelitis Moderate neutropenia: absolute neutrophil count (ANC)* of 500-1,000/µL Severe neutropenia: ANC <500/µL * ANC = white blood cell count (WBC) x % neutrophils Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. In many instances, the clinical diagnosis of poikiloderma with neutropenia (PN) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for pathogenic variants can be performed first in individuals of geographic regions with known founder pathogenic variants (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Poikiloderma with Neutropenia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and canonical and non-canonical splice site variants and small intragenic deletions/insertions; typically, structural rearrangements involving the gene and/or its flanking regions require long read sequencing techniques. For issues to consider in interpretation of sequence analysis results, click Data derived from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae • After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) (See • Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis). • In the first two years of life, recurrent sinopulmonary infections, often complicated by bronchiectasis • Adolescent- and adult-onset non-healing skin ulcers • Cellulitis, osteomyelitis • Moderate neutropenia: absolute neutrophil count (ANC)* of 500-1,000/µL • Severe neutropenia: ANC <500/µL • * ANC = white blood cell count (WBC) x % neutrophils ## Suggestive Findings Poikiloderma with neutropenia (PN) Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) (See Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis). In the first two years of life, recurrent sinopulmonary infections, often complicated by bronchiectasis Adolescent- and adult-onset non-healing skin ulcers Cellulitis, osteomyelitis Moderate neutropenia: absolute neutrophil count (ANC)* of 500-1,000/µL Severe neutropenia: ANC <500/µL * ANC = white blood cell count (WBC) x % neutrophils Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. • Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae • After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) (See • Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis). • In the first two years of life, recurrent sinopulmonary infections, often complicated by bronchiectasis • Adolescent- and adult-onset non-healing skin ulcers • Cellulitis, osteomyelitis • Moderate neutropenia: absolute neutrophil count (ANC)* of 500-1,000/µL • Severe neutropenia: ANC <500/µL • * ANC = white blood cell count (WBC) x % neutrophils ## Clinical Findings Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) (See Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis). In the first two years of life, recurrent sinopulmonary infections, often complicated by bronchiectasis Adolescent- and adult-onset non-healing skin ulcers Cellulitis, osteomyelitis • Between ages six and 12 months, inflammatory eczematous rash appearing first on the limbs and progressing to the trunk, face, and on occasion the pinnae • After age two years, post-inflammatory poikiloderma (areas of hyper- and hypopigmentation, atrophy, and telangiectasias) (See • Note: The telangiectasia may be subclinical and seen only on skin biopsy (which is not necessary for diagnosis). • In the first two years of life, recurrent sinopulmonary infections, often complicated by bronchiectasis • Adolescent- and adult-onset non-healing skin ulcers • Cellulitis, osteomyelitis ## Laboratory Findings Moderate neutropenia: absolute neutrophil count (ANC)* of 500-1,000/µL Severe neutropenia: ANC <500/µL * ANC = white blood cell count (WBC) x % neutrophils • Moderate neutropenia: absolute neutrophil count (ANC)* of 500-1,000/µL • Severe neutropenia: ANC <500/µL • * ANC = white blood cell count (WBC) x % neutrophils ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis In many instances, the clinical diagnosis of poikiloderma with neutropenia (PN) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for pathogenic variants can be performed first in individuals of geographic regions with known founder pathogenic variants (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Poikiloderma with Neutropenia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and canonical and non-canonical splice site variants and small intragenic deletions/insertions; typically, structural rearrangements involving the gene and/or its flanking regions require long read sequencing techniques. For issues to consider in interpretation of sequence analysis results, click Data derived from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 Note: Targeted analysis for pathogenic variants can be performed first in individuals of geographic regions with known founder pathogenic variants (see For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Poikiloderma with Neutropenia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and canonical and non-canonical splice site variants and small intragenic deletions/insertions; typically, structural rearrangements involving the gene and/or its flanking regions require long read sequencing techniques. For issues to consider in interpretation of sequence analysis results, click Data derived from Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics Poikiloderma with neutropenia (PN) is characterized by post-inflammatory poikiloderma and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections and often bronchiectasis. There is increased risk for myelodysplastic syndrome, which may evolve into acute myelogenous leukemia, and skin squamous cell carcinoma. Other ectodermal findings include thickened nails, nail dystrophy, and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease, and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers [ Poikiloderma with Neutropenia: Frequency of Select Features Based on Palmar/plantar hyperkeratosis is common, can range from mild to severe, and can be debilitating [ Calcinosis cutis – small nodules that may be localized to the elbows, knees, and pinnae or can be more diffuse – may develop in childhood [ Children and adults are prone to cellulitis (a manifestation of neutropenia) that may progress to non-healing skin ulcers or even abscesses [ Photosensitivity and blistering have been reported in a few individuals [ Squamous cell carcinoma of the skin has been reported in a handful of individuals at young ages (age 13 to 20 years) [ Most individuals with PN who are not acutely ill have moderate neutropenia, although some have severe neutropenia [ Quantitative immunoglobulins and lymphocyte subset panels are normal. Bone marrow studies have been described in a portion of reported individuals and have shown hypocellularity and premyelodysplastic changes (often defined as <10% abnormal cells), including increased number of immature cells and myeloid maturation defects. Some individuals with PN initially have normal bone marrow studies and subsequently develop bone marrow changes. Global impaired bone marrow production has been reported, affecting the development of all three major lineages [ Facial features are usually normal at birth; however, over time characteristic craniofacial features of prominent forehead, frontal bossing, depressed nasal bridge, and midface retrusion usually develop (see Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [ Macrocephaly and microcephaly Hypermobile fingers with "swan neck deformity" [ Osteomyelitis due to recurrent infections and persistent neutropenia causing loss of digits [ Isolated reports of lens opacity [ Genotype-phenotype correlations have not been established to date. Individuals homozygous for Poikiloderma with neutropenia was termed "immune-deficient poikiloderma" in the publication by In 2005 Van Hove proposed renaming the disorder Clericuzio-type poikiloderma with neutropenia [ First described in the Navajo Native American population [ Pathogenic variant • Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [ • Macrocephaly and microcephaly • Hypermobile fingers with "swan neck deformity" [ • Osteomyelitis due to recurrent infections and persistent neutropenia causing loss of digits [ • Isolated reports of lens opacity [ ## Clinical Description Poikiloderma with neutropenia (PN) is characterized by post-inflammatory poikiloderma and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections and often bronchiectasis. There is increased risk for myelodysplastic syndrome, which may evolve into acute myelogenous leukemia, and skin squamous cell carcinoma. Other ectodermal findings include thickened nails, nail dystrophy, and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease, and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers [ Poikiloderma with Neutropenia: Frequency of Select Features Based on Palmar/plantar hyperkeratosis is common, can range from mild to severe, and can be debilitating [ Calcinosis cutis – small nodules that may be localized to the elbows, knees, and pinnae or can be more diffuse – may develop in childhood [ Children and adults are prone to cellulitis (a manifestation of neutropenia) that may progress to non-healing skin ulcers or even abscesses [ Photosensitivity and blistering have been reported in a few individuals [ Squamous cell carcinoma of the skin has been reported in a handful of individuals at young ages (age 13 to 20 years) [ Most individuals with PN who are not acutely ill have moderate neutropenia, although some have severe neutropenia [ Quantitative immunoglobulins and lymphocyte subset panels are normal. Bone marrow studies have been described in a portion of reported individuals and have shown hypocellularity and premyelodysplastic changes (often defined as <10% abnormal cells), including increased number of immature cells and myeloid maturation defects. Some individuals with PN initially have normal bone marrow studies and subsequently develop bone marrow changes. Global impaired bone marrow production has been reported, affecting the development of all three major lineages [ Facial features are usually normal at birth; however, over time characteristic craniofacial features of prominent forehead, frontal bossing, depressed nasal bridge, and midface retrusion usually develop (see Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [ Macrocephaly and microcephaly Hypermobile fingers with "swan neck deformity" [ Osteomyelitis due to recurrent infections and persistent neutropenia causing loss of digits [ Isolated reports of lens opacity [ • Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [ • Macrocephaly and microcephaly • Hypermobile fingers with "swan neck deformity" [ • Osteomyelitis due to recurrent infections and persistent neutropenia causing loss of digits [ • Isolated reports of lens opacity [ ## Ectodermal Features Palmar/plantar hyperkeratosis is common, can range from mild to severe, and can be debilitating [ Calcinosis cutis – small nodules that may be localized to the elbows, knees, and pinnae or can be more diffuse – may develop in childhood [ Children and adults are prone to cellulitis (a manifestation of neutropenia) that may progress to non-healing skin ulcers or even abscesses [ Photosensitivity and blistering have been reported in a few individuals [ Squamous cell carcinoma of the skin has been reported in a handful of individuals at young ages (age 13 to 20 years) [ ## Hematologic Findings Most individuals with PN who are not acutely ill have moderate neutropenia, although some have severe neutropenia [ Quantitative immunoglobulins and lymphocyte subset panels are normal. ## Myelodysplasia and Hematologic Malignancies Bone marrow studies have been described in a portion of reported individuals and have shown hypocellularity and premyelodysplastic changes (often defined as <10% abnormal cells), including increased number of immature cells and myeloid maturation defects. Some individuals with PN initially have normal bone marrow studies and subsequently develop bone marrow changes. Global impaired bone marrow production has been reported, affecting the development of all three major lineages [ ## Facial Features Facial features are usually normal at birth; however, over time characteristic craniofacial features of prominent forehead, frontal bossing, depressed nasal bridge, and midface retrusion usually develop (see ## Endocrine Manifestations ## Other Findings Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [ Macrocephaly and microcephaly Hypermobile fingers with "swan neck deformity" [ Osteomyelitis due to recurrent infections and persistent neutropenia causing loss of digits [ Isolated reports of lens opacity [ • Epiphora due to lacrimal duct obstruction and vocal cord nodules with hyperkeratinization, resulting in high-pitched voice [ • Macrocephaly and microcephaly • Hypermobile fingers with "swan neck deformity" [ • Osteomyelitis due to recurrent infections and persistent neutropenia causing loss of digits [ • Isolated reports of lens opacity [ ## Genotype-Phenotype Correlations Genotype-phenotype correlations have not been established to date. Individuals homozygous for ## Nomenclature Poikiloderma with neutropenia was termed "immune-deficient poikiloderma" in the publication by In 2005 Van Hove proposed renaming the disorder Clericuzio-type poikiloderma with neutropenia [ ## Prevalence First described in the Navajo Native American population [ Pathogenic variant ## Genetically Related (Allelic) Disorders No phenotypes other than poikiloderma with neutropenia are known to be associated with germline pathogenic variants in ## Differential Diagnosis Of note, prior to Additional considerations in the differential diagnosis of PN include severe congenital Disorders to Consider in the Differential Diagnosis of Poikiloderma with Neutropenia Poikiloderma Acute myelogenous leukemia Myelodysplasia Nail dystrophy Poikiloderma on upper chest/neck Oral leukoplakia, pulmonary fibrosis. & short telomeres (on lab testing) Early-onset poikiloderma Dental abnormalities Nail dystrophy Palmar/plantar hyperkeratosis Skin SCC Short stature Sparse hair & eyebrows/lashes Rash typically starts on face & spreads to extremities. Skeletal defects (incl radial ray defects), GI disturbance, & cataracts Osteosarcoma is the predominant cancer. Neutropenia is cyclic & severe. Not assoc w/poikiloderma or nail dystrophy. Poikiloderma Nail dysplasia Palmar/plantar hyperkeratosis Recurrent bronchitis Short stature Sparse/absent eyelashes &/or eyebrows Thrombocytopenia, marrow hypocellularity Poikiloderma is localized to face. Hypohidrosis, muscle contractures, lymphedema of the extremities, myopathy, exocrine pancreatic insufficiency, & pulmonary fibrosis Poikiloderma Blistering Photosensitivity Skin atrophy Hyperkeratosis Nail dystrophy Loss of dermatoglyphics Mucocutaneous SCC Blistering is early onset & severe, while poikiloderma is later onset. Generalized atrophy & oral mucosal fragility is prominent & may lead to strictures. AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance; PN = poikiloderma with neutropenia; SCC = squamous cell carcinoma; XL = X-linked The mode of inheritance of dyskeratosis congenita & related telomere biology disorders varies by gene (see • Poikiloderma • Acute myelogenous leukemia • Myelodysplasia • Nail dystrophy • Poikiloderma on upper chest/neck • Oral leukoplakia, pulmonary fibrosis. & short telomeres (on lab testing) • Early-onset poikiloderma • Dental abnormalities • Nail dystrophy • Palmar/plantar hyperkeratosis • Skin SCC • Short stature • Sparse hair & eyebrows/lashes • Rash typically starts on face & spreads to extremities. • Skeletal defects (incl radial ray defects), GI disturbance, & cataracts • Osteosarcoma is the predominant cancer. • Neutropenia is cyclic & severe. • Not assoc w/poikiloderma or nail dystrophy. • Poikiloderma • Nail dysplasia • Palmar/plantar hyperkeratosis • Recurrent bronchitis • Short stature • Sparse/absent eyelashes &/or eyebrows • Thrombocytopenia, marrow hypocellularity • Poikiloderma is localized to face. • Hypohidrosis, muscle contractures, lymphedema of the extremities, myopathy, exocrine pancreatic insufficiency, & pulmonary fibrosis • Poikiloderma • Blistering • Photosensitivity • Skin atrophy • Hyperkeratosis • Nail dystrophy • Loss of dermatoglyphics • Mucocutaneous SCC • Blistering is early onset & severe, while poikiloderma is later onset. • Generalized atrophy & oral mucosal fragility is prominent & may lead to strictures. ## Management To establish the extent of disease and needs in an individual diagnosed with poikiloderma with neutropenia (PN), the evaluations summarized in Poikiloderma with Neutropenia: Recommended Evaluations Following Initial Diagnosis CBC w/differential & platelet count Hematology/oncology consultation to eval for need for bone marrow exam (e.g., if >1 cell line is abnormal on CBC) AST & ALT GI eval if hepatosplenomegaly &/or ↑ liver transaminases are present ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; MOI = mode of inheritance; PN = poikiloderma with neutropenia Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Poikiloderma with Neutropenia: Treatment of Manifestations Gentle skin care using bland emollients (creams or ointments) Use of sunscreens w/UVA & UVB protection to ↓ risk of skin cancer Sun-protective clothing 40% urea Compounded salicylic acid mixed in cream or propylene glycol Aggressive antibiotic treatment until clinical resolution & normalization of inflammatory markers. Annual influenza vaccine There is no rationale for immunoglobulin therapy in the absence of low immunoglobulin levels. Consider hyperbaric oxygen treatment for refractory cellulitis, as reported in 1 person. Mgmt of premyelodysplastic changes per hematologist/oncologist Standard mgmt of myelodysplastic syndrome & acute myelogenous leukemia ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor; PN = poikiloderma with neutropenia To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Poikiloderma with Neutropenia: Recommended Surveillance CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; PN = poikiloderma with neutropenia Avoid excessive sun exposure due to the increased risk of skin cancer. Avoid exposure to secondhand cigarette or wood smoke and persons with respiratory illnesses due to increased risk of respiratory infections. It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance for potential complications. Evaluations can include the following: If the If the pathogenic variants in the family are not known: Examination by a clinician familiar with PN to evaluate for the characteristic skin changes Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash See Search • CBC w/differential & platelet count • Hematology/oncology consultation to eval for need for bone marrow exam (e.g., if >1 cell line is abnormal on CBC) • AST & ALT • GI eval if hepatosplenomegaly &/or ↑ liver transaminases are present • Gentle skin care using bland emollients (creams or ointments) • Use of sunscreens w/UVA & UVB protection to ↓ risk of skin cancer • Sun-protective clothing • 40% urea • Compounded salicylic acid mixed in cream or propylene glycol • Aggressive antibiotic treatment until clinical resolution & normalization of inflammatory markers. • Annual influenza vaccine • There is no rationale for immunoglobulin therapy in the absence of low immunoglobulin levels. • Consider hyperbaric oxygen treatment for refractory cellulitis, as reported in 1 person. • Mgmt of premyelodysplastic changes per hematologist/oncologist • Standard mgmt of myelodysplastic syndrome & acute myelogenous leukemia • If the • If the pathogenic variants in the family are not known: • Examination by a clinician familiar with PN to evaluate for the characteristic skin changes • Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash • Examination by a clinician familiar with PN to evaluate for the characteristic skin changes • Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash • Examination by a clinician familiar with PN to evaluate for the characteristic skin changes • Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with poikiloderma with neutropenia (PN), the evaluations summarized in Poikiloderma with Neutropenia: Recommended Evaluations Following Initial Diagnosis CBC w/differential & platelet count Hematology/oncology consultation to eval for need for bone marrow exam (e.g., if >1 cell line is abnormal on CBC) AST & ALT GI eval if hepatosplenomegaly &/or ↑ liver transaminases are present ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; MOI = mode of inheritance; PN = poikiloderma with neutropenia Medical geneticist, certified genetic counselor, certified advanced genetic nurse • CBC w/differential & platelet count • Hematology/oncology consultation to eval for need for bone marrow exam (e.g., if >1 cell line is abnormal on CBC) • AST & ALT • GI eval if hepatosplenomegaly &/or ↑ liver transaminases are present ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Poikiloderma with Neutropenia: Treatment of Manifestations Gentle skin care using bland emollients (creams or ointments) Use of sunscreens w/UVA & UVB protection to ↓ risk of skin cancer Sun-protective clothing 40% urea Compounded salicylic acid mixed in cream or propylene glycol Aggressive antibiotic treatment until clinical resolution & normalization of inflammatory markers. Annual influenza vaccine There is no rationale for immunoglobulin therapy in the absence of low immunoglobulin levels. Consider hyperbaric oxygen treatment for refractory cellulitis, as reported in 1 person. Mgmt of premyelodysplastic changes per hematologist/oncologist Standard mgmt of myelodysplastic syndrome & acute myelogenous leukemia ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor; PN = poikiloderma with neutropenia • Gentle skin care using bland emollients (creams or ointments) • Use of sunscreens w/UVA & UVB protection to ↓ risk of skin cancer • Sun-protective clothing • 40% urea • Compounded salicylic acid mixed in cream or propylene glycol • Aggressive antibiotic treatment until clinical resolution & normalization of inflammatory markers. • Annual influenza vaccine • There is no rationale for immunoglobulin therapy in the absence of low immunoglobulin levels. • Consider hyperbaric oxygen treatment for refractory cellulitis, as reported in 1 person. • Mgmt of premyelodysplastic changes per hematologist/oncologist • Standard mgmt of myelodysplastic syndrome & acute myelogenous leukemia ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Poikiloderma with Neutropenia: Recommended Surveillance CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; PN = poikiloderma with neutropenia ## Agents/Circumstances to Avoid Avoid excessive sun exposure due to the increased risk of skin cancer. Avoid exposure to secondhand cigarette or wood smoke and persons with respiratory illnesses due to increased risk of respiratory infections. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance for potential complications. Evaluations can include the following: If the If the pathogenic variants in the family are not known: Examination by a clinician familiar with PN to evaluate for the characteristic skin changes Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash See • If the • If the pathogenic variants in the family are not known: • Examination by a clinician familiar with PN to evaluate for the characteristic skin changes • Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash • Examination by a clinician familiar with PN to evaluate for the characteristic skin changes • Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash • Examination by a clinician familiar with PN to evaluate for the characteristic skin changes • Complete blood count with differential and platelet count, especially in newborn sibs who have not manifested a skin rash ## Therapies Under Investigation Search ## Genetic Counseling Poikiloderma with neutropenia (PN) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis (see Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Variability in midfacial hypoplasia, poikiloderma, neutropenia [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for the reproductive partners of known carriers and for the reproductive partners individuals affected with PN should be considered, particularly if consanguinity is likely. Founder variants have been identified in several population groups (see Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis (see • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis (see • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis (see • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Variability in midfacial hypoplasia, poikiloderma, neutropenia [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of known carriers and for the reproductive partners individuals affected with PN should be considered, particularly if consanguinity is likely. Founder variants have been identified in several population groups (see ## Mode of Inheritance Poikiloderma with neutropenia (PN) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis (see Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Variability in midfacial hypoplasia, poikiloderma, neutropenia [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis (see • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis (see • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis (see • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Variability in midfacial hypoplasia, poikiloderma, neutropenia [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for the reproductive partners of known carriers and for the reproductive partners individuals affected with PN should be considered, particularly if consanguinity is likely. Founder variants have been identified in several population groups (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of known carriers and for the reproductive partners individuals affected with PN should be considered, particularly if consanguinity is likely. Founder variants have been identified in several population groups (see ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics Poikiloderma with Neutropenia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Poikiloderma with Neutropenia ( USB1 regulates hematopoietic development by primarily acting as microRNA (miRNA) deadenylase [ A study initiated by the management of two affected sibs (one with a non-healing fistula) demonstrated, by multiparametric analyses of their mononuclear cells, the virtual absence of nonclassic CD16 Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. ## Molecular Pathogenesis USB1 regulates hematopoietic development by primarily acting as microRNA (miRNA) deadenylase [ A study initiated by the management of two affected sibs (one with a non-healing fistula) demonstrated, by multiparametric analyses of their mononuclear cells, the virtual absence of nonclassic CD16 Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. ## Chapter Notes Dr Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, particularly osteosarcoma. She has a long-standing interest in Rothmund-Thomson syndrome and related disorders. Dr Clericuzio is a clinical geneticist and dysmorphologist at University of New Mexico Health Sciences Center with an interest in cancer syndromes. She was the first to identify poikiloderma with neutropenia as a unique disorder in 1991. Dr Larizza is a former professor of Medical Genetics at the University of Milan with a long-lasting interest in rare diseases, particularly cancer-predisposing syndromes. In 2010 her group identified We thank Dr D Concolino for providing the photographs in L Larizza thanks Dr EA Colombo (curator of the 22 February 2024 (sw) Comprehensive update posted live 26 October 2017 (bp) Review posted live 19 December 2016 (lw) Original submission • 22 February 2024 (sw) Comprehensive update posted live • 26 October 2017 (bp) Review posted live • 19 December 2016 (lw) Original submission ## Author Notes Dr Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, particularly osteosarcoma. She has a long-standing interest in Rothmund-Thomson syndrome and related disorders. Dr Clericuzio is a clinical geneticist and dysmorphologist at University of New Mexico Health Sciences Center with an interest in cancer syndromes. She was the first to identify poikiloderma with neutropenia as a unique disorder in 1991. Dr Larizza is a former professor of Medical Genetics at the University of Milan with a long-lasting interest in rare diseases, particularly cancer-predisposing syndromes. In 2010 her group identified ## Acknowledgments We thank Dr D Concolino for providing the photographs in L Larizza thanks Dr EA Colombo (curator of the ## Revision History 22 February 2024 (sw) Comprehensive update posted live 26 October 2017 (bp) Review posted live 19 December 2016 (lw) Original submission • 22 February 2024 (sw) Comprehensive update posted live • 26 October 2017 (bp) Review posted live • 19 December 2016 (lw) Original submission ## References ## Literature Cited Post-inflammatory poikiloderma in a boy age ten years; note hypo- and hyperpigmentation. A. Nail dystrophy in a girl age five years B. Dysplastic toenails and squamous cell carcinoma (blue arrow) in a girl age 14 years Three Italian sibs with typical midfacial hypoplasia	[]	26/10/2017	22/2/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pol3-leuk	pol3-leuk	[ "4H Leukodystrophy", "4H Leukodystrophy", "DNA-directed RNA polymerase III subunit RPC1", "DNA-directed RNA polymerase III subunit RPC2", "DNA-directed RNA polymerases I and III subunit RPAC1", "POLR1C", "POLR3A", "POLR3B", "POLR3-Related Leukodystrophy" ]	POLR3-Related Leukodystrophy	Geneviève Bernard, Adeline Vanderver	Summary POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions) Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth) Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3-related leukodystrophy is diagnosed by the combination of classic clinical findings, typical brain MRI features, and the presence of biallelic pathogenic variants in POLR3-related leukodystrophy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants in the family are known.	## Diagnosis POLR3-related leukodystrophy Neurologic dysfunction: progressive cerebellar features, including: Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features Abnormal dentition (e.g., hypodontia, oligodontia, delayed teeth eruption) [ Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe Note: Although this tetrad is highly suggestive of the diagnosis, not all features are present in all individuals who have POLR3-related leukodystrophy. A hypomyelinating leukodystrophy pattern characterized by T Relative preservation of myelination of specific brain structures, i.e. T Variably present: cerebellar atrophy and thinning of the corpus callosum [ Rarely, an atypical MRI pattern with either Selective hypomyelination of the corticospinal tracts; or Cerebellar atrophy with or without focal hypomyelination [ Involvement of the striata and red nuclei [ See The diagnosis of POLR3-related leukodystrophy Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include In French-Canadian individuals, sequencing of If no pathogenic variant is found, sequencing of For individuals of European ancestry sequencing of If a single variant is detected, gene-targeted deletion/duplication analysis of If no pathogenic variant is found, sequencing of For individuals from the non-French-Canadian and non-European ancestry, sequencing can start with either For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in POLR3-Related Leukodystrophy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Neurologic dysfunction: progressive cerebellar features, including: • Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and • To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features • Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and • To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features • Abnormal dentition (e.g., hypodontia, oligodontia, delayed teeth eruption) [ • Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty • Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe • Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and • To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features • A hypomyelinating leukodystrophy pattern characterized by T • Relative preservation of myelination of specific brain structures, i.e. T • Variably present: cerebellar atrophy and thinning of the corpus callosum [ • Rarely, an atypical MRI pattern with either • Selective hypomyelination of the corticospinal tracts; or • Cerebellar atrophy with or without focal hypomyelination [ • Involvement of the striata and red nuclei [ • Selective hypomyelination of the corticospinal tracts; or • Cerebellar atrophy with or without focal hypomyelination [ • Involvement of the striata and red nuclei [ • Selective hypomyelination of the corticospinal tracts; or • Cerebellar atrophy with or without focal hypomyelination [ • Involvement of the striata and red nuclei [ • In French-Canadian individuals, sequencing of • If no pathogenic variant is found, sequencing of • If no pathogenic variant is found, sequencing of • For individuals of European ancestry sequencing of • If a single variant is detected, gene-targeted deletion/duplication analysis of • If no pathogenic variant is found, sequencing of • If a single variant is detected, gene-targeted deletion/duplication analysis of • If no pathogenic variant is found, sequencing of • For individuals from the non-French-Canadian and non-European ancestry, sequencing can start with either • If no pathogenic variant is found, sequencing of • If a single variant is detected, gene-targeted deletion/duplication analysis of • If no pathogenic variant is found, sequencing of ## Suggestive Findings POLR3-related leukodystrophy Neurologic dysfunction: progressive cerebellar features, including: Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features Abnormal dentition (e.g., hypodontia, oligodontia, delayed teeth eruption) [ Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe Note: Although this tetrad is highly suggestive of the diagnosis, not all features are present in all individuals who have POLR3-related leukodystrophy. A hypomyelinating leukodystrophy pattern characterized by T Relative preservation of myelination of specific brain structures, i.e. T Variably present: cerebellar atrophy and thinning of the corpus callosum [ Rarely, an atypical MRI pattern with either Selective hypomyelination of the corticospinal tracts; or Cerebellar atrophy with or without focal hypomyelination [ Involvement of the striata and red nuclei [ See • Neurologic dysfunction: progressive cerebellar features, including: • Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and • To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features • Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and • To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features • Abnormal dentition (e.g., hypodontia, oligodontia, delayed teeth eruption) [ • Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty • Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe • Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and • To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features • A hypomyelinating leukodystrophy pattern characterized by T • Relative preservation of myelination of specific brain structures, i.e. T • Variably present: cerebellar atrophy and thinning of the corpus callosum [ • Rarely, an atypical MRI pattern with either • Selective hypomyelination of the corticospinal tracts; or • Cerebellar atrophy with or without focal hypomyelination [ • Involvement of the striata and red nuclei [ • Selective hypomyelination of the corticospinal tracts; or • Cerebellar atrophy with or without focal hypomyelination [ • Involvement of the striata and red nuclei [ • Selective hypomyelination of the corticospinal tracts; or • Cerebellar atrophy with or without focal hypomyelination [ • Involvement of the striata and red nuclei [ ## Establishing the Diagnosis The diagnosis of POLR3-related leukodystrophy Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular testing approaches can include In French-Canadian individuals, sequencing of If no pathogenic variant is found, sequencing of For individuals of European ancestry sequencing of If a single variant is detected, gene-targeted deletion/duplication analysis of If no pathogenic variant is found, sequencing of For individuals from the non-French-Canadian and non-European ancestry, sequencing can start with either For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in POLR3-Related Leukodystrophy See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • In French-Canadian individuals, sequencing of • If no pathogenic variant is found, sequencing of • If no pathogenic variant is found, sequencing of • For individuals of European ancestry sequencing of • If a single variant is detected, gene-targeted deletion/duplication analysis of • If no pathogenic variant is found, sequencing of • If a single variant is detected, gene-targeted deletion/duplication analysis of • If no pathogenic variant is found, sequencing of • For individuals from the non-French-Canadian and non-European ancestry, sequencing can start with either • If no pathogenic variant is found, sequencing of • If a single variant is detected, gene-targeted deletion/duplication analysis of • If no pathogenic variant is found, sequencing of ## Clinical Characteristics POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurologic (cerebellar, extrapyramidal, pyramidal, and cognitive) and non-neurologic (dental, endocrine, and ocular) features. Before the identification of the involved genes, five overlapping clinical phenotypes were described and are now all recognized as part of the spectrum of POLR3-related leukodystrophy: Individuals may also develop extrapyramidal features – almost always dystonia. Mild pyramidal features are typically present but are not problematic in the vast majority of individuals. An upper-extremity tremor (usually cerebellar in nature) with or without a dystonic component may be a presenting sign. Cognitive decline typically occurs later, except in late-onset cases. Approximately 10% of individuals have later onset and slower progression; they typically present with academic difficulties and cognitive decline which manifests as a plateau in learning at school. Those with later onset may have also behavioral abnormalities. Optic atrophy Cataracts reported in four individuals [ Individuals with A single female infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have biallelic truncating pathogenic variants in Individuals with Those with The common The prevalence of POLR3-related leukodystrophy is unknown. Individuals with POLR3-related leukodystrophy have been identified worldwide [ • Individuals may also develop extrapyramidal features – almost always dystonia. • Mild pyramidal features are typically present but are not problematic in the vast majority of individuals. • An upper-extremity tremor (usually cerebellar in nature) with or without a dystonic component may be a presenting sign. • Cognitive decline typically occurs later, except in late-onset cases. • Approximately 10% of individuals have later onset and slower progression; they typically present with academic difficulties and cognitive decline which manifests as a plateau in learning at school. Those with later onset may have also behavioral abnormalities. • • Optic atrophy • Cataracts reported in four individuals [ • Optic atrophy • Cataracts reported in four individuals [ • Optic atrophy • Cataracts reported in four individuals [ • Individuals with • A single female infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have biallelic truncating pathogenic variants in • Individuals with • Those with • The common ## Clinical Description POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurologic (cerebellar, extrapyramidal, pyramidal, and cognitive) and non-neurologic (dental, endocrine, and ocular) features. Before the identification of the involved genes, five overlapping clinical phenotypes were described and are now all recognized as part of the spectrum of POLR3-related leukodystrophy: Individuals may also develop extrapyramidal features – almost always dystonia. Mild pyramidal features are typically present but are not problematic in the vast majority of individuals. An upper-extremity tremor (usually cerebellar in nature) with or without a dystonic component may be a presenting sign. Cognitive decline typically occurs later, except in late-onset cases. Approximately 10% of individuals have later onset and slower progression; they typically present with academic difficulties and cognitive decline which manifests as a plateau in learning at school. Those with later onset may have also behavioral abnormalities. Optic atrophy Cataracts reported in four individuals [ • Individuals may also develop extrapyramidal features – almost always dystonia. • Mild pyramidal features are typically present but are not problematic in the vast majority of individuals. • An upper-extremity tremor (usually cerebellar in nature) with or without a dystonic component may be a presenting sign. • Cognitive decline typically occurs later, except in late-onset cases. • Approximately 10% of individuals have later onset and slower progression; they typically present with academic difficulties and cognitive decline which manifests as a plateau in learning at school. Those with later onset may have also behavioral abnormalities. • • Optic atrophy • Cataracts reported in four individuals [ • Optic atrophy • Cataracts reported in four individuals [ • Optic atrophy • Cataracts reported in four individuals [ ## Genotype-Phenotype Correlations Individuals with A single female infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have biallelic truncating pathogenic variants in Individuals with Those with The common • Individuals with • A single female infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have biallelic truncating pathogenic variants in • Individuals with • Those with • The common ## Prevalence The prevalence of POLR3-related leukodystrophy is unknown. Individuals with POLR3-related leukodystrophy have been identified worldwide [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Different biallelic pathogenic variants ## Differential Diagnosis The differential diagnosis of POLR3-related leukodystrophy includes other hypomyelinating leukodystrophies. See Hypomyelinating Leukodystrophies to Consider in the Differential Diagnosis of POLR3-Related Leukodystrophy Variable age of onset Severe hypomyelination in earlier-onset forms on brain MRI Prominent cerebellar features in severe "connatal" form of Severity ranging from: neonatal presentation w/nystagmus, axial hypotonia evolving into spastic quadraparesis, & ataxia (PMD); to an infantile-onset disorder (HEMS); to a later-onset presentation w/spastic paraparesis (SPG2) Typically, prominent spasticity & absence of non-neurologic manifestations seen in POLR3-related leukodystrophy In HEMS, individuals present w/infantile-onset nystagmus, gait ataxia, axial hypotonia, & dysarthria with or without spasticity. They have a characteristic brain MRI pattern w/mild T In later-onset forms (spastic paraparesis), no (or more discrete) abnormalities on brain MRI Variable age of onset & severity More severe disease in those w/early-infantile onset Brain MRI findings similar to those seen in PMD, i.e., diffuse hypomyelination but w/characteristic involvement of the brain stem, in particular the pons Spastic paraparesis designated as SPG44 in those w/later onset Typically, early childhood presentation Main non-neurologic clinical features: postnatal growth failure, dysmorphic facial traits, propensity to cavities, skin hypersensitivity to sunlight Neurologic features typically not seen in POLR3-related leukodystrophy: acquired progressive microcephaly, peripheral neuropathy Delayed myelination (instead of hypomyelination), cerebral atrophy & brain calcifications variably seen on MRI Brittle hair "Tiger tail" appearance of hair on light microscopy Skin hypersensitivity to sun exposure Ichthyosis Infertility Neurologic manifestations that may incl ID, microcephaly, ataxia Early childhood onset Cerebellar features On MRI: hypomyelination w/or w/out thinning of the corpus callosum, cerebellar atrophy Variable severity Progressive facial coarsening Onset typically in infancy w/congenital cataracts (variably present) & psychomotor regression Peripheral neuropathy present in most individuals Diffuse hypomyelination w/superimposed T Prominent extrapyramidal features, more specifically dystonia Progressive atrophy of the basal ganglia (specifically the putamen) & cerebellum characteristically seen on brain MRI Differentiated from other hypomyelinating leukodystrophies by multisystemic findings: dysmorphisms; endocrine, cardiac, immune, & musculoskeletal abnormalities 2 main white-matter abnormalities on brain MRI: hypomyelination; multifocal T Structural brain abnormalities (heterotopias, Type 1. Differentiated clinically from the other hypomyelinating leukodystrophies by presence of coarse facial features, hepatosplenomegaly, & cardiomegaly Type 2. Typically differentiated by presence of mild coarsening, growth restriction, & angiokeratoma corporis diffusum On MRI, distinctive hypomyelinating pattern; w/time, atrophy involving both the cerebrum & cerebellum, w/hypointensities of the globi pallidi, substantia nigra, & thalami Hypomyelinating leukodystrophy Cerebellar features Prominent spasticity of the legs Involvement of specific tracts on MRI Peripheral demyelinating neuropathy (leading to sensory deficits & loss of stretch reflexes) Hypomyelinating leukodystrophy (leading to early-onset hypotonia, DD, & nystagmus evolving over time into spasticity & cerebellar ataxia) Hirschsprung disease AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DN = Most affected individuals reported to date have had a • Variable age of onset • Severe hypomyelination in earlier-onset forms on brain MRI • Prominent cerebellar features in severe "connatal" form of • Severity ranging from: neonatal presentation w/nystagmus, axial hypotonia evolving into spastic quadraparesis, & ataxia (PMD); to an infantile-onset disorder (HEMS); to a later-onset presentation w/spastic paraparesis (SPG2) • Typically, prominent spasticity & absence of non-neurologic manifestations seen in POLR3-related leukodystrophy • In HEMS, individuals present w/infantile-onset nystagmus, gait ataxia, axial hypotonia, & dysarthria with or without spasticity. They have a characteristic brain MRI pattern w/mild T • In later-onset forms (spastic paraparesis), no (or more discrete) abnormalities on brain MRI • Variable age of onset & severity • More severe disease in those w/early-infantile onset • Brain MRI findings similar to those seen in PMD, i.e., diffuse hypomyelination but w/characteristic involvement of the brain stem, in particular the pons • Spastic paraparesis designated as SPG44 in those w/later onset • Typically, early childhood presentation • Main non-neurologic clinical features: postnatal growth failure, dysmorphic facial traits, propensity to cavities, skin hypersensitivity to sunlight • Neurologic features typically not seen in POLR3-related leukodystrophy: acquired progressive microcephaly, peripheral neuropathy • Delayed myelination (instead of hypomyelination), cerebral atrophy & brain calcifications variably seen on MRI • Brittle hair • "Tiger tail" appearance of hair on light microscopy • Skin hypersensitivity to sun exposure • Ichthyosis • Infertility • Neurologic manifestations that may incl ID, microcephaly, ataxia • Early childhood onset • Cerebellar features • On MRI: hypomyelination w/or w/out thinning of the corpus callosum, cerebellar atrophy • Variable severity • Progressive facial coarsening • Onset typically in infancy w/congenital cataracts (variably present) & psychomotor regression • Peripheral neuropathy present in most individuals • Diffuse hypomyelination w/superimposed T • Prominent extrapyramidal features, more specifically dystonia • Progressive atrophy of the basal ganglia (specifically the putamen) & cerebellum characteristically seen on brain MRI • Differentiated from other hypomyelinating leukodystrophies by multisystemic findings: dysmorphisms; endocrine, cardiac, immune, & musculoskeletal abnormalities • 2 main white-matter abnormalities on brain MRI: hypomyelination; multifocal T • Structural brain abnormalities (heterotopias, • Type 1. Differentiated clinically from the other hypomyelinating leukodystrophies by presence of coarse facial features, hepatosplenomegaly, & cardiomegaly • Type 2. Typically differentiated by presence of mild coarsening, growth restriction, & angiokeratoma corporis diffusum • On MRI, distinctive hypomyelinating pattern; w/time, atrophy involving both the cerebrum & cerebellum, w/hypointensities of the globi pallidi, substantia nigra, & thalami • Hypomyelinating leukodystrophy • Cerebellar features • Prominent spasticity of the legs • Involvement of specific tracts on MRI • Peripheral demyelinating neuropathy (leading to sensory deficits & loss of stretch reflexes) • Hypomyelinating leukodystrophy (leading to early-onset hypotonia, DD, & nystagmus evolving over time into spasticity & cerebellar ataxia) • Hirschsprung disease ## Management To establish the extent of disease and needs of an individual diagnosed with a POLR3-related leukodystrophy, the following are recommended: Pediatric neurology consultation Swallowing assessment Physiotherapy evaluation Occupational therapy evaluation Speech and language pathology assessment Rehabilitation physician (i.e., physiatrist) consultation Neuropsychology evaluation Brain MRI, if not performed at the time of diagnosis Dentistry consultation Endocrine consultation Ophthalmologic evaluation Ear-nose-and-throat specialist consultation for hypersalivation and swallowing issues Consultation with a clinical geneticist and/or genetic counselor Individualized care by a multidisciplinary team including a pediatric neurologist, clinical geneticist, physiotherapist, occupational therapist, speech and language pathologist, neuropsychologist, rehabilitation physician, dentist, endocrinologist, ophthalmologist, ear-nose-and-throat specialist, and primary care physician is recommended. Manifestations such as ambulation difficulties and seizures are managed in a routine manner. Special caution needs to be taken when managing dysphagia in this disorder as it is known to be quite variable, even in a single day. This is probably due to the prominent cerebellar involvement, leading to more incoordination of swallowing with fatigue, but also with some unpredictability. Dysphagia management is therefore important. Swallowing difficulties will progress over time and individuals may require gastrostomy to manage nutrition. Spasticity and dystonia should be monitored and treated to prevent complications and to improve the quality of life. Hypersalivation is managed with the multidisciplinary team and an otolaryngologist. Treatment must be individualized. Therapies to consider include rehabilitation (e.g., oromotor therapy, behavioral therapy); medical therapy (e.g., anticholinergic medications, botulinum toxin injections); and, in severe cases, surgery (e.g., relocation of the parotid ducts and relocation of the submandibular ducts with or without sublingual gland excision). Learning difficulties are likely to progress slowly. The cognitive involvement is typically much less severe than the motor involvement. In contrast, activities of daily living are likely to become problematic early on in the disease course as motor difficulties make individuals progressively more dependent on assistance from others. Dental manifestations should be managed, when necessary, by a dentist and/or orthodontist. Affected individuals should be followed regularly by an endocrinologist. The decision to treat sex and growth hormone deficiency, when present, should be made on an individual basis. Individuals need to be followed regularly by an ophthalmologist. A significant proportion of affected individuals will have progressive myopia over several years, which will become severe before stabilizing. No general surveillance guidelines have been developed to date; monitoring should be individualized. Avoid the following: Foods that are likely to lead to choking Medications acting on D2 receptor blockers (e.g., neuroleptics such as haloperidol or risperidone, anti-nausea medications such as metoclopramide) as these can exacerbate the extrapyramidal features See Search • Pediatric neurology consultation • Swallowing assessment • Physiotherapy evaluation • Occupational therapy evaluation • Speech and language pathology assessment • Rehabilitation physician (i.e., physiatrist) consultation • Neuropsychology evaluation • Brain MRI, if not performed at the time of diagnosis • Dentistry consultation • Endocrine consultation • Ophthalmologic evaluation • Ear-nose-and-throat specialist consultation for hypersalivation and swallowing issues • Consultation with a clinical geneticist and/or genetic counselor • Foods that are likely to lead to choking • Medications acting on D2 receptor blockers (e.g., neuroleptics such as haloperidol or risperidone, anti-nausea medications such as metoclopramide) as these can exacerbate the extrapyramidal features ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with a POLR3-related leukodystrophy, the following are recommended: Pediatric neurology consultation Swallowing assessment Physiotherapy evaluation Occupational therapy evaluation Speech and language pathology assessment Rehabilitation physician (i.e., physiatrist) consultation Neuropsychology evaluation Brain MRI, if not performed at the time of diagnosis Dentistry consultation Endocrine consultation Ophthalmologic evaluation Ear-nose-and-throat specialist consultation for hypersalivation and swallowing issues Consultation with a clinical geneticist and/or genetic counselor • Pediatric neurology consultation • Swallowing assessment • Physiotherapy evaluation • Occupational therapy evaluation • Speech and language pathology assessment • Rehabilitation physician (i.e., physiatrist) consultation • Neuropsychology evaluation • Brain MRI, if not performed at the time of diagnosis • Dentistry consultation • Endocrine consultation • Ophthalmologic evaluation • Ear-nose-and-throat specialist consultation for hypersalivation and swallowing issues • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Individualized care by a multidisciplinary team including a pediatric neurologist, clinical geneticist, physiotherapist, occupational therapist, speech and language pathologist, neuropsychologist, rehabilitation physician, dentist, endocrinologist, ophthalmologist, ear-nose-and-throat specialist, and primary care physician is recommended. Manifestations such as ambulation difficulties and seizures are managed in a routine manner. Special caution needs to be taken when managing dysphagia in this disorder as it is known to be quite variable, even in a single day. This is probably due to the prominent cerebellar involvement, leading to more incoordination of swallowing with fatigue, but also with some unpredictability. Dysphagia management is therefore important. Swallowing difficulties will progress over time and individuals may require gastrostomy to manage nutrition. Spasticity and dystonia should be monitored and treated to prevent complications and to improve the quality of life. Hypersalivation is managed with the multidisciplinary team and an otolaryngologist. Treatment must be individualized. Therapies to consider include rehabilitation (e.g., oromotor therapy, behavioral therapy); medical therapy (e.g., anticholinergic medications, botulinum toxin injections); and, in severe cases, surgery (e.g., relocation of the parotid ducts and relocation of the submandibular ducts with or without sublingual gland excision). Learning difficulties are likely to progress slowly. The cognitive involvement is typically much less severe than the motor involvement. In contrast, activities of daily living are likely to become problematic early on in the disease course as motor difficulties make individuals progressively more dependent on assistance from others. Dental manifestations should be managed, when necessary, by a dentist and/or orthodontist. Affected individuals should be followed regularly by an endocrinologist. The decision to treat sex and growth hormone deficiency, when present, should be made on an individual basis. Individuals need to be followed regularly by an ophthalmologist. A significant proportion of affected individuals will have progressive myopia over several years, which will become severe before stabilizing. ## Surveillance No general surveillance guidelines have been developed to date; monitoring should be individualized. ## Agents/Circumstances to Avoid Avoid the following: Foods that are likely to lead to choking Medications acting on D2 receptor blockers (e.g., neuroleptics such as haloperidol or risperidone, anti-nausea medications such as metoclopramide) as these can exacerbate the extrapyramidal features • Foods that are likely to lead to choking • Medications acting on D2 receptor blockers (e.g., neuroleptics such as haloperidol or risperidone, anti-nausea medications such as metoclopramide) as these can exacerbate the extrapyramidal features ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling POLR3-related leukodystrophy is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: The phenotype is similar among family members; however, the severity can vary. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: The phenotype is similar among family members; however, the severity can vary. • Heterozygotes (carriers) are asymptomatic. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance POLR3-related leukodystrophy is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: The phenotype is similar among family members; however, the severity can vary. Heterozygotes (carriers) are asymptomatic. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: The phenotype is similar among family members; however, the severity can vary. • Heterozygotes (carriers) are asymptomatic. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources Fighting for People Affected by 4H Leukodystrophy Australia Canada • • Fighting for People Affected by 4H Leukodystrophy • • • • • Australia • • • Canada • • • • • ## Molecular Genetics POLR3-Related Leukodystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for POLR3-Related Leukodystrophy ( Three types of RNA polymerases (Pol I [POLR1], Pol II [POLR2], and Pol III [POLR3]) are responsible for the transcription of DNA into RNA [ In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). No affected individual has been found to have two null pathogenic variants, which may be explained by the role of Western blot studies on fibroblasts and brain tissue from an individual with 4H leukodystrophy and known These later findings have led us to hypothesize that pathogenic variants in No affected individual has been found to have two null pathogenic variants, which may be explained by the role of • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). • POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ • POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ • POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). • POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ • POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ • POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). • POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ • POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ • POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). ## Molecular Pathogenesis Three types of RNA polymerases (Pol I [POLR1], Pol II [POLR2], and Pol III [POLR3]) are responsible for the transcription of DNA into RNA [ In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). No affected individual has been found to have two null pathogenic variants, which may be explained by the role of Western blot studies on fibroblasts and brain tissue from an individual with 4H leukodystrophy and known These later findings have led us to hypothesize that pathogenic variants in No affected individual has been found to have two null pathogenic variants, which may be explained by the role of • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). • POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ • POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ • POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). • POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ • POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ • POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of POLR2). • POLR3 may play a role in the transcription of some miRNAs, but not to the same extent as POLR2 [ • POLR3 is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [ • POLR3 transcribes vault RNAs, which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm). ## No affected individual has been found to have two null pathogenic variants, which may be explained by the role of Western blot studies on fibroblasts and brain tissue from an individual with 4H leukodystrophy and known These later findings have led us to hypothesize that pathogenic variants in ## No affected individual has been found to have two null pathogenic variants, which may be explained by the role of ## ## Chapter Notes Contact information for Dr Geneviève Bernard's laboratory at the Research Institute of the McGill University Health Centre: Email: [email protected] Phone: 514-934-1934 ext 23380 Drs Bernard and Vanderver wish to thank all patients and their families as well as all the collaborators involved in the POLR3-related leukodystrophy project. Dr Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec en Santé (FRQS) 2012-2016 and a Canadian Institute of Health Research New Investigator salary award (2017-2022) (201512MSH-360766-171036). She wishes to thank the Canadian Institutes of Health Research (CIHR MOP-G-287547 and MOP-G2-341146-159133-BRIDG), the Réseau de Médecine Génétique Appliquée (RMGA), the Leuko Dystrophy Foundation, the "Fondation du Grand Défi Pierre Lavoie," the European Leukodystrophy Association, and the "Fondation les Amis D'Elliot," for financing her research projects on leukodystrophies. Dr Vanderver wishes to thank the Intramural Research Program of the National Human Genome Research Institute and the Myelin Disorders Bioregistry Project. 11 May 2017 (ha) Comprehensive update posted live 2 August 2012 (me) Review posted live 1 March 2012 (av) Original submission • 11 May 2017 (ha) Comprehensive update posted live • 2 August 2012 (me) Review posted live • 1 March 2012 (av) Original submission ## Author Notes Contact information for Dr Geneviève Bernard's laboratory at the Research Institute of the McGill University Health Centre: Email: [email protected] Phone: 514-934-1934 ext 23380 ## Acknowledgments Drs Bernard and Vanderver wish to thank all patients and their families as well as all the collaborators involved in the POLR3-related leukodystrophy project. Dr Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec en Santé (FRQS) 2012-2016 and a Canadian Institute of Health Research New Investigator salary award (2017-2022) (201512MSH-360766-171036). She wishes to thank the Canadian Institutes of Health Research (CIHR MOP-G-287547 and MOP-G2-341146-159133-BRIDG), the Réseau de Médecine Génétique Appliquée (RMGA), the Leuko Dystrophy Foundation, the "Fondation du Grand Défi Pierre Lavoie," the European Leukodystrophy Association, and the "Fondation les Amis D'Elliot," for financing her research projects on leukodystrophies. Dr Vanderver wishes to thank the Intramural Research Program of the National Human Genome Research Institute and the Myelin Disorders Bioregistry Project. ## Revision History 11 May 2017 (ha) Comprehensive update posted live 2 August 2012 (me) Review posted live 1 March 2012 (av) Original submission • 11 May 2017 (ha) Comprehensive update posted live • 2 August 2012 (me) Review posted live • 1 March 2012 (av) Original submission ## References Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC, et al. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab. 2015;114:516-26. [ • Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC, et al. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab. 2015;114:516-26. [ ## Published Guidelines / Consensus Statements Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC, et al. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab. 2015;114:516-26. [ • Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC, et al. Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab. 2015;114:516-26. [ ## Literature Cited MRI of the brain of an individual with molecularly confirmed 4H syndrome A. Sagittal T B. Axial T C. Axial T	[]	2/8/2012	11/5/2017		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
poly	poly	[ "Polymicrogyria", "Overview" ]	Polymicrogyria Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Chloe A Stutterd, William B Dobyns, Anna Jansen, Ghayda Mirzaa, Richard J Leventer	Summary The following are the goals of this overview. Describe the neuroimaging Review the Provide an Inform	## Definition and Clinical Characteristics of Polymicrogyria Polymicrogyria (PMG) is a malformation of the developing brain characterized by abnormal cortical lamination and an unusual folding pattern of the cerebral cortex such that all or part of the brain surface is taken up by an excessive number of small gyri (folds). PMG, one of the most common brain malformations, accounts for approximately 20% of all malformations of cortical development [ With high-quality MRI, microgyri and microsulci may be appreciated and stippling of the gray-white junction (a specific feature of PMG not seen in other malformations of cortical development) may be observed [ While PMG is usually an isolated finding (i.e., occurring in the absence of other brain malformations), it can be seen in association with other brain malformations including gray matter heterotopia and ventriculomegaly, as well as abnormalities of the white matter, corpus callosum, brain stem, and cerebellum. MRI – when interpreted by an expert – can reliably differentiate PMG from other malformations of cortical development (see Patterns of PMG: MRI and Clinical Findings All MRI images are T For information on neuropathology of PMG click Other malformations of cortical development that need to be distinguished from PMG: Pachygyria/lissencephaly, a distinct brain malformation in which reduced or absent cortical folding is combined with a thick cortex. Pachygyria and PMG may look similar on low-resolution neuroimaging (e.g., CT) because in both conditions the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth. The cortex in PMG is overfolded but not thickened. The microgyri and microsulci of PMG and stippling of the gray-white junction that can be appreciated with high-quality MRI can distinguish PMG from pachygyria [ Cobblestone lissencephaly, a brain surface that has a bumpy contour resulting from migration of neurons and glial cells through the basement membrane into the leptomeninges. Sometimes regions populated by these misplaced cells are incorrectly initially diagnosed as PMG based on the MRI appearance and are only distinguished from PMG by the presence of other brain abnormalities (e.g., white matter and cerebellar abnormalities) in combination with ocular anomalies and congenital muscular dystrophy. The cobblestone lissencephalies comprise brain malformations associated with congenital muscular dystrophy, including Walker-Warburg syndrome, muscle-eye-brain disease, and Schizencephaly, a specific pattern of PMG that describes a full-thickness cleft in the brain lined by PMG. While either CT or MRI is usually sufficient to diagnose schizencephaly, MRI is preferred when determining if the schizencephaly is open- or closed-lipped. • Pachygyria/lissencephaly, a distinct brain malformation in which reduced or absent cortical folding is combined with a thick cortex. Pachygyria and PMG may look similar on low-resolution neuroimaging (e.g., CT) because in both conditions the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth. The cortex in PMG is overfolded but not thickened. The microgyri and microsulci of PMG and stippling of the gray-white junction that can be appreciated with high-quality MRI can distinguish PMG from pachygyria [ • Cobblestone lissencephaly, a brain surface that has a bumpy contour resulting from migration of neurons and glial cells through the basement membrane into the leptomeninges. Sometimes regions populated by these misplaced cells are incorrectly initially diagnosed as PMG based on the MRI appearance and are only distinguished from PMG by the presence of other brain abnormalities (e.g., white matter and cerebellar abnormalities) in combination with ocular anomalies and congenital muscular dystrophy. The cobblestone lissencephalies comprise brain malformations associated with congenital muscular dystrophy, including Walker-Warburg syndrome, muscle-eye-brain disease, and • Schizencephaly, a specific pattern of PMG that describes a full-thickness cleft in the brain lined by PMG. While either CT or MRI is usually sufficient to diagnose schizencephaly, MRI is preferred when determining if the schizencephaly is open- or closed-lipped. ## Differential Diagnosis Other malformations of cortical development that need to be distinguished from PMG: Pachygyria/lissencephaly, a distinct brain malformation in which reduced or absent cortical folding is combined with a thick cortex. Pachygyria and PMG may look similar on low-resolution neuroimaging (e.g., CT) because in both conditions the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth. The cortex in PMG is overfolded but not thickened. The microgyri and microsulci of PMG and stippling of the gray-white junction that can be appreciated with high-quality MRI can distinguish PMG from pachygyria [ Cobblestone lissencephaly, a brain surface that has a bumpy contour resulting from migration of neurons and glial cells through the basement membrane into the leptomeninges. Sometimes regions populated by these misplaced cells are incorrectly initially diagnosed as PMG based on the MRI appearance and are only distinguished from PMG by the presence of other brain abnormalities (e.g., white matter and cerebellar abnormalities) in combination with ocular anomalies and congenital muscular dystrophy. The cobblestone lissencephalies comprise brain malformations associated with congenital muscular dystrophy, including Walker-Warburg syndrome, muscle-eye-brain disease, and Schizencephaly, a specific pattern of PMG that describes a full-thickness cleft in the brain lined by PMG. While either CT or MRI is usually sufficient to diagnose schizencephaly, MRI is preferred when determining if the schizencephaly is open- or closed-lipped. • Pachygyria/lissencephaly, a distinct brain malformation in which reduced or absent cortical folding is combined with a thick cortex. Pachygyria and PMG may look similar on low-resolution neuroimaging (e.g., CT) because in both conditions the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth. The cortex in PMG is overfolded but not thickened. The microgyri and microsulci of PMG and stippling of the gray-white junction that can be appreciated with high-quality MRI can distinguish PMG from pachygyria [ • Cobblestone lissencephaly, a brain surface that has a bumpy contour resulting from migration of neurons and glial cells through the basement membrane into the leptomeninges. Sometimes regions populated by these misplaced cells are incorrectly initially diagnosed as PMG based on the MRI appearance and are only distinguished from PMG by the presence of other brain abnormalities (e.g., white matter and cerebellar abnormalities) in combination with ocular anomalies and congenital muscular dystrophy. The cobblestone lissencephalies comprise brain malformations associated with congenital muscular dystrophy, including Walker-Warburg syndrome, muscle-eye-brain disease, and • Schizencephaly, a specific pattern of PMG that describes a full-thickness cleft in the brain lined by PMG. While either CT or MRI is usually sufficient to diagnose schizencephaly, MRI is preferred when determining if the schizencephaly is open- or closed-lipped. ## Genetic Causes of Polymicrogyria Genetic causes of polymicrogyria (PMG) include both contiguous-gene and single-gene disorders. PMG has been implicated in a number of chromosome copy number variants (CNVs) (summarized in The most common copy number variants associated with PMG: 1p36 deletion (OMIM Other copy number variants with which PMG may be associated are deletion of 4q21, 6q26, 13q3, 18p11, and 21q2 and duplication of 2p13 [ To date more than 40 genes have been associated with PMG. This The mTORopathies (the PI3K-AKT-MTOR pathway) The tubulinopathies Cobblestone dysplasia – alpha dystroglycanopathies Cobblestone dysplasia – other (including laminopathies and congenital disorders of glycosylation) Other pathways/pathologies Additional disorders not included in PMG-Associated Genes Grouped by Pathway/Pathology Note: The table does not list genes that can be associated with PMG and metabolic disorders ( A = anterior; ACC = absence of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MCAP = megalencephaly-capillary malformation-PMG; MOI = mode of inheritance; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus; P = posterior; PNH = periventricular nodular heterotopia; XL = X-linked; XLD = X-linked dominant; XLR = X-linked recessive Genes are in alphabetic order. Head size:N/MS = normal / mildly small (i.e., head circumference >3 SD and 97%) RAB18 deficiency is a spectrum that includes Warburg micro syndrome (at the severe end) and Martsolf syndrome (at the mild end). Additional findings are eye involvement (bilateral congenital cataracts, microphthalmia, and microcornea); severe-to-profound intellectual disability; and hypogonadism. Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in Note: While heterozygous pathogenic variants in Selected Metabolic Disorders Commonly Associated with PMG Zellweger syndrome and fumaric aciduria are the most common metabolic causes of PMG of those addressed in • 1p36 deletion (OMIM • The mTORopathies (the PI3K-AKT-MTOR pathway) • The tubulinopathies • Cobblestone dysplasia – alpha dystroglycanopathies • Cobblestone dysplasia – other (including laminopathies and congenital disorders of glycosylation) • Other pathways/pathologies ## Contiguous-Gene Disorders PMG has been implicated in a number of chromosome copy number variants (CNVs) (summarized in The most common copy number variants associated with PMG: 1p36 deletion (OMIM Other copy number variants with which PMG may be associated are deletion of 4q21, 6q26, 13q3, 18p11, and 21q2 and duplication of 2p13 [ • 1p36 deletion (OMIM ## Single-Gene Disorders To date more than 40 genes have been associated with PMG. This The mTORopathies (the PI3K-AKT-MTOR pathway) The tubulinopathies Cobblestone dysplasia – alpha dystroglycanopathies Cobblestone dysplasia – other (including laminopathies and congenital disorders of glycosylation) Other pathways/pathologies Additional disorders not included in PMG-Associated Genes Grouped by Pathway/Pathology Note: The table does not list genes that can be associated with PMG and metabolic disorders ( A = anterior; ACC = absence of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MCAP = megalencephaly-capillary malformation-PMG; MOI = mode of inheritance; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus; P = posterior; PNH = periventricular nodular heterotopia; XL = X-linked; XLD = X-linked dominant; XLR = X-linked recessive Genes are in alphabetic order. Head size:N/MS = normal / mildly small (i.e., head circumference >3 SD and 97%) RAB18 deficiency is a spectrum that includes Warburg micro syndrome (at the severe end) and Martsolf syndrome (at the mild end). Additional findings are eye involvement (bilateral congenital cataracts, microphthalmia, and microcornea); severe-to-profound intellectual disability; and hypogonadism. Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in Note: While heterozygous pathogenic variants in Selected Metabolic Disorders Commonly Associated with PMG Zellweger syndrome and fumaric aciduria are the most common metabolic causes of PMG of those addressed in • The mTORopathies (the PI3K-AKT-MTOR pathway) • The tubulinopathies • Cobblestone dysplasia – alpha dystroglycanopathies • Cobblestone dysplasia – other (including laminopathies and congenital disorders of glycosylation) • Other pathways/pathologies ## Evaluation Strategy to Identify the Genetic Cause of PMG in a Proband The approach outlined in this section can be used to determine if a specific genetic cause or mode of inheritance can be identified to aid in discussions of prognosis and genetic counseling. Confirming PMG as the underlying cortical malformation and ruling out other brain malformations that may be confused with PMG (e.g., pachgyria and other forms of cortical dysplasia) requires consultation with an expert in interpretation of the MRI findings of PMG. Note that while the gold standard for the diagnosis of PMG is postmortem histopathologic examination, the clinical diagnosis relies on neuroimaging. If no genetic cause has been identified and if familial PMG is suspected, it may be reasonable to perform a brain MRI (if not previously performed) on close relatives (i.e., parents or sibs) with the following: Neurologic problems including seizures, cognitive delay, motor impairment, pseudobulbar signs, and/or focal weakness What appear to be minor findings, such as a lisp or an isolated learning disability Head size is a useful first step in clinical assessment to aid in focusing genetic testing. In the absence of systemic findings: Note that a subset of individuals have hydrocephalus (requiring shunting) and/or polydactyly of fingers/toes In the presence of other systemic features such as somatic overgrowth or pigmentary skin changes: Fetal brain disruption pattern on imaging: Complex additional brain malformations: Pseudo-TORCH syndrome Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See Testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and comprehensive genomic testing (exome sequencing, exome array, or chromosomal microarray analysis [CMA]). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not. Options include the following: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Neurologic problems including seizures, cognitive delay, motor impairment, pseudobulbar signs, and/or focal weakness • What appear to be minor findings, such as a lisp or an isolated learning disability • In the absence of systemic findings: • Note that a subset of individuals have hydrocephalus (requiring shunting) and/or polydactyly of fingers/toes • In the presence of other systemic features such as somatic overgrowth or pigmentary skin changes: • Fetal brain disruption pattern on imaging: • • • Complex additional brain malformations: • Pseudo-TORCH syndrome • • Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See • Pseudo-TORCH syndrome • • Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See • • Pseudo-TORCH syndrome • • Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Confirming the Clinical Diagnosis Confirming PMG as the underlying cortical malformation and ruling out other brain malformations that may be confused with PMG (e.g., pachgyria and other forms of cortical dysplasia) requires consultation with an expert in interpretation of the MRI findings of PMG. Note that while the gold standard for the diagnosis of PMG is postmortem histopathologic examination, the clinical diagnosis relies on neuroimaging. ## History If no genetic cause has been identified and if familial PMG is suspected, it may be reasonable to perform a brain MRI (if not previously performed) on close relatives (i.e., parents or sibs) with the following: Neurologic problems including seizures, cognitive delay, motor impairment, pseudobulbar signs, and/or focal weakness What appear to be minor findings, such as a lisp or an isolated learning disability • Neurologic problems including seizures, cognitive delay, motor impairment, pseudobulbar signs, and/or focal weakness • What appear to be minor findings, such as a lisp or an isolated learning disability ## Physical Examination Head size is a useful first step in clinical assessment to aid in focusing genetic testing. In the absence of systemic findings: Note that a subset of individuals have hydrocephalus (requiring shunting) and/or polydactyly of fingers/toes In the presence of other systemic features such as somatic overgrowth or pigmentary skin changes: Fetal brain disruption pattern on imaging: Complex additional brain malformations: Pseudo-TORCH syndrome Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See • In the absence of systemic findings: • Note that a subset of individuals have hydrocephalus (requiring shunting) and/or polydactyly of fingers/toes • In the presence of other systemic features such as somatic overgrowth or pigmentary skin changes: • Fetal brain disruption pattern on imaging: • • • Complex additional brain malformations: • Pseudo-TORCH syndrome • • Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See • Pseudo-TORCH syndrome • • Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See • • Pseudo-TORCH syndrome • • Tubulinopathies (typically patchy and asymmetric cortical dysplasia with callosal, cerebellar, and brain stem anomalies) (See ## Molecular Genetic Testing Testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and comprehensive genomic testing (exome sequencing, exome array, or chromosomal microarray analysis [CMA]). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not. Options include the following: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Genetic Counseling of Family Members of an Individual with PMG Hereditary polymicrogyria (PMG) may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific genetic cause of PMG in an individual. Some individuals diagnosed with PMG have an affected parent. Many individuals diagnosed with PMG have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent The family history may appear to be negative because of failure to recognize the disorder in a family member or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing and/or clinical evaluation has been performed. Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom-free. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PMG-related pathogenic variant). Heterozygotes are asymptomatic. The father of an affected male will not have the disorder nor will he be hemizygous for the PMG-related pathogenic variant; therefore, he does not require further evaluation/testing. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the PMG-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a If the mother of the proband has the PMG-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PMG-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. Once the PMG-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Some individuals diagnosed with PMG have an affected parent. • Many individuals diagnosed with PMG have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • The family history may appear to be negative because of failure to recognize the disorder in a family member or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing and/or clinical evaluation has been performed. • Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom-free. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PMG-related pathogenic variant). • Heterozygotes are asymptomatic. • The father of an affected male will not have the disorder nor will he be hemizygous for the PMG-related pathogenic variant; therefore, he does not require further evaluation/testing. • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the PMG-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a • If the mother of the proband has the PMG-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PMG-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. ## Mode of Inheritance Hereditary polymicrogyria (PMG) may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific genetic cause of PMG in an individual. ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with PMG have an affected parent. Many individuals diagnosed with PMG have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent The family history may appear to be negative because of failure to recognize the disorder in a family member or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing and/or clinical evaluation has been performed. Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom-free. • Some individuals diagnosed with PMG have an affected parent. • Many individuals diagnosed with PMG have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • The family history may appear to be negative because of failure to recognize the disorder in a family member or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing and/or clinical evaluation has been performed. • Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom-free. ## Autosomal Recessive Inheritance ‒ Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PMG-related pathogenic variant). Heterozygotes are asymptomatic. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PMG-related pathogenic variant). • Heterozygotes are asymptomatic. ## X-Linked Inheritance ‒ Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the PMG-related pathogenic variant; therefore, he does not require further evaluation/testing. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the PMG-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a If the mother of the proband has the PMG-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PMG-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. • The father of an affected male will not have the disorder nor will he be hemizygous for the PMG-related pathogenic variant; therefore, he does not require further evaluation/testing. • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the PMG-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a • If the mother of the proband has the PMG-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PMG-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. ## Prenatal Testing and Preimplantation Genetic Testing Once the PMG-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Chapter Notes Dr Ghayda Mirzaa is a geneticist and researcher at Seattle Children's Hospital. The goal of her research is to study the underlying causes, natural history, and medical management of developmental brain disorders including brain malformations, autism, and epilepsy. We acknowledge the assistance of Ms Stefanie Brock in the preparation of Kira Apse, ScM; Harvard Medical School (2004-2018)Adria Bodell, MS, CGC; Harvard Medical School (2004-2018)Bernard Chang, MD; Harvard Medical School (2004-2018)William Dobyns, MD (2018-present)Anna Jansen, MD, PhD (2018-present)Richard J Leventer, MBBS, BMedSci, PhD, FRACP (2018-present)Ghayda Mirzaa, MD (2018-present)Chloe Stutterd, MBBS, FRACP (2018-present)Christopher A Walsh, MD, PhD; Harvard Medical School (2004-2018) 6 June 2024 (ma) Chapter retired: phenotype is too broad 16 August 2018 (bp) Comprehensive update posted live 6 August 2007 (me) Comprehensive update posted live 18 April 2005 (me) Overview posted live 24 August 2004 (bc) Original submission • 6 June 2024 (ma) Chapter retired: phenotype is too broad • 16 August 2018 (bp) Comprehensive update posted live • 6 August 2007 (me) Comprehensive update posted live • 18 April 2005 (me) Overview posted live • 24 August 2004 (bc) Original submission ## Acknowledgments We acknowledge the assistance of Ms Stefanie Brock in the preparation of ## Author History Kira Apse, ScM; Harvard Medical School (2004-2018)Adria Bodell, MS, CGC; Harvard Medical School (2004-2018)Bernard Chang, MD; Harvard Medical School (2004-2018)William Dobyns, MD (2018-present)Anna Jansen, MD, PhD (2018-present)Richard J Leventer, MBBS, BMedSci, PhD, FRACP (2018-present)Ghayda Mirzaa, MD (2018-present)Chloe Stutterd, MBBS, FRACP (2018-present)Christopher A Walsh, MD, PhD; Harvard Medical School (2004-2018) ## Revision History 6 June 2024 (ma) Chapter retired: phenotype is too broad 16 August 2018 (bp) Comprehensive update posted live 6 August 2007 (me) Comprehensive update posted live 18 April 2005 (me) Overview posted live 24 August 2004 (bc) Original submission • 6 June 2024 (ma) Chapter retired: phenotype is too broad • 16 August 2018 (bp) Comprehensive update posted live • 6 August 2007 (me) Comprehensive update posted live • 18 April 2005 (me) Overview posted live • 24 August 2004 (bc) Original submission ## References ## Literature Cited	[]	18/4/2005	16/8/2018		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pomc-def	pomc-def	[ "POMC Deficiency", "POMC Deficiency", "Pro-opiomelanocortin", "POMC", "Proopiomelanocortin Deficiency" ]	Proopiomelanocortin Deficiency – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Ben G Challis, George WM Millington	Summary Proopiomelanocortin (POMC) deficiency is characterized by severe, early-onset hyperphagic obesity and congenital adrenal insufficiency, the latter secondary to corticotropin (ACTH) deficiency. In the first months of life most children with POMC deficiency experience exponential weight gain, hyperphagia, cholestasis, and adrenal insufficiency. Weight gain continues rapidly, so that by the end of the first year of life obesity is severe (i.e., weight well above the 98th centile for age, without increased height). Red hair and Fitzpatrick type 1 skin (which always burns and never tans) are common, but not invariably present. On occasion central hypothyroidism (resulting from thyroid stimulating hormone [TSH] deficiency), adolescent-onset growth hormone (GH) deficiency, and adolescent-onset hypogonadotropic hypogonadism resulting from deficiency of luteinizing hormone (LH) and follicule stimulating hormone (FSH) can be observed. The diagnosis of POMC deficiency is confirmed by the presence of biallelic If POMC deficiency has been previously diagnosed in a family and if the POMC deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the	## Diagnosis There are no formal diagnostic criteria for proopiomelanocortin (POMC) deficiency. The diagnosis of POMC deficiency Severe, hyperphagic obesity of onset in infancy Congenital adrenal insufficiency, resulting from corticotropin (ACTH) deficiency The diagnosis of POMC deficiency in a proband Very fair skin (Fitzpatrick skin type 1) which will never tan and always burns [ Red hair Positive family history of obesity in sibs or other relatives who could share two pathogenic alleles with the proband Central hypothyroidism (triodothyronine, tetraiodothyronine and thyrotropin, or TSH deficiency) Growth hormone (GH) deficiency in later childhood or adolescence Hypogonadotropic hypogonadism (deficiency of the gonadotropins LH and FSH) The diagnosis of POMC deficiency Molecular Genetic Testing Used in Proopiomelanocortin Deficiency See See The ability of the test method used to detect a pathogenic variant that is present in the indicated gene Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. No deletions or duplications of • Severe, hyperphagic obesity of onset in infancy • Congenital adrenal insufficiency, resulting from corticotropin (ACTH) deficiency • Very fair skin (Fitzpatrick skin type 1) which will never tan and always burns [ • Red hair • Positive family history of obesity in sibs or other relatives who could share two pathogenic alleles with the proband • Central hypothyroidism (triodothyronine, tetraiodothyronine and thyrotropin, or TSH deficiency) • Growth hormone (GH) deficiency in later childhood or adolescence • Hypogonadotropic hypogonadism (deficiency of the gonadotropins LH and FSH) ## Clinical Characteristics In the first months of life most children with proopiomelanocortin (POMC) deficiency experience exponential weight gain, hyperphagia, cholestasis, and adrenal insufficiency. Weight gain continues rapidly, so that by the end of the first year of life obesity is severe (i.e., weight well above 98th centile for age without increased height). Red hair and Fitzpatrick type 1 skin (which always burns and never tans) are common but not invariably present. The phenotypic consequences of POMC deficiency (including adrenal insufficiency, altered pigmentation, and severe obesity) result from reduced or absent melanocortin signaling in target tissues. For example: Impaired ACTH signaling through the MC2R in the adrenal cortex results in hypoadrenalism (i.e., absence of adrenal steroidogenesis). Absence of α-MSH induced activation of MC1R in skin melanocytes results in the red hair and pale skin observed in some affected individuals. Reduced activation of MC3- and MC4R proteins in the hypothalamic nuclei that regulate energy homeostasis causes severe early-onset obesity, in a manner similar to the severe early-onset obesity observed in children with deficiency of the MC4R protein itself. Large numbers of pathogenic variants (see However, a number of individuals described have a single (i.e., heterozygous) base-pair pathogenic variant in a critical site, leading to severe, early-onset obesity without adrenal insufficiency or hypopigmentation [ Proopiomelanocortin (POMC) was previously called proopiocortin (POC). POMC is an extremely rare disease. Fewer than 50 affected individuals have been reported in the world literature. There is no known increased prevalence in any particular ethnic group or geographic location. • Impaired ACTH signaling through the MC2R in the adrenal cortex results in hypoadrenalism (i.e., absence of adrenal steroidogenesis). • Absence of α-MSH induced activation of MC1R in skin melanocytes results in the red hair and pale skin observed in some affected individuals. • Reduced activation of MC3- and MC4R proteins in the hypothalamic nuclei that regulate energy homeostasis causes severe early-onset obesity, in a manner similar to the severe early-onset obesity observed in children with deficiency of the MC4R protein itself. ## Clinical Description In the first months of life most children with proopiomelanocortin (POMC) deficiency experience exponential weight gain, hyperphagia, cholestasis, and adrenal insufficiency. Weight gain continues rapidly, so that by the end of the first year of life obesity is severe (i.e., weight well above 98th centile for age without increased height). Red hair and Fitzpatrick type 1 skin (which always burns and never tans) are common but not invariably present. ## Pathogenesis The phenotypic consequences of POMC deficiency (including adrenal insufficiency, altered pigmentation, and severe obesity) result from reduced or absent melanocortin signaling in target tissues. For example: Impaired ACTH signaling through the MC2R in the adrenal cortex results in hypoadrenalism (i.e., absence of adrenal steroidogenesis). Absence of α-MSH induced activation of MC1R in skin melanocytes results in the red hair and pale skin observed in some affected individuals. Reduced activation of MC3- and MC4R proteins in the hypothalamic nuclei that regulate energy homeostasis causes severe early-onset obesity, in a manner similar to the severe early-onset obesity observed in children with deficiency of the MC4R protein itself. • Impaired ACTH signaling through the MC2R in the adrenal cortex results in hypoadrenalism (i.e., absence of adrenal steroidogenesis). • Absence of α-MSH induced activation of MC1R in skin melanocytes results in the red hair and pale skin observed in some affected individuals. • Reduced activation of MC3- and MC4R proteins in the hypothalamic nuclei that regulate energy homeostasis causes severe early-onset obesity, in a manner similar to the severe early-onset obesity observed in children with deficiency of the MC4R protein itself. ## Genotype-Phenotype Correlations Large numbers of pathogenic variants (see However, a number of individuals described have a single (i.e., heterozygous) base-pair pathogenic variant in a critical site, leading to severe, early-onset obesity without adrenal insufficiency or hypopigmentation [ ## Nomenclature Proopiomelanocortin (POMC) was previously called proopiocortin (POC). ## Prevalence POMC is an extremely rare disease. Fewer than 50 affected individuals have been reported in the world literature. There is no known increased prevalence in any particular ethnic group or geographic location. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The following are all causes of childhood-onset obesity: Monogenic Obesity Syndromes Chromosome locus included when gene is unknown The following inherited disorders of Melanocortin-2 receptor deficiency (OMIM Melanocortin 2 receptor accessory protein (MRAP) deficiency (OMIM Steroidogenic acute regulatory protein (STAR) deficiency (OMIM Nicotinamide nucleotide transhydrogenase (NNT) deficiency (OMIM Autoimmune polyendocrine syndrome, type 1 (OMIM Natural killer cell and glucocorticoid deficiency with DNA repair defect (OMIM Combined pituitary hormone deficiency, type 1 and • Melanocortin-2 receptor deficiency (OMIM • Melanocortin 2 receptor accessory protein (MRAP) deficiency (OMIM • Steroidogenic acute regulatory protein (STAR) deficiency (OMIM • Nicotinamide nucleotide transhydrogenase (NNT) deficiency (OMIM • • Autoimmune polyendocrine syndrome, type 1 (OMIM • Natural killer cell and glucocorticoid deficiency with DNA repair defect (OMIM • Combined pituitary hormone deficiency, type 1 and ## Management To establish the extent of disease and needs in an individual diagnosed with proopiomelanocortin (POMC) deficiency, the following evaluations are recommended: For adrenal insufficiency as a result of ACTH deficiency: 9 am plasma cortisol; plasma ACTH concentration; ACTH stimulation test For central hypothyroidism: TRH test, serum TSH, total T4 For adolescent-onset growth hormone (GH) deficiency: insulin tolerance test and serum IGF-1 levels For adolescent-onset hypogonadism: FSH, LH, testosterone and/or estradiol Consultation with a clinical geneticist and/or genetic counselor The main treatment for POMC deficiency is hormone replacement therapy with glucocorticoids with other hormones as required, as well as skin care in the sun. Prompt treatment of ACTH, TSH, GH, LH, and FSH deficiency prevents the consequences of these hormone deficiencies. From the time of diagnosis, annual monitoring for deficiencies of TSH, GH, LH, and FSH is indicated. Surveillance of skin for premalignant lesions may be necessary depending on latitude and history of sun exposure. Malignant skin lesions have not specifically been reported to be associated with POMC deficiency, though a theoretic risk is assumed to exist. If the pathogenic variants in the family are known, prenatal testing can clarify the genetic status of at-risk pregnancies so that glucocorticoid therapy can be initiated as soon as possible after birth in those newborns known to have POMC deficiency. If POMC deficiency has been previously diagnosed in a family member, and if the pathogenic variants in the family are not known or if prenatal testing has not been performed, it is necessary to evaluate any at-risk newborn (e.g., sibs of a proband) for evidence of adrenal insufficiency and to initiate glucocorticoid therapy as soon as possible if adrenal insufficiency is found. See Search • For adrenal insufficiency as a result of ACTH deficiency: 9 am plasma cortisol; plasma ACTH concentration; ACTH stimulation test • For central hypothyroidism: TRH test, serum TSH, total T4 • For adolescent-onset growth hormone (GH) deficiency: insulin tolerance test and serum IGF-1 levels • For adolescent-onset hypogonadism: FSH, LH, testosterone and/or estradiol • Consultation with a clinical geneticist and/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with proopiomelanocortin (POMC) deficiency, the following evaluations are recommended: For adrenal insufficiency as a result of ACTH deficiency: 9 am plasma cortisol; plasma ACTH concentration; ACTH stimulation test For central hypothyroidism: TRH test, serum TSH, total T4 For adolescent-onset growth hormone (GH) deficiency: insulin tolerance test and serum IGF-1 levels For adolescent-onset hypogonadism: FSH, LH, testosterone and/or estradiol Consultation with a clinical geneticist and/or genetic counselor • For adrenal insufficiency as a result of ACTH deficiency: 9 am plasma cortisol; plasma ACTH concentration; ACTH stimulation test • For central hypothyroidism: TRH test, serum TSH, total T4 • For adolescent-onset growth hormone (GH) deficiency: insulin tolerance test and serum IGF-1 levels • For adolescent-onset hypogonadism: FSH, LH, testosterone and/or estradiol • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The main treatment for POMC deficiency is hormone replacement therapy with glucocorticoids with other hormones as required, as well as skin care in the sun. ## Prevention of Primary Manifestations Prompt treatment of ACTH, TSH, GH, LH, and FSH deficiency prevents the consequences of these hormone deficiencies. ## Surveillance From the time of diagnosis, annual monitoring for deficiencies of TSH, GH, LH, and FSH is indicated. Surveillance of skin for premalignant lesions may be necessary depending on latitude and history of sun exposure. Malignant skin lesions have not specifically been reported to be associated with POMC deficiency, though a theoretic risk is assumed to exist. ## Evaluation of Relatives at Risk If the pathogenic variants in the family are known, prenatal testing can clarify the genetic status of at-risk pregnancies so that glucocorticoid therapy can be initiated as soon as possible after birth in those newborns known to have POMC deficiency. If POMC deficiency has been previously diagnosed in a family member, and if the pathogenic variants in the family are not known or if prenatal testing has not been performed, it is necessary to evaluate any at-risk newborn (e.g., sibs of a proband) for evidence of adrenal insufficiency and to initiate glucocorticoid therapy as soon as possible if adrenal insufficiency is found. See ## Therapies Under Investigation Search ## Genetic Counseling Proopiomelanocortin (POMC) deficiency is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant). Heterozygotes (carriers) are asymptomatic. Although they are not at risk of developing adrenal insufficiency, they have a predisposition to obesity [ At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic and are not at risk of developing adrenal insufficiency; however, a predisposition to obesity is conferred. It is unknown whether fertility is reduced in individuals with POMC deficiency. The offspring of an individual with POMC deficiency are obligate heterozygotes (carriers) for a Each sib of the proband’s parents is at a 50% risk of being a carrier. Two of the proband’s four grandparents are also expected to be carriers, unless the familial pathogenic variant has been shown to be Carrier testing for at-risk relatives is possible if the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for POMC deficiency are possible. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant). • Heterozygotes (carriers) are asymptomatic. Although they are not at risk of developing adrenal insufficiency, they have a predisposition to obesity [ • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing adrenal insufficiency; however, a predisposition to obesity is conferred. • It is unknown whether fertility is reduced in individuals with POMC deficiency. • The offspring of an individual with POMC deficiency are obligate heterozygotes (carriers) for a • Each sib of the proband’s parents is at a 50% risk of being a carrier. • Two of the proband’s four grandparents are also expected to be carriers, unless the familial pathogenic variant has been shown to be • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Proopiomelanocortin (POMC) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant). Heterozygotes (carriers) are asymptomatic. Although they are not at risk of developing adrenal insufficiency, they have a predisposition to obesity [ At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic and are not at risk of developing adrenal insufficiency; however, a predisposition to obesity is conferred. It is unknown whether fertility is reduced in individuals with POMC deficiency. The offspring of an individual with POMC deficiency are obligate heterozygotes (carriers) for a Each sib of the proband’s parents is at a 50% risk of being a carrier. Two of the proband’s four grandparents are also expected to be carriers, unless the familial pathogenic variant has been shown to be • The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant). • Heterozygotes (carriers) are asymptomatic. Although they are not at risk of developing adrenal insufficiency, they have a predisposition to obesity [ • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing adrenal insufficiency; however, a predisposition to obesity is conferred. • It is unknown whether fertility is reduced in individuals with POMC deficiency. • The offspring of an individual with POMC deficiency are obligate heterozygotes (carriers) for a • Each sib of the proband’s parents is at a 50% risk of being a carrier. • Two of the proband’s four grandparents are also expected to be carriers, unless the familial pathogenic variant has been shown to be ## Carrier (Heterozygote) Detection Carrier testing for at-risk relatives is possible if the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for POMC deficiency are possible. ## Resources 505 Northern Boulevard Great Neck NY 11021 • • 505 Northern Boulevard • Great Neck NY 11021 • ## Molecular Genetics Proopiomelanocortin Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Proopiomelanocortin Deficiency ( A girl age three years was compound heterozygous for two pathogenic nonsense variants in exon 3 ( The second unrelated child was homozygous for a pathogenic variant ( See • A girl age three years was compound heterozygous for two pathogenic nonsense variants in exon 3 ( • The second unrelated child was homozygous for a pathogenic variant ( ## References ## Literature Cited ## Chapter Notes 16 April 2020 (ma) Chapter retired: extremely rare 12 December 2013 (bp) Review posted live 13 August 2013 (bgc) Original submission • 16 April 2020 (ma) Chapter retired: extremely rare • 12 December 2013 (bp) Review posted live • 13 August 2013 (bgc) Original submission ## Revision History 16 April 2020 (ma) Chapter retired: extremely rare 12 December 2013 (bp) Review posted live 13 August 2013 (bgc) Original submission • 16 April 2020 (ma) Chapter retired: extremely rare • 12 December 2013 (bp) Review posted live • 13 August 2013 (bgc) Original submission	[ "IR Aslan, SA Ranadive, I Valle, S Kollipara, JA Noble, C Vaisse. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus.. Int J Obes (Lond) 2014;38:148-51", "BG Challis, LE Pritchard, JWM Creemers, J Delplanque, JM Keogh, J Luan, NJ Wareham, GSH Yeo, S Bhattacharyya, P Froguel, A White, IS Farooqi, S O’Rahilly. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism.. Human Molecular Genetics. 2002;11:1997-2004", "G Cirillo, R Marini, S Ito, K Wakamatsu, S Scianguetta, C Bizzarri, A Romano, A Grandone, L Perrone, M Cappa, E. Miraglia Del Giudice. Lack of red hair phenotype in a North-African obese child homozygous for a novel POMC null mutation: nonsense-mediated decay RNA evaluation and hair pigment chemical analysis.. Br J Dermatol. 2012;167:1393-5", "K Clément, B Dubern, M Mencarelli, P Czernichow, S Ito, K Wakamatsu, GS Barsh, C Vaisse, J Leger. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene.. J Clin Endocrinol Metab. 2008;93:4955-62", "B Dubern, C Lubrano-Berthelier, M Mencarelli, B Ersoy, ML Frelut, D Bouglé, B Costes, C Simon, P Tounian, C Vaisse, K Clément. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain.. Pediatr Res. 2008;63:211-6", "IS Farooqi, S Drop, A Clements, JM Keogh, J Biernacka, S Lowenbein, BG Challis, S O'Rahilly. Heterozygosity for a POMC-null mutation and increased obesity risk in humans.. Diabetes. 2006;55:2549-53", "H Krude, H Biebermann, W Luck, R Horn, G Brabant, A Grüters. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.. Nat Genet. 1998;19:155-7", "H Krude, H Biebermann, D Schnabel, MZ Tansek, P Theunissen, PE Mullis, A Grüters. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10.. J Clin Endocrinol Metab. 2003;88:4633-40", "YS Lee, BG Challis, DA Thompson, GS Yeo, JM Keogh, ME Madonna, V Wraight, M Sims, V Vatin, D Meyre, J Shield, C Burren, Z Ibrahim, T Cheetham, P Swift, A Blackwood, CC Hung, NJ Wareham, P Froguel, GL Millhauser, S O'Rahilly, IS Farooqi. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.. Cell Metab. 2006;3:135-40", "MS Mendiratta, Y Yang, AE Balazs, AS Willis, CM Eng, LP Karaviti, L Potocki. Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation.. Int J Pediatr Endocrinol. 2011:5", "WE Roberts. Skin type classification systems old and new.. Dermatol Clin. 2009;27:529-33" ]	12/12/2013			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
porphyria-ct	porphyria-ct	[ "Familial PCT (F-PCT)", "Porphyria Cutanea Tarda, Type II (Type II PCT)", "UROD-Related Porphyria Cutanea Tarda", "Familial PCT (F-PCT)", "Porphyria Cutanea Tarda, Type II (Type II PCT)", "UROD-Related Porphyria Cutanea Tarda", "Uroporphyrinogen decarboxylase", "UROD", "Familial Porphyria Cutanea Tarda" ]	Familial Porphyria Cutanea Tarda	Sean Rudnick, John Phillips, Herbert Bonkovsky	Summary Familial porphyria cutanea tarda (F-PCT) is characterized by: skin findings including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma); and an increased risk for hepatocellular carcinoma (HCC). The diagnosis of F-PCT is established in a proband with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) and a heterozygous pathogenic variant in F-PCT is inherited in an autosomal dominant manner with reduced penetrance. Most individuals diagnosed with F-PCT inherited a	## Diagnosis Familial porphyria cutanea tarda (F-PCT) Photosensitivity resulting in fluid-filled vesicles, bullae, blisters, and sores developing over the dorsal aspects of the hands and other sun-exposed areas of skin (e.g., forearms, face and scalp, ears, neck, legs, and feet). Because the blister fluid is high in porphyrin content, it may appear pink to red. Upon rupturing, these lesions can crust over, heal slowly, and result in secondary infection. Skin fragility after minor trauma (which may occur over the same areas where the blisters develop) Facial hypertrichosis and hyperpigmentation Severe thickening of the affected skin areas (pseudoscleroderma) that resembles progressive systemic sclerosis Increased urine or plasma total porphyrins (first-line testing; sensitive, not specific) Fractionate urine porphyrins showing a predominance of uroporphyrin & heptacarboxylporphyrin (second-line testing) See Normal or minimally increased urine delta-aminolevulinic acid levels In some persons with severe F-PCT, pink-appearing urine that fluoresces bright pink when excited by long UV-blue light Complete Biochemical Features of Familial Porphyria Cutanea Tarda Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm The diagnosis of familial porphyria cutanea tarda (F-PCT) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Porphyria Cutanea Tarda See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Photosensitivity resulting in fluid-filled vesicles, bullae, blisters, and sores developing over the dorsal aspects of the hands and other sun-exposed areas of skin (e.g., forearms, face and scalp, ears, neck, legs, and feet). Because the blister fluid is high in porphyrin content, it may appear pink to red. Upon rupturing, these lesions can crust over, heal slowly, and result in secondary infection. • Skin fragility after minor trauma (which may occur over the same areas where the blisters develop) • Facial hypertrichosis and hyperpigmentation • Severe thickening of the affected skin areas (pseudoscleroderma) that resembles progressive systemic sclerosis • Increased urine or plasma total porphyrins (first-line testing; sensitive, not specific) • Fractionate urine porphyrins showing a predominance of uroporphyrin & heptacarboxylporphyrin (second-line testing) • See • Normal or minimally increased urine delta-aminolevulinic acid levels • In some persons with severe F-PCT, pink-appearing urine that fluoresces bright pink when excited by long UV-blue light ## Suggestive Findings Familial porphyria cutanea tarda (F-PCT) Photosensitivity resulting in fluid-filled vesicles, bullae, blisters, and sores developing over the dorsal aspects of the hands and other sun-exposed areas of skin (e.g., forearms, face and scalp, ears, neck, legs, and feet). Because the blister fluid is high in porphyrin content, it may appear pink to red. Upon rupturing, these lesions can crust over, heal slowly, and result in secondary infection. Skin fragility after minor trauma (which may occur over the same areas where the blisters develop) Facial hypertrichosis and hyperpigmentation Severe thickening of the affected skin areas (pseudoscleroderma) that resembles progressive systemic sclerosis Increased urine or plasma total porphyrins (first-line testing; sensitive, not specific) Fractionate urine porphyrins showing a predominance of uroporphyrin & heptacarboxylporphyrin (second-line testing) See Normal or minimally increased urine delta-aminolevulinic acid levels In some persons with severe F-PCT, pink-appearing urine that fluoresces bright pink when excited by long UV-blue light Complete Biochemical Features of Familial Porphyria Cutanea Tarda Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm • Photosensitivity resulting in fluid-filled vesicles, bullae, blisters, and sores developing over the dorsal aspects of the hands and other sun-exposed areas of skin (e.g., forearms, face and scalp, ears, neck, legs, and feet). Because the blister fluid is high in porphyrin content, it may appear pink to red. Upon rupturing, these lesions can crust over, heal slowly, and result in secondary infection. • Skin fragility after minor trauma (which may occur over the same areas where the blisters develop) • Facial hypertrichosis and hyperpigmentation • Severe thickening of the affected skin areas (pseudoscleroderma) that resembles progressive systemic sclerosis • Increased urine or plasma total porphyrins (first-line testing; sensitive, not specific) • Fractionate urine porphyrins showing a predominance of uroporphyrin & heptacarboxylporphyrin (second-line testing) • See • Normal or minimally increased urine delta-aminolevulinic acid levels • In some persons with severe F-PCT, pink-appearing urine that fluoresces bright pink when excited by long UV-blue light ## Establishing the Diagnosis The diagnosis of familial porphyria cutanea tarda (F-PCT) Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved ( For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Porphyria Cutanea Tarda See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Familial Porphyria Cutanea Tarda See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Familial porphyria cutanea tarda (F-PCT) is characterized by cutaneous findings including skin friability and chronic blistering over sun-exposed areas (classically the dorsal aspects of the hands). In contrast to the acute hepatic porphyrias or erythropoietic cutaneous porphyrias, F-PCT does not manifest as acute episodes of pain or acute/painful skin changes upon sun exposure, respectively. Hepatic involvement of F-PCT is characterized by elevation in aminotransferases, increased iron stores, and varying degrees of fibrosis accompanied by an increased risk for hepatocellular carcinoma. Histopathology of the skin in F-PCT demonstrates subepidermal fluid collections (blistering), hyperkeratosis, and lipid proteinosis. Additional findings can include deposition of PAS-positive material around blood vessels and fine fibrillar material in the upper dermis, as well as splitting of the lamina lucida of the basement membrane at the dermoepithelial junction [ Some affected individuals will demonstrate evidence of hepatic iron overload, suggested by elevated serum ferritin concentration and elevated transferrin saturation. While cirrhosis may develop in 30%-40% of individuals, predisposing factors are concomitant infection with hepatitis C virus and use of alcohol. The risk for hepatocellular carcinoma is increased in individuals with F-PCT, especially in those with other risk factors predisposing to advanced liver disease (see Development of clinical manifestations of familial porphyria cutanea tarda (F-PCT) requires Inherited, environmental, medical, and infectious factors that are known or suspected to influence disease susceptibility in F-PTC include the following [ Secondary iron overload. Some degree of hepatic siderosis (mild-to-moderate iron overload) is seen in most individuals with F-PCT. Conversely, iron deficiency is protective. Excessive alcohol consumption Tobacco use Oral estrogen use Estrogen mimetics/antagonists (e.g., tamoxifen) Exposure to toxins such as polychlorinated biphenyls, hexochlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes End-stage kidney disease (ESKD) can lead to manifestations of F-PCT that are often more severe than usual because the lack of urinary porphyrin excretion results in much higher porphyrin plasma concentrations (which are poorly dialyzable). In addition, the blood transfusions necessary to treat the anemia that often accompanies ESKD can result in secondary iron overload. Hepatitis C infection is a modifiable risk factor for PCT, the prevalence of which has ranged from 21% to 92% in various countries [ Human immunodeficiency virus (HIV) infection Factors that substantially reduce plasma levels of ascorbate and carotenoids [ No Presence of biallelic null variants is lethal [ Porphyria cutanea tarda (PCT) that is not associated with a F-PCT (i.e., porphyria cutanea tarda caused by a heterozygous pathogenic variant in Porphyria Classification Systems ALA = aminolevulinic acid See also The penetrance of F-PCT is low, given that in addition to heterozygosity for a The prevalence of F-PCT is approximately 8:1,000,000 (based on the estimated prevalence of PCT as 40:1,000,000 and of F-PCT as ~20% of PCT) [ • Secondary iron overload. Some degree of hepatic siderosis (mild-to-moderate iron overload) is seen in most individuals with F-PCT. Conversely, iron deficiency is protective. • Excessive alcohol consumption • Tobacco use • Oral estrogen use • Estrogen mimetics/antagonists (e.g., tamoxifen) • Exposure to toxins such as polychlorinated biphenyls, hexochlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes • End-stage kidney disease (ESKD) can lead to manifestations of F-PCT that are often more severe than usual because the lack of urinary porphyrin excretion results in much higher porphyrin plasma concentrations (which are poorly dialyzable). In addition, the blood transfusions necessary to treat the anemia that often accompanies ESKD can result in secondary iron overload. • Hepatitis C infection is a modifiable risk factor for PCT, the prevalence of which has ranged from 21% to 92% in various countries [ • Human immunodeficiency virus (HIV) infection • Factors that substantially reduce plasma levels of ascorbate and carotenoids [ ## Clinical Description Familial porphyria cutanea tarda (F-PCT) is characterized by cutaneous findings including skin friability and chronic blistering over sun-exposed areas (classically the dorsal aspects of the hands). In contrast to the acute hepatic porphyrias or erythropoietic cutaneous porphyrias, F-PCT does not manifest as acute episodes of pain or acute/painful skin changes upon sun exposure, respectively. Hepatic involvement of F-PCT is characterized by elevation in aminotransferases, increased iron stores, and varying degrees of fibrosis accompanied by an increased risk for hepatocellular carcinoma. Histopathology of the skin in F-PCT demonstrates subepidermal fluid collections (blistering), hyperkeratosis, and lipid proteinosis. Additional findings can include deposition of PAS-positive material around blood vessels and fine fibrillar material in the upper dermis, as well as splitting of the lamina lucida of the basement membrane at the dermoepithelial junction [ Some affected individuals will demonstrate evidence of hepatic iron overload, suggested by elevated serum ferritin concentration and elevated transferrin saturation. While cirrhosis may develop in 30%-40% of individuals, predisposing factors are concomitant infection with hepatitis C virus and use of alcohol. The risk for hepatocellular carcinoma is increased in individuals with F-PCT, especially in those with other risk factors predisposing to advanced liver disease (see ## Pathophysiology Development of clinical manifestations of familial porphyria cutanea tarda (F-PCT) requires Inherited, environmental, medical, and infectious factors that are known or suspected to influence disease susceptibility in F-PTC include the following [ Secondary iron overload. Some degree of hepatic siderosis (mild-to-moderate iron overload) is seen in most individuals with F-PCT. Conversely, iron deficiency is protective. Excessive alcohol consumption Tobacco use Oral estrogen use Estrogen mimetics/antagonists (e.g., tamoxifen) Exposure to toxins such as polychlorinated biphenyls, hexochlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes End-stage kidney disease (ESKD) can lead to manifestations of F-PCT that are often more severe than usual because the lack of urinary porphyrin excretion results in much higher porphyrin plasma concentrations (which are poorly dialyzable). In addition, the blood transfusions necessary to treat the anemia that often accompanies ESKD can result in secondary iron overload. Hepatitis C infection is a modifiable risk factor for PCT, the prevalence of which has ranged from 21% to 92% in various countries [ Human immunodeficiency virus (HIV) infection Factors that substantially reduce plasma levels of ascorbate and carotenoids [ • Secondary iron overload. Some degree of hepatic siderosis (mild-to-moderate iron overload) is seen in most individuals with F-PCT. Conversely, iron deficiency is protective. • Excessive alcohol consumption • Tobacco use • Oral estrogen use • Estrogen mimetics/antagonists (e.g., tamoxifen) • Exposure to toxins such as polychlorinated biphenyls, hexochlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes • End-stage kidney disease (ESKD) can lead to manifestations of F-PCT that are often more severe than usual because the lack of urinary porphyrin excretion results in much higher porphyrin plasma concentrations (which are poorly dialyzable). In addition, the blood transfusions necessary to treat the anemia that often accompanies ESKD can result in secondary iron overload. • Hepatitis C infection is a modifiable risk factor for PCT, the prevalence of which has ranged from 21% to 92% in various countries [ • Human immunodeficiency virus (HIV) infection • Factors that substantially reduce plasma levels of ascorbate and carotenoids [ ## Susceptibility Factors Inherited, environmental, medical, and infectious factors that are known or suspected to influence disease susceptibility in F-PTC include the following [ Secondary iron overload. Some degree of hepatic siderosis (mild-to-moderate iron overload) is seen in most individuals with F-PCT. Conversely, iron deficiency is protective. Excessive alcohol consumption Tobacco use Oral estrogen use Estrogen mimetics/antagonists (e.g., tamoxifen) Exposure to toxins such as polychlorinated biphenyls, hexochlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes End-stage kidney disease (ESKD) can lead to manifestations of F-PCT that are often more severe than usual because the lack of urinary porphyrin excretion results in much higher porphyrin plasma concentrations (which are poorly dialyzable). In addition, the blood transfusions necessary to treat the anemia that often accompanies ESKD can result in secondary iron overload. Hepatitis C infection is a modifiable risk factor for PCT, the prevalence of which has ranged from 21% to 92% in various countries [ Human immunodeficiency virus (HIV) infection Factors that substantially reduce plasma levels of ascorbate and carotenoids [ • Secondary iron overload. Some degree of hepatic siderosis (mild-to-moderate iron overload) is seen in most individuals with F-PCT. Conversely, iron deficiency is protective. • Excessive alcohol consumption • Tobacco use • Oral estrogen use • Estrogen mimetics/antagonists (e.g., tamoxifen) • Exposure to toxins such as polychlorinated biphenyls, hexochlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes • End-stage kidney disease (ESKD) can lead to manifestations of F-PCT that are often more severe than usual because the lack of urinary porphyrin excretion results in much higher porphyrin plasma concentrations (which are poorly dialyzable). In addition, the blood transfusions necessary to treat the anemia that often accompanies ESKD can result in secondary iron overload. • Hepatitis C infection is a modifiable risk factor for PCT, the prevalence of which has ranged from 21% to 92% in various countries [ • Human immunodeficiency virus (HIV) infection • Factors that substantially reduce plasma levels of ascorbate and carotenoids [ ## Genotype-Phenotype Correlations No Presence of biallelic null variants is lethal [ ## Nomenclature Porphyria cutanea tarda (PCT) that is not associated with a F-PCT (i.e., porphyria cutanea tarda caused by a heterozygous pathogenic variant in Porphyria Classification Systems ALA = aminolevulinic acid See also ## Penetrance The penetrance of F-PCT is low, given that in addition to heterozygosity for a ## Prevalence The prevalence of F-PCT is approximately 8:1,000,000 (based on the estimated prevalence of PCT as 40:1,000,000 and of F-PCT as ~20% of PCT) [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Porphyria cutanea tarda (PCT) is the most common type of porphyria and encompasses both familial Other types of hereditary porphyria in the differential diagnosis of F-PCT are summarized in Other Types of Porphyria in the Differential Diagnosis of Familial Porphyria Cutanea Tarda AD = autosomal dominant; AIP = acute intermittent porphyria; AR = autosomal recessive; MOI = mode of inheritance; PCT = porphyria cutanea tarda A pathogenic variant in ## Other Disorders in the Differential Diagnosis of F-PCT ## Management No clinical practice guidelines for familial porphyria cutanea tarda (F-PCT) have been published. To establish the extent of disease and needs in an individual diagnosed with familial porphyria cutanea tarda (F-PCT), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Evaluation of skin findings, including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma) Medical history regarding susceptibility factors that are known to influence the presence and/or severity of clinical manifestations (see Pathophysiology, Presence of Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation Alcohol consumption Tobacco use Oral estrogen use Chronic kidney disease / end-stage kidney disease Presence of hepatitis C and/or human immunodeficiency virus infection Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of F-PCT in order to facilitate medical and personal decision making There are no effective treatment regimens to restore UROD enzyme levels in individuals with F-PCT. The mainstays of therapy for PCT that are highly effective in individuals with F-PCT are: Reduction of body iron stores and liver iron content; Use of low-dose antimalarial agents (hydroxychloroquine). In addition, addressing modifiable risk factors such as ceasing alcohol/tobacco use, modifying estrogen use, and treatment of hepatitis C infection, if present, is warranted. Phlebotomy therapy is also guided by plasma (or serum) porphyrin levels, which can more easily be measured repeatedly than urine porphyrins, and which decrease more slowly than the serum ferritin concentration. Plasma porphyrin levels usually decline from initial concentrations of 10-25 μg/dL to below the upper limit of normal (~1 μg/dL) within three to six weeks after phlebotomies are completed [ Development of new skin lesions generally ceases as plasma porphyrin levels normalize; however, therapy should be continued until the serum ferritin concentration has reached the low end of normal. The chronic skin lesions of PCT are slow to resolve, and some chronic scarring may remain indefinitely. After remission has been achieved, continued phlebotomies are generally not needed unless initial evaluation has determined the presence of Note: Treatment of PCT in persons with ESRD is more difficult because the option for phlebotomy is often limited by anemia. However, in several instances erythropoietin therapy has been shown to improve anemia, mobilize iron, and support phlebotomy [ In addition, the ingestion of tea with lunch or dinner further reduces the gastrointestinal absorption of iron. A low-dose regimen of twice-weekly hydroxychloroquine (100 mg) or chloroquine (125 mg) is also effective and most appropriate when phlebotomy is contraindicated or poorly tolerated. Note: Chloroquine is not recommended in persons with increased serum ferritin concentration [ Although the use of low-dose antimalarial agents is preferred at some centers because they are less costly and more convenient, these agents do not deplete hepatic iron, and the mechanism of their action in the treatment of PCT is not fully understood. Combining both treatment modalities (i.e., antimalarial agent therapy and phlebotomy) may be beneficial if the individual is unable to tolerate full courses of phlebotomy. Individuals are advised to stop drinking alcohol and smoking and to discontinue further oral estrogen use. If hormone replacement therapy is indicated, switching to a transdermal alternative is recommended. Manifestations of F-PCT may also improve after treatment of coexisting hepatitis C. F-PCT should be treated first in most individuals. F-PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C. Some evidence shows that hepatitis C treatment with interferon-based therapies is more effective after iron reduction [ Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and may also reduce the risk of developing hepatocellular carcinoma [ Vaccination against hepatitis A and B is appropriate. Although adequate intake of ascorbic acid and other nutrients may be recommended, this is not considered a primary therapy. Monitor urinary porphyrin levels annually. For those who have been treated by phlebotomy, resume iron reduction by therapeutic phlebotomies if and when urinary uroporphyrins and heptacarboxylporphyrins increase to greater than 400 µg/g creatinine (see Because of reports of an association between diabetes mellitus and PCT [ Hepatocellular cancer (HCC) surveillance relies on a combination of serum alpha-fetoprotein determinations and hepatic ultrasonography or cross-sectional imaging (CT or MRI). No guidelines as to the frequency of these tests are currently available because of the rarity of F-PCT and even rarer occurrence of HCC. Surveillance is usually performed annually; however, in those with cirrhosis, hepatologists generally agree that surveillance for HCC should be at least every six months. Avoid the following: Susceptibility factors (if known) (e.g., iron supplements, alcohol consumption, smoking, estrogen use, and hepatotoxins such as hexachlorobenzene) (See Pathophysiology, Exposure to sunlight in symptomatic phase (i.e., when new skin changes appear) Testing at-risk relatives of an individual with F-PCT to identify those with a See Women with active F-PCT should be able to carry pregnancies to term, though the pregnancy should be considered "high risk" and followed by an appropriately qualified obstetrician [ It is recommended that women with F-PCT and iron overload (which is rather unusual in women during their child-bearing years) be treated to reduce body iron stores prior to the onset of planned pregnancies (see The use of hydroxychloroquine during human pregnancy is not thought to lead to adverse fetal effects. The use of chloroquine at higher doses has produced adverse embryonic effects in animal pregnancies; however, case reports of low doses of chloroquine used in human pregnancy for rheumatic disease have not been associated with adverse fetal outcomes. The US FDA recommends that chloroquine or hydroxychloroquine not be used in pregnant or lactating women unless the expected benefit outweighs the possible risks. No formal grade for use in such women has been assigned. While iron chelation therapy is not a treatment of choice, some pregnant women may be taking an iron chelator at the time of conception or during pregnancy. Data on the use of deferoxamine during human pregnancy suggest that it is not likely to cause adverse fetal effects. Data on use of deferasirox during human pregnancy are more limited, although reassuring. Data on the use of deferiprone during human pregnancy are very limited. See A Phase II open-label trial ( Search • Evaluation of skin findings, including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma) • Medical history regarding susceptibility factors that are known to influence the presence and/or severity of clinical manifestations (see Pathophysiology, • Presence of • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation • Alcohol consumption • Tobacco use • Oral estrogen use • Chronic kidney disease / end-stage kidney disease • Presence of hepatitis C and/or human immunodeficiency virus infection • Presence of • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation • Alcohol consumption • Tobacco use • Oral estrogen use • Chronic kidney disease / end-stage kidney disease • Presence of hepatitis C and/or human immunodeficiency virus infection • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of F-PCT in order to facilitate medical and personal decision making • Presence of • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation • Alcohol consumption • Tobacco use • Oral estrogen use • Chronic kidney disease / end-stage kidney disease • Presence of hepatitis C and/or human immunodeficiency virus infection • Reduction of body iron stores and liver iron content; • Use of low-dose antimalarial agents (hydroxychloroquine). • F-PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C. • Some evidence shows that hepatitis C treatment with interferon-based therapies is more effective after iron reduction [ • Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and may also reduce the risk of developing hepatocellular carcinoma [ • Susceptibility factors (if known) (e.g., iron supplements, alcohol consumption, smoking, estrogen use, and hepatotoxins such as hexachlorobenzene) (See Pathophysiology, • Exposure to sunlight in symptomatic phase (i.e., when new skin changes appear) • Data on the use of deferoxamine during human pregnancy suggest that it is not likely to cause adverse fetal effects. • Data on use of deferasirox during human pregnancy are more limited, although reassuring. • Data on the use of deferiprone during human pregnancy are very limited. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with familial porphyria cutanea tarda (F-PCT), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Evaluation of skin findings, including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma) Medical history regarding susceptibility factors that are known to influence the presence and/or severity of clinical manifestations (see Pathophysiology, Presence of Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation Alcohol consumption Tobacco use Oral estrogen use Chronic kidney disease / end-stage kidney disease Presence of hepatitis C and/or human immunodeficiency virus infection Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of F-PCT in order to facilitate medical and personal decision making • Evaluation of skin findings, including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma) • Medical history regarding susceptibility factors that are known to influence the presence and/or severity of clinical manifestations (see Pathophysiology, • Presence of • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation • Alcohol consumption • Tobacco use • Oral estrogen use • Chronic kidney disease / end-stage kidney disease • Presence of hepatitis C and/or human immunodeficiency virus infection • Presence of • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation • Alcohol consumption • Tobacco use • Oral estrogen use • Chronic kidney disease / end-stage kidney disease • Presence of hepatitis C and/or human immunodeficiency virus infection • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of F-PCT in order to facilitate medical and personal decision making • Presence of • Excess iron based on iron indices: serum ferritin level; serum iron concentration, total iron binding capacity, and percent iron saturation • Alcohol consumption • Tobacco use • Oral estrogen use • Chronic kidney disease / end-stage kidney disease • Presence of hepatitis C and/or human immunodeficiency virus infection ## Treatment of Manifestations There are no effective treatment regimens to restore UROD enzyme levels in individuals with F-PCT. The mainstays of therapy for PCT that are highly effective in individuals with F-PCT are: Reduction of body iron stores and liver iron content; Use of low-dose antimalarial agents (hydroxychloroquine). In addition, addressing modifiable risk factors such as ceasing alcohol/tobacco use, modifying estrogen use, and treatment of hepatitis C infection, if present, is warranted. Phlebotomy therapy is also guided by plasma (or serum) porphyrin levels, which can more easily be measured repeatedly than urine porphyrins, and which decrease more slowly than the serum ferritin concentration. Plasma porphyrin levels usually decline from initial concentrations of 10-25 μg/dL to below the upper limit of normal (~1 μg/dL) within three to six weeks after phlebotomies are completed [ Development of new skin lesions generally ceases as plasma porphyrin levels normalize; however, therapy should be continued until the serum ferritin concentration has reached the low end of normal. The chronic skin lesions of PCT are slow to resolve, and some chronic scarring may remain indefinitely. After remission has been achieved, continued phlebotomies are generally not needed unless initial evaluation has determined the presence of Note: Treatment of PCT in persons with ESRD is more difficult because the option for phlebotomy is often limited by anemia. However, in several instances erythropoietin therapy has been shown to improve anemia, mobilize iron, and support phlebotomy [ In addition, the ingestion of tea with lunch or dinner further reduces the gastrointestinal absorption of iron. A low-dose regimen of twice-weekly hydroxychloroquine (100 mg) or chloroquine (125 mg) is also effective and most appropriate when phlebotomy is contraindicated or poorly tolerated. Note: Chloroquine is not recommended in persons with increased serum ferritin concentration [ Although the use of low-dose antimalarial agents is preferred at some centers because they are less costly and more convenient, these agents do not deplete hepatic iron, and the mechanism of their action in the treatment of PCT is not fully understood. Combining both treatment modalities (i.e., antimalarial agent therapy and phlebotomy) may be beneficial if the individual is unable to tolerate full courses of phlebotomy. Individuals are advised to stop drinking alcohol and smoking and to discontinue further oral estrogen use. If hormone replacement therapy is indicated, switching to a transdermal alternative is recommended. Manifestations of F-PCT may also improve after treatment of coexisting hepatitis C. F-PCT should be treated first in most individuals. F-PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C. Some evidence shows that hepatitis C treatment with interferon-based therapies is more effective after iron reduction [ Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and may also reduce the risk of developing hepatocellular carcinoma [ Vaccination against hepatitis A and B is appropriate. Although adequate intake of ascorbic acid and other nutrients may be recommended, this is not considered a primary therapy. • Reduction of body iron stores and liver iron content; • Use of low-dose antimalarial agents (hydroxychloroquine). • F-PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C. • Some evidence shows that hepatitis C treatment with interferon-based therapies is more effective after iron reduction [ • Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and may also reduce the risk of developing hepatocellular carcinoma [ ## Reduction of Body Iron Stores and Liver Iron Content Phlebotomy therapy is also guided by plasma (or serum) porphyrin levels, which can more easily be measured repeatedly than urine porphyrins, and which decrease more slowly than the serum ferritin concentration. Plasma porphyrin levels usually decline from initial concentrations of 10-25 μg/dL to below the upper limit of normal (~1 μg/dL) within three to six weeks after phlebotomies are completed [ Development of new skin lesions generally ceases as plasma porphyrin levels normalize; however, therapy should be continued until the serum ferritin concentration has reached the low end of normal. The chronic skin lesions of PCT are slow to resolve, and some chronic scarring may remain indefinitely. After remission has been achieved, continued phlebotomies are generally not needed unless initial evaluation has determined the presence of Note: Treatment of PCT in persons with ESRD is more difficult because the option for phlebotomy is often limited by anemia. However, in several instances erythropoietin therapy has been shown to improve anemia, mobilize iron, and support phlebotomy [ In addition, the ingestion of tea with lunch or dinner further reduces the gastrointestinal absorption of iron. ## Low-Dose Antimalarial Agents A low-dose regimen of twice-weekly hydroxychloroquine (100 mg) or chloroquine (125 mg) is also effective and most appropriate when phlebotomy is contraindicated or poorly tolerated. Note: Chloroquine is not recommended in persons with increased serum ferritin concentration [ Although the use of low-dose antimalarial agents is preferred at some centers because they are less costly and more convenient, these agents do not deplete hepatic iron, and the mechanism of their action in the treatment of PCT is not fully understood. Combining both treatment modalities (i.e., antimalarial agent therapy and phlebotomy) may be beneficial if the individual is unable to tolerate full courses of phlebotomy. ## Other Individuals are advised to stop drinking alcohol and smoking and to discontinue further oral estrogen use. If hormone replacement therapy is indicated, switching to a transdermal alternative is recommended. Manifestations of F-PCT may also improve after treatment of coexisting hepatitis C. F-PCT should be treated first in most individuals. F-PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C. Some evidence shows that hepatitis C treatment with interferon-based therapies is more effective after iron reduction [ Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and may also reduce the risk of developing hepatocellular carcinoma [ Vaccination against hepatitis A and B is appropriate. Although adequate intake of ascorbic acid and other nutrients may be recommended, this is not considered a primary therapy. • F-PCT generally causes more symptoms and can be treated more quickly and effectively than hepatitis C. • Some evidence shows that hepatitis C treatment with interferon-based therapies is more effective after iron reduction [ • Attainment and maintenance of an iron-reduced state decreases the severity and progression of chronic hepatitis C and may also reduce the risk of developing hepatocellular carcinoma [ ## Surveillance Monitor urinary porphyrin levels annually. For those who have been treated by phlebotomy, resume iron reduction by therapeutic phlebotomies if and when urinary uroporphyrins and heptacarboxylporphyrins increase to greater than 400 µg/g creatinine (see Because of reports of an association between diabetes mellitus and PCT [ Hepatocellular cancer (HCC) surveillance relies on a combination of serum alpha-fetoprotein determinations and hepatic ultrasonography or cross-sectional imaging (CT or MRI). No guidelines as to the frequency of these tests are currently available because of the rarity of F-PCT and even rarer occurrence of HCC. Surveillance is usually performed annually; however, in those with cirrhosis, hepatologists generally agree that surveillance for HCC should be at least every six months. ## Agents/Circumstances to Avoid Avoid the following: Susceptibility factors (if known) (e.g., iron supplements, alcohol consumption, smoking, estrogen use, and hepatotoxins such as hexachlorobenzene) (See Pathophysiology, Exposure to sunlight in symptomatic phase (i.e., when new skin changes appear) • Susceptibility factors (if known) (e.g., iron supplements, alcohol consumption, smoking, estrogen use, and hepatotoxins such as hexachlorobenzene) (See Pathophysiology, • Exposure to sunlight in symptomatic phase (i.e., when new skin changes appear) ## Evaluation of Relatives at Risk Testing at-risk relatives of an individual with F-PCT to identify those with a See ## Pregnancy Management Women with active F-PCT should be able to carry pregnancies to term, though the pregnancy should be considered "high risk" and followed by an appropriately qualified obstetrician [ It is recommended that women with F-PCT and iron overload (which is rather unusual in women during their child-bearing years) be treated to reduce body iron stores prior to the onset of planned pregnancies (see The use of hydroxychloroquine during human pregnancy is not thought to lead to adverse fetal effects. The use of chloroquine at higher doses has produced adverse embryonic effects in animal pregnancies; however, case reports of low doses of chloroquine used in human pregnancy for rheumatic disease have not been associated with adverse fetal outcomes. The US FDA recommends that chloroquine or hydroxychloroquine not be used in pregnant or lactating women unless the expected benefit outweighs the possible risks. No formal grade for use in such women has been assigned. While iron chelation therapy is not a treatment of choice, some pregnant women may be taking an iron chelator at the time of conception or during pregnancy. Data on the use of deferoxamine during human pregnancy suggest that it is not likely to cause adverse fetal effects. Data on use of deferasirox during human pregnancy are more limited, although reassuring. Data on the use of deferiprone during human pregnancy are very limited. See • Data on the use of deferoxamine during human pregnancy suggest that it is not likely to cause adverse fetal effects. • Data on use of deferasirox during human pregnancy are more limited, although reassuring. • Data on the use of deferiprone during human pregnancy are very limited. ## Therapies Under Investigation A Phase II open-label trial ( Search ## Genetic Counseling Familial porphyria cutanea tarda (F-PCT) is inherited in an autosomal dominant manner with reduced Note: The penetrance of F-PCT is low, given that in addition to heterozygosity for a Most individuals diagnosed with F-PCT inherited a Some individuals diagnosed with F-PCT have the disorder as the result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed may appear to be negative because of the low penetrance F-PCT in heterozygous individuals. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the If the proband has a known See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with F-PCT. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with F-PCT inherited a • Some individuals diagnosed with F-PCT have the disorder as the result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed may appear to be negative because of the low penetrance F-PCT in heterozygous individuals. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the • If the proband has a known • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with F-PCT. ## Mode of Inheritance Familial porphyria cutanea tarda (F-PCT) is inherited in an autosomal dominant manner with reduced Note: The penetrance of F-PCT is low, given that in addition to heterozygosity for a ## Risk to Family Members Most individuals diagnosed with F-PCT inherited a Some individuals diagnosed with F-PCT have the disorder as the result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed may appear to be negative because of the low penetrance F-PCT in heterozygous individuals. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the If the proband has a known • Most individuals diagnosed with F-PCT inherited a • Some individuals diagnosed with F-PCT have the disorder as the result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed may appear to be negative because of the low penetrance F-PCT in heterozygous individuals. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the • If the proband has a known ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with F-PCT. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with F-PCT. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Sweden • • United Kingdom • • • • • • • • • • • • • • • • Sweden • ## Molecular Genetics Familial Porphyria Cutanea Tarda: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Familial Porphyria Cutanea Tarda ( ## Molecular Pathogenesis ## Chapter Notes On behalf of the Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network; including Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX; Dr Bruce Wang, University of California, San Francisco, CA; Drs Herbert Bonkovsky and Sean Rudnick, Atrium Health Wake Forest Baptist, Winston-Salem, NC; Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT; Drs Brendan McGuire and Mohamed Kazamel, Univ of Alabama at Birmingham, Birmingham, AL; Drs Manisha Balwani and Robert Desnick, Icahn School of Medicine at Mt Sinai, New York, NY; and the United Porphyria Association. Herbert Bonkovsky, MD (2013-present)Lawrence U Liu, MD; Icahn School of Medicine at Mount Sinai (2013-2022)John Phillips, PhD (2013-present)Sean Rudnick, MD (2022-present) 9 June 2022 (bp) Comprehensive update posted live 8 September 2016 (sw) Comprehensive update posted live 22 August 2013 (me) Comprehensive update posted live; 6 June 2013 (me) Review posted live 26 April 2012 (hb) Original Submission • 9 June 2022 (bp) Comprehensive update posted live • 8 September 2016 (sw) Comprehensive update posted live • 22 August 2013 (me) Comprehensive update posted live; • 6 June 2013 (me) Review posted live • 26 April 2012 (hb) Original Submission ## Acknowledgments On behalf of the Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network; including Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX; Dr Bruce Wang, University of California, San Francisco, CA; Drs Herbert Bonkovsky and Sean Rudnick, Atrium Health Wake Forest Baptist, Winston-Salem, NC; Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT; Drs Brendan McGuire and Mohamed Kazamel, Univ of Alabama at Birmingham, Birmingham, AL; Drs Manisha Balwani and Robert Desnick, Icahn School of Medicine at Mt Sinai, New York, NY; and the United Porphyria Association. ## Author History Herbert Bonkovsky, MD (2013-present)Lawrence U Liu, MD; Icahn School of Medicine at Mount Sinai (2013-2022)John Phillips, PhD (2013-present)Sean Rudnick, MD (2022-present) ## Revision History 9 June 2022 (bp) Comprehensive update posted live 8 September 2016 (sw) Comprehensive update posted live 22 August 2013 (me) Comprehensive update posted live; 6 June 2013 (me) Review posted live 26 April 2012 (hb) Original Submission • 9 June 2022 (bp) Comprehensive update posted live • 8 September 2016 (sw) Comprehensive update posted live • 22 August 2013 (me) Comprehensive update posted live; • 6 June 2013 (me) Review posted live • 26 April 2012 (hb) Original Submission ## References ## Literature Cited	[ "A Aziz Ibrahim, UI Esen. 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Proc Natl Acad Sci U S A 2007;104:5079-84", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "S Ratnaike, D Blake, D Campbell, P Cowen, G Varigos. Plasma ferritin levels as a guide to the treatment of porphyria cutanea tarda by venesection.. Australas J Dermatol 1988;29:3-8", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "E Rocchi, G Casalgrandi, A Masini, F Giovannini, D Ceccarelli, M Ferrali, S Marchini, E Ventura. Circulating pro- and antioxidant factors in iron and porphyrin metabolism disorders.. Ital J Gastroenterol Hepatol 1999;31:861-7", "E Rocchi, P Gibertini, M Cassanelli, A Pietrangelo, A Borghi, E Ventura. Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda.. J Lab Clin Med 1986;107:36-42", "N Rodrigues, F Caeiro, A Santana, T Mendes, L Lopes. Porphyria cutanea tarda in a patient with end-stage renal disease: A case of successful treatment with deferoxamine and ferric carboxymaltose.. Case Rep Nephrol. 2017;2017", "F Ryan Caballes, H Sendi, HL Bonkovsky. Hepatitis C, porphyria cutanea tarda and liver iron: an update.. Liver Int. 2012;32:880-93", "S Shieh, JL Cohen, HW Lim. Management of porphyria cutanea tarda in the setting of chronic renal failure: a case report and review.. J Am Acad Dermatol 2000;42:645-52", "PR Sinclair, N Gorman, SI Shedlofsky, CP Honsinger, JF Sinclair, MR Karagas, KE Anderson. Ascorbic acid deficiency in porphyria cutanea tarda.. J Lab Clin Med 1997;130:197-201", "AK Singal, C Kormos-Hallberg, C Lee, VM Sadagoparamanujam, JJ Grady, DH Freeman, KE Anderson. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda.. Clin Gastroenterol Hepatol 2012;10:1402-9", "AG Smith, GH Elder. Complex gene-chemical interactions: hepatic uroporphyria as a paradigm.. Chem Res Toxicol. 2010;23:712-23", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "MC Tollånes, AK Aarsand, S Sandberg. Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study.. J Inherit Metab Dis. 2011;34:217-23", "Y Weiss, B Chen, M Yasuda, I Nazarenko, KE Anderson, RJ Desnick. Porphyria cutanea tarda and hepatoerythropoietic porphyria: identification of 19 novel uroporphyrinogen III decarboxylase mutations.. Mol Genet Metab 2019;128:363-6" ]	6/6/2013	9/6/2022		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
porphyria-var	porphyria-var	[ "Porphyria Variegata", "Porphyria Variegata", "Protoporphyrinogen oxidase", "PPOX", "Variegate Porphyria" ]	Variegate Porphyria	Ashwani K Singal, Karl E Anderson	Summary Variegate porphyria (VP) is both a cutaneous porphyria (with chronic blistering skin lesions) and an acute porphyria (with severe episodic neurovisceral symptoms). The most common manifestation of VP is adult-onset cutaneous blistering lesions (subepidermal vesicles, bullae, and erosions that crust over and heal slowly) of sun-exposed skin, especially the hands and face. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. Cutaneous manifestations may improve in winter and be less prevalent in northern regions and in dark-skinned individuals. Acute neurovisceral symptoms can occur any time after puberty, but less often in the elderly. Acute manifestations are highly variable, but may be similar from episode to episode in a person with recurrent attacks; not all manifestations are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common manifestations are abdominal pain; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a primarily motor neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis. Psychiatric disturbances and autonomic neuropathy can also be observed. Acute attacks may be severe and are potentially fatal. The biochemical diagnosis of VP is established in an individual with elevated urine porphobilinogen (PBG) or porphyrins and a fluorescence peak at ~626 nm on plasma fluorescence scanning; fecal porphyrins are also elevated, with a predominance of coproporphyrin III and protoporphyrin. The molecular diagnosis of VP is established by identification of a heterozygous pathogenic variant in Although mild attacks (without seizures, weakness, or hyponatremia and not requiring narcotics) can sometimes be treated in an outpatient setting with glucose loading, most attacks require treatment with intravenous hemin and in-patient observation for additional supportive management. Cutaneous manifestations are best managed by wearing protective clothing and avoiding exposure to sunlight. Symptoms may decrease when exacerbating factors are removed. No treatment is known to be effective in lowering porphyrin levels and reducing cutaneous symptoms. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. VP is inherited in an autosomal dominant manner with reduced penetrance.	## Diagnosis Variegate porphyria (VP) Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. Constipation Pain in the back, chest, and extremities Anxiety Seizures Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack (see Management, When initial biochemical laboratory findings support an acute porphyria (i.e., elevated urine PBG or porphyrins) or a blistering cutaneous porphyria (i.e., elevated plasma or urine porphyrins), further diagnostic biochemical testing ( Biochemical Characteristics of Variegate Porphyria (VP) Active = symptomatic This enzyme oxidizes protoporphyrinogen to protoporphyrin and its deficiency leads to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin. The enzyme assay is not needed for diagnostic purposes and is not widely available. PBG elevation should be detected by a quantitative method such as that described by Active VP is suggested by a quantitative PBG that is substantially elevated. For screening, it is also useful to measure total porphyrins in the same urine sample, since levels of PBG can be less elevated in VP and HCP than in AIP and decrease to normal more rapidly. Note: Unlike a substantial increase in PBG, a substantial increase in urinary porphyrins does not indicate porphyria, as urinary porphyrins are increased in many other medical conditions, especially when the hepatobiliary system or bone marrow is affected. PBG and total porphyrins may not be elevated in persons whose symptoms have resolved. If an acute porphyria is suspected to have caused past symptoms, full biochemical testing to include urinary ALA, PBG, and porphyrins, fecal porphyrins, and plasma porphyrins may be indicated. Fecal porphyrins are markedly elevated in HCP and VP, whereas in AIP there is little or no elevation. The pattern of fecal porphyrins differentiates HCP and VP, with marked predominance of coproporphyrin III in HCP, and roughly equal elevations of coproporphyrin III and protoporphyrin in VP. A fluorescence scan of diluted plasma at neutral pH provides a fluorescence peak at wavelength ~626 nm in VP that is highly sensitive and specific for this porphyria [ Identification of the causative pathogenic variant is now considered standard of care in VP and other acute porphyrias to confirm the diagnosis and inform genetic counseling (see Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Variegate Porphyria See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Multiexon deletions of VP is especially common in South Africa, where the founder variant • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. • Constipation • Pain in the back, chest, and extremities • Anxiety • Seizures • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. • Constipation • Pain in the back, chest, and extremities • Anxiety • Seizures • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. • Constipation • Pain in the back, chest, and extremities • Anxiety • Seizures • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ • Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack (see Management, • Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, • Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. • For an introduction to multigene panels click ## Suggestive Findings Variegate porphyria (VP) Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. Constipation Pain in the back, chest, and extremities Anxiety Seizures Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack (see Management, • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. • Constipation • Pain in the back, chest, and extremities • Anxiety • Seizures • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. • Constipation • Pain in the back, chest, and extremities • Anxiety • Seizures • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ • Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. • Constipation • Pain in the back, chest, and extremities • Anxiety • Seizures • Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. • Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [ • Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack (see Management, ## Establishing the Diagnosis When initial biochemical laboratory findings support an acute porphyria (i.e., elevated urine PBG or porphyrins) or a blistering cutaneous porphyria (i.e., elevated plasma or urine porphyrins), further diagnostic biochemical testing ( Biochemical Characteristics of Variegate Porphyria (VP) Active = symptomatic This enzyme oxidizes protoporphyrinogen to protoporphyrin and its deficiency leads to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin. The enzyme assay is not needed for diagnostic purposes and is not widely available. PBG elevation should be detected by a quantitative method such as that described by Active VP is suggested by a quantitative PBG that is substantially elevated. For screening, it is also useful to measure total porphyrins in the same urine sample, since levels of PBG can be less elevated in VP and HCP than in AIP and decrease to normal more rapidly. Note: Unlike a substantial increase in PBG, a substantial increase in urinary porphyrins does not indicate porphyria, as urinary porphyrins are increased in many other medical conditions, especially when the hepatobiliary system or bone marrow is affected. PBG and total porphyrins may not be elevated in persons whose symptoms have resolved. If an acute porphyria is suspected to have caused past symptoms, full biochemical testing to include urinary ALA, PBG, and porphyrins, fecal porphyrins, and plasma porphyrins may be indicated. Fecal porphyrins are markedly elevated in HCP and VP, whereas in AIP there is little or no elevation. The pattern of fecal porphyrins differentiates HCP and VP, with marked predominance of coproporphyrin III in HCP, and roughly equal elevations of coproporphyrin III and protoporphyrin in VP. A fluorescence scan of diluted plasma at neutral pH provides a fluorescence peak at wavelength ~626 nm in VP that is highly sensitive and specific for this porphyria [ Identification of the causative pathogenic variant is now considered standard of care in VP and other acute porphyrias to confirm the diagnosis and inform genetic counseling (see Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Variegate Porphyria See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Multiexon deletions of VP is especially common in South Africa, where the founder variant • Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, • Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. • For an introduction to multigene panels click ## Biochemical Diagnosis When initial biochemical laboratory findings support an acute porphyria (i.e., elevated urine PBG or porphyrins) or a blistering cutaneous porphyria (i.e., elevated plasma or urine porphyrins), further diagnostic biochemical testing ( Biochemical Characteristics of Variegate Porphyria (VP) Active = symptomatic This enzyme oxidizes protoporphyrinogen to protoporphyrin and its deficiency leads to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin. The enzyme assay is not needed for diagnostic purposes and is not widely available. PBG elevation should be detected by a quantitative method such as that described by Active VP is suggested by a quantitative PBG that is substantially elevated. For screening, it is also useful to measure total porphyrins in the same urine sample, since levels of PBG can be less elevated in VP and HCP than in AIP and decrease to normal more rapidly. Note: Unlike a substantial increase in PBG, a substantial increase in urinary porphyrins does not indicate porphyria, as urinary porphyrins are increased in many other medical conditions, especially when the hepatobiliary system or bone marrow is affected. PBG and total porphyrins may not be elevated in persons whose symptoms have resolved. If an acute porphyria is suspected to have caused past symptoms, full biochemical testing to include urinary ALA, PBG, and porphyrins, fecal porphyrins, and plasma porphyrins may be indicated. Fecal porphyrins are markedly elevated in HCP and VP, whereas in AIP there is little or no elevation. The pattern of fecal porphyrins differentiates HCP and VP, with marked predominance of coproporphyrin III in HCP, and roughly equal elevations of coproporphyrin III and protoporphyrin in VP. A fluorescence scan of diluted plasma at neutral pH provides a fluorescence peak at wavelength ~626 nm in VP that is highly sensitive and specific for this porphyria [ ## Molecular Diagnosis Identification of the causative pathogenic variant is now considered standard of care in VP and other acute porphyrias to confirm the diagnosis and inform genetic counseling (see Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Variegate Porphyria See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Multiexon deletions of VP is especially common in South Africa, where the founder variant • Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, • Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. • For an introduction to multigene panels click ## Clinical Characteristics Variegate porphyria (VP) is classified as both a cutaneous and an acute porphyria. It can present with chronic blistering cutaneous manifestations and/or acute attacks of neurovisceral manifestations that may become chronic. These and other manifestations of VP appear typically in adulthood and rarely before puberty. The subepidermal vesicles, bullae, and erosions crust over and heal slowly. When blisters rupture they may become infected and painful. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. The skin manifestations are identical to those seen in Of note, the great majority of individuals who are heterozygous for a The neurovisceral symptoms are identical to those in the other acute porphyrias (see Acute manifestations vary. The most common symptoms are abdominal pain; nausea and vomiting; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a predominantly motor peripheral neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis [ Motor neuropathy usually manifests initially as proximal upper-extremity muscle weakness and can be difficult to detect. Hyperreflexia may be seen initially, followed by hyporeflexia as the motor neuropathy progresses. The motor neuropathy may be accompanied by sensory loss. Note: Motor neuropathy due to acute porphyrias is accompanied by little or no elevation of cerebrospinal fluid protein, which helps to differentiate it from the Landry Guillain-Barré syndrome [ Because abdominal pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. An acute attack can be fatal in the presence of severe manifestations including neuropathy, seizures, and respiratory compromise. If managed properly, the outcome of an acute attack is generally good. Even severe motor neuropathy is reversible with recovery over a variable period of months and sometimes over several years. Factors that predispose to acute attacks that are often identified include exposure to a harmful drug, alcohol, reduced dietary intake, or stress from an infection or other illness. Most harmful drugs are known to be inducers of hepatic δ-aminolevulinic acid synthase (ALAS) and hepatic cytochrome P450 enzymes (see Physical findings such as tachycardia, hypertension, restlessness, and agitation result from autonomic neuropathy and increased circulating catecholamines. Chronic pain may be a manifestation of VP and other acute porphyrias. Depression may be more difficult to link to the disease. Chronic pain and depression may become important management issues. Chronic liver abnormalities, particularly mild elevation of serum transaminases, are common. Risks for development of hepatocellular carcinoma and chronic renal disease are increased in VP (as well as in Note: The speculation that King George III (and perhaps others in the British royal family) had VP has been discounted [ Note: Typically double heterozygosity is suspected because of unusual biochemical patterns, and thus is unlikely to be recognized without comprehensive biochemical testing [ Variegate porphyria (VP) and VP has also been referred to as South African acute porphyria or protocoproporphyria. In the past, familial It is estimated that in the South African population three individuals per 1,000 are heterozygous for the The prevalence of VP with present or past symptoms in Europe is about half that for acute intermittent porphyria ( ## Clinical Description Variegate porphyria (VP) is classified as both a cutaneous and an acute porphyria. It can present with chronic blistering cutaneous manifestations and/or acute attacks of neurovisceral manifestations that may become chronic. These and other manifestations of VP appear typically in adulthood and rarely before puberty. The subepidermal vesicles, bullae, and erosions crust over and heal slowly. When blisters rupture they may become infected and painful. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. The skin manifestations are identical to those seen in Of note, the great majority of individuals who are heterozygous for a The neurovisceral symptoms are identical to those in the other acute porphyrias (see Acute manifestations vary. The most common symptoms are abdominal pain; nausea and vomiting; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a predominantly motor peripheral neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis [ Motor neuropathy usually manifests initially as proximal upper-extremity muscle weakness and can be difficult to detect. Hyperreflexia may be seen initially, followed by hyporeflexia as the motor neuropathy progresses. The motor neuropathy may be accompanied by sensory loss. Note: Motor neuropathy due to acute porphyrias is accompanied by little or no elevation of cerebrospinal fluid protein, which helps to differentiate it from the Landry Guillain-Barré syndrome [ Because abdominal pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. An acute attack can be fatal in the presence of severe manifestations including neuropathy, seizures, and respiratory compromise. If managed properly, the outcome of an acute attack is generally good. Even severe motor neuropathy is reversible with recovery over a variable period of months and sometimes over several years. Factors that predispose to acute attacks that are often identified include exposure to a harmful drug, alcohol, reduced dietary intake, or stress from an infection or other illness. Most harmful drugs are known to be inducers of hepatic δ-aminolevulinic acid synthase (ALAS) and hepatic cytochrome P450 enzymes (see Physical findings such as tachycardia, hypertension, restlessness, and agitation result from autonomic neuropathy and increased circulating catecholamines. Chronic pain may be a manifestation of VP and other acute porphyrias. Depression may be more difficult to link to the disease. Chronic pain and depression may become important management issues. Chronic liver abnormalities, particularly mild elevation of serum transaminases, are common. Risks for development of hepatocellular carcinoma and chronic renal disease are increased in VP (as well as in Note: The speculation that King George III (and perhaps others in the British royal family) had VP has been discounted [ ## Genotype-Phenotype Correlations Note: Typically double heterozygosity is suspected because of unusual biochemical patterns, and thus is unlikely to be recognized without comprehensive biochemical testing [ ## Penetrance ## Nomenclature Variegate porphyria (VP) and VP has also been referred to as South African acute porphyria or protocoproporphyria. In the past, familial ## Prevalence It is estimated that in the South African population three individuals per 1,000 are heterozygous for the The prevalence of VP with present or past symptoms in Europe is about half that for acute intermittent porphyria ( ## Genetically Related (Allelic) Disorders ## Differential Diagnosis The genetic porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in characteristic patterns of accumulation of pathway intermediates ( In Porphyrias with neurologic manifestations are considered acute because the symptoms usually occur as discrete, severe episodes, which may be induced by endogenous hormones, drugs and dietary changes; they are difficult to diagnose due to their rarity and the nonspecific nature of symptoms, even when severe. The four acute porphyrias (often referred to as acute hepatic porphyrias) are: ALA dehydratase deficiency porphyria (ADP), Porphyrias with cutaneous manifestations include those causing chronic blistering skin lesions (i.e., VP as well as Classification of the Hereditary Porphyrias 0 = no symptoms; + = mild to severe symptoms; AD = autosomal dominant; ADP = ALA dehydratase-deficiency porphyria; AIP = acute intermittent porphyria; AR = autosomal recessive; CEP = congenital erythropoietic porphyria; EPP = erythropoietic protoporphyria; HCP = hereditary coproporphyria; HEP = hepatoerythropoietic porphyria; MOI = mode of inheritance; PCT = porphyria cutanea tarda; VP = variegate porphyria; XL = X-linked; XLP = X-linked protoporphyria Porphyrias with neurovisceral manifestations have been considered "acute" because symptoms usually occur acutely as discrete, severe episodes; however, some affected individuals develop chronic manifestations. PCT is primarily an acquired, iron-related disorder with multiple susceptibility factors. Approximately 20% of individuals with PCT have a heterozygous pathogenic variant in HEP is the homozygous form of PCT type II (familial). CEP is most commonly associated with biallelic Photocutaneous manifestations of EPP and XLP are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP). In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias (AIP, VP, HCP, and ADP), the entity most likely to be considered is acute ascending polyneuropathy, the Landry Guillain-Barré syndrome. Abdominal pain, constipation, and tachycardia usually accompany the acute neurologic illness in the acute porphyrias but not in Landry Guillain-Barré syndrome. CSF protein is usually normal in the acute porphyrias, but usually elevated in Landry Guillain-Barré syndrome. Most importantly, urinary PBG is markedly elevated in the acute porphyrias especially when symptoms are present, but normal in Landry Guillain-Barré syndrome. The blistering skin lesions of Blistering skin manifestations occur in Cutaneous manifestations of Pseudoporphyria is a little-understood condition with cutaneous findings similar to PCT and VP but without significant porphyrin elevations. • Abdominal pain, constipation, and tachycardia usually accompany the acute neurologic illness in the acute porphyrias but not in Landry Guillain-Barré syndrome. • CSF protein is usually normal in the acute porphyrias, but usually elevated in Landry Guillain-Barré syndrome. • Most importantly, urinary PBG is markedly elevated in the acute porphyrias especially when symptoms are present, but normal in Landry Guillain-Barré syndrome. • The blistering skin lesions of • Blistering skin manifestations occur in • Cutaneous manifestations of • Pseudoporphyria is a little-understood condition with cutaneous findings similar to PCT and VP but without significant porphyrin elevations. ## Management To establish the extent of disease and to plan the management of an individual diagnosed with variegate porphyria (VP), the following clinical and laboratory evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Degree of elevations on plasma and urine porphyrins and urine porphobilinogen (PBG), if not determined at the time of diagnosis Clinical evaluation of any current acute neurovisceral manifestations to determine the need for hospital admission and treatment with hemin. Nervous system. Assessment of the extent of neurologic involvement causing paresis, pain or sensory changes Psychiatric evaluation if depression or other psychiatric features are present Liver. Liver function tests to indicate chronic liver involvement and liver imaging in patients older than age 50 years Kidneys. Kidney function tests to assess for presence and progression of kidney damage Skin. Assessment of blistering cutaneous lesions to assess their relationship to VP Contributions of medications (see Consultation with a clinical geneticist and/or genetic counselor Most acute neurovisceral attacks require hospital admission; patients with mild attacks (not requiring narcotic analgesics and without hyponatremia, seizures, or muscle weakness) are sometimes treated as outpatients. A rapid, thorough, and multidisciplinary evaluation is optimized by in-patient management. As with other acute porphyrias, evaluation should include identification of exacerbating drugs and other precipitating factors. Harmful medications include barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Harmful medications should be discontinued [ Seizures, motor neuropathy, and hyponatremia suggest severe disease and should be managed in the ICU with adequate supportive treatment. Evidence of reversible cerebral vasospasm may be found by MRI [ Narcotic analgesics are usually required for pain and ondansetron or a related drug for nausea and vomiting. A phenothiazine is also effective for nausea and for psychiatric symptoms (e.g., agitation, hallucinations) [ Mild attacks (not requiring narcotics and without hyponatremia, seizures, or motor neuropathy) can be treated with glucose loading, but most attacks should be treated with intravenous hemin [ Note: "Hemin" refers to the oxidized form of iron protoporphyrin IX, but is also the generic term for heme preparations used as intravenous therapies for acute porphyrias, such as lyophilized hematin (heme hydroxide) and heme arginate. When these hemin preparations are infused intravenously, the heme is bound to circulating albumin as heme albumin. The latter is taken up by hepatocytes and decreases the synthesis of hepatic ALAS1, the rate-controlling enzyme for heme synthesis in the liver. Patients with acute attack should be carefully monitored for muscle weakness and respiratory impairment that may require ventilatory support. Hyponatremia should be corrected slowly and seizures treated with medications that do not exacerbate porphyria. Liver transplantation, which has been effective in persons with Progression of renal disease may be prevented to some degree by controlling hypertension. Porphyrin levels may decrease and photosensitivity improve if exacerbating factors can be identified and removed; otherwise, there is no effective treatment that lowers porphyrin levels. Treatment with hemin may lower porphyrins in the short term only. Patients should wear protective clothing and avoid exposure to sunlight. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Topical steroids are of little or no benefit. Specific measures effective in the treatment of Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided (see Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with gonadotropin-releasing hormone analogs [ Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking [ Givosiran, a small interfering RNA (siRNA) therapeutic, was recently approved by the FDA for treatment of acute porphyrias, including VP. In particular, monthly subcutaneous injections of givosiran can be effective for prevention of frequently recurring attacks [ Hepatocellular carcinoma may develop especially after age 50 years in patients with acute porphyrias and persistent elevations in porphobilinogen or porphyrins; liver imaging at six-month intervals beginning at age 50 years may detect early lesions [ Precipitating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Updated lists are maintained at the websites of the Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated. Fasting and very low calorie diets should be avoided. Bariatric surgery should be avoided in patients who have had frequent exacerbations of VP and other acute porphyrias. Patients who wish to lose weight should do so gradually with moderate, long-term reductions in calorie intake under guidance of a dietician. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of a proband. This will identify individuals heterozygous for the familial See Pregnancy is usually well tolerated in women with variegate porphyria (VP); however, some women with VP may experience exacerbations during pregnancy. Experience with heme hydroxide (hematin) is also limited but suggests no adverse effects during pregnancy [ A fetus heterozygous for a See Search • Degree of elevations on plasma and urine porphyrins and urine porphobilinogen (PBG), if not determined at the time of diagnosis • Clinical evaluation of any current acute neurovisceral manifestations to determine the need for hospital admission and treatment with hemin. • Nervous system. Assessment of the extent of neurologic involvement causing paresis, pain or sensory changes • Psychiatric evaluation if depression or other psychiatric features are present • Liver. Liver function tests to indicate chronic liver involvement and liver imaging in patients older than age 50 years • Kidneys. Kidney function tests to assess for presence and progression of kidney damage • Skin. Assessment of blistering cutaneous lesions to assess their relationship to VP • Contributions of medications (see • Consultation with a clinical geneticist and/or genetic counselor • Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided (see • Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with gonadotropin-releasing hormone analogs [ • Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking [ • Givosiran, a small interfering RNA (siRNA) therapeutic, was recently approved by the FDA for treatment of acute porphyrias, including VP. In particular, monthly subcutaneous injections of givosiran can be effective for prevention of frequently recurring attacks [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and to plan the management of an individual diagnosed with variegate porphyria (VP), the following clinical and laboratory evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Degree of elevations on plasma and urine porphyrins and urine porphobilinogen (PBG), if not determined at the time of diagnosis Clinical evaluation of any current acute neurovisceral manifestations to determine the need for hospital admission and treatment with hemin. Nervous system. Assessment of the extent of neurologic involvement causing paresis, pain or sensory changes Psychiatric evaluation if depression or other psychiatric features are present Liver. Liver function tests to indicate chronic liver involvement and liver imaging in patients older than age 50 years Kidneys. Kidney function tests to assess for presence and progression of kidney damage Skin. Assessment of blistering cutaneous lesions to assess their relationship to VP Contributions of medications (see Consultation with a clinical geneticist and/or genetic counselor • Degree of elevations on plasma and urine porphyrins and urine porphobilinogen (PBG), if not determined at the time of diagnosis • Clinical evaluation of any current acute neurovisceral manifestations to determine the need for hospital admission and treatment with hemin. • Nervous system. Assessment of the extent of neurologic involvement causing paresis, pain or sensory changes • Psychiatric evaluation if depression or other psychiatric features are present • Liver. Liver function tests to indicate chronic liver involvement and liver imaging in patients older than age 50 years • Kidneys. Kidney function tests to assess for presence and progression of kidney damage • Skin. Assessment of blistering cutaneous lesions to assess their relationship to VP • Contributions of medications (see • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Most acute neurovisceral attacks require hospital admission; patients with mild attacks (not requiring narcotic analgesics and without hyponatremia, seizures, or muscle weakness) are sometimes treated as outpatients. A rapid, thorough, and multidisciplinary evaluation is optimized by in-patient management. As with other acute porphyrias, evaluation should include identification of exacerbating drugs and other precipitating factors. Harmful medications include barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Harmful medications should be discontinued [ Seizures, motor neuropathy, and hyponatremia suggest severe disease and should be managed in the ICU with adequate supportive treatment. Evidence of reversible cerebral vasospasm may be found by MRI [ Narcotic analgesics are usually required for pain and ondansetron or a related drug for nausea and vomiting. A phenothiazine is also effective for nausea and for psychiatric symptoms (e.g., agitation, hallucinations) [ Mild attacks (not requiring narcotics and without hyponatremia, seizures, or motor neuropathy) can be treated with glucose loading, but most attacks should be treated with intravenous hemin [ Note: "Hemin" refers to the oxidized form of iron protoporphyrin IX, but is also the generic term for heme preparations used as intravenous therapies for acute porphyrias, such as lyophilized hematin (heme hydroxide) and heme arginate. When these hemin preparations are infused intravenously, the heme is bound to circulating albumin as heme albumin. The latter is taken up by hepatocytes and decreases the synthesis of hepatic ALAS1, the rate-controlling enzyme for heme synthesis in the liver. Patients with acute attack should be carefully monitored for muscle weakness and respiratory impairment that may require ventilatory support. Hyponatremia should be corrected slowly and seizures treated with medications that do not exacerbate porphyria. Liver transplantation, which has been effective in persons with Progression of renal disease may be prevented to some degree by controlling hypertension. Porphyrin levels may decrease and photosensitivity improve if exacerbating factors can be identified and removed; otherwise, there is no effective treatment that lowers porphyrin levels. Treatment with hemin may lower porphyrins in the short term only. Patients should wear protective clothing and avoid exposure to sunlight. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Topical steroids are of little or no benefit. Specific measures effective in the treatment of ## Neurovisceral Symptoms Most acute neurovisceral attacks require hospital admission; patients with mild attacks (not requiring narcotic analgesics and without hyponatremia, seizures, or muscle weakness) are sometimes treated as outpatients. A rapid, thorough, and multidisciplinary evaluation is optimized by in-patient management. As with other acute porphyrias, evaluation should include identification of exacerbating drugs and other precipitating factors. Harmful medications include barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Harmful medications should be discontinued [ Seizures, motor neuropathy, and hyponatremia suggest severe disease and should be managed in the ICU with adequate supportive treatment. Evidence of reversible cerebral vasospasm may be found by MRI [ Narcotic analgesics are usually required for pain and ondansetron or a related drug for nausea and vomiting. A phenothiazine is also effective for nausea and for psychiatric symptoms (e.g., agitation, hallucinations) [ Mild attacks (not requiring narcotics and without hyponatremia, seizures, or motor neuropathy) can be treated with glucose loading, but most attacks should be treated with intravenous hemin [ Note: "Hemin" refers to the oxidized form of iron protoporphyrin IX, but is also the generic term for heme preparations used as intravenous therapies for acute porphyrias, such as lyophilized hematin (heme hydroxide) and heme arginate. When these hemin preparations are infused intravenously, the heme is bound to circulating albumin as heme albumin. The latter is taken up by hepatocytes and decreases the synthesis of hepatic ALAS1, the rate-controlling enzyme for heme synthesis in the liver. Patients with acute attack should be carefully monitored for muscle weakness and respiratory impairment that may require ventilatory support. Hyponatremia should be corrected slowly and seizures treated with medications that do not exacerbate porphyria. Liver transplantation, which has been effective in persons with Progression of renal disease may be prevented to some degree by controlling hypertension. ## Cutaneous Manifestations Porphyrin levels may decrease and photosensitivity improve if exacerbating factors can be identified and removed; otherwise, there is no effective treatment that lowers porphyrin levels. Treatment with hemin may lower porphyrins in the short term only. Patients should wear protective clothing and avoid exposure to sunlight. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Topical steroids are of little or no benefit. Specific measures effective in the treatment of ## Prevention of Primary Manifestations Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided (see Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with gonadotropin-releasing hormone analogs [ Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking [ Givosiran, a small interfering RNA (siRNA) therapeutic, was recently approved by the FDA for treatment of acute porphyrias, including VP. In particular, monthly subcutaneous injections of givosiran can be effective for prevention of frequently recurring attacks [ • Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided (see • Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with gonadotropin-releasing hormone analogs [ • Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking [ • Givosiran, a small interfering RNA (siRNA) therapeutic, was recently approved by the FDA for treatment of acute porphyrias, including VP. In particular, monthly subcutaneous injections of givosiran can be effective for prevention of frequently recurring attacks [ ## Surveillance Hepatocellular carcinoma may develop especially after age 50 years in patients with acute porphyrias and persistent elevations in porphobilinogen or porphyrins; liver imaging at six-month intervals beginning at age 50 years may detect early lesions [ ## Agents/Circumstances to Avoid Precipitating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Updated lists are maintained at the websites of the Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated. Fasting and very low calorie diets should be avoided. Bariatric surgery should be avoided in patients who have had frequent exacerbations of VP and other acute porphyrias. Patients who wish to lose weight should do so gradually with moderate, long-term reductions in calorie intake under guidance of a dietician. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of a proband. This will identify individuals heterozygous for the familial See ## Pregnancy Management Pregnancy is usually well tolerated in women with variegate porphyria (VP); however, some women with VP may experience exacerbations during pregnancy. Experience with heme hydroxide (hematin) is also limited but suggests no adverse effects during pregnancy [ A fetus heterozygous for a See ## Therapies Under Investigation Search ## Genetic Counseling Variegate porphyria (VP) is inherited in an autosomal dominant manner with reduced penetrance. Typically, one parent of an individual diagnosed with VP is heterozygous for the Rarely, an individual diagnosed with VP may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with VP may appear to be negative because of reduced penetrance or failure to recognize the disorder as the cause of nonspecific symptoms in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband. If a parent of the proband has the If the proband has a known VP-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant. Offspring who inherit the pathogenic variant may or may not develop symptoms. The risk to other family members depends on the status of the proband's parents: if a parent has the A family member with the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Typically, one parent of an individual diagnosed with VP is heterozygous for the • Rarely, an individual diagnosed with VP may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with VP may appear to be negative because of reduced penetrance or failure to recognize the disorder as the cause of nonspecific symptoms in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband. • If a parent of the proband has the • If the proband has a known VP-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant. • Offspring who inherit the pathogenic variant may or may not develop symptoms. • The risk to other family members depends on the status of the proband's parents: if a parent has the • A family member with the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Variegate porphyria (VP) is inherited in an autosomal dominant manner with reduced penetrance. ## Risk to Family Members Typically, one parent of an individual diagnosed with VP is heterozygous for the Rarely, an individual diagnosed with VP may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with VP may appear to be negative because of reduced penetrance or failure to recognize the disorder as the cause of nonspecific symptoms in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband. If a parent of the proband has the If the proband has a known VP-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant. Offspring who inherit the pathogenic variant may or may not develop symptoms. The risk to other family members depends on the status of the proband's parents: if a parent has the A family member with the • Typically, one parent of an individual diagnosed with VP is heterozygous for the • Rarely, an individual diagnosed with VP may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with VP may appear to be negative because of reduced penetrance or failure to recognize the disorder as the cause of nonspecific symptoms in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband. • If a parent of the proband has the • If the proband has a known VP-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant. • Offspring who inherit the pathogenic variant may or may not develop symptoms. • The risk to other family members depends on the status of the proband's parents: if a parent has the • A family member with the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 4915 St. Elmo Avenue Suite 200 Bethesda MD 20814 United Kingdom Canada American Porphyria Foundation South Africa United Kingdom Sweden • • 4915 St. Elmo Avenue • Suite 200 • Bethesda MD 20814 • • • United Kingdom • • • Canada • • • American Porphyria Foundation • • • • • South Africa • • • • United Kingdom • • • • • • • Sweden • ## Molecular Genetics Variegate Porphyria: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Variegate Porphyria ( PPOX catalyzes the oxidation of protoporphyrinogen to protoporphyrin, with removal of six protons. The partial deficiency of PPOX in VP limits heme synthesis, particularly in the presence of factors that lead to increased hepatic heme synthesis and induction of δ-aminolevulinic acid synthase-1 (ALAS1) in the liver. ALAS1 is the ubiquitous form of ALAS, which is found in all tissues, in contrast to the erythroid-specific form known as ALAS2, which is produced only in the bone marrow. Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis PPOX catalyzes the oxidation of protoporphyrinogen to protoporphyrin, with removal of six protons. The partial deficiency of PPOX in VP limits heme synthesis, particularly in the presence of factors that lead to increased hepatic heme synthesis and induction of δ-aminolevulinic acid synthase-1 (ALAS1) in the liver. ALAS1 is the ubiquitous form of ALAS, which is found in all tissues, in contrast to the erythroid-specific form known as ALAS2, which is produced only in the bone marrow. Notable Variants listed in the table have been provided by the authors. ## References ## Literature Cited ## Chapter Notes This work is supported by the Porphyrias Consortium funded by the NIH/NIDDK and part of the Rare Diseases Clinical Research Network, and the American Porphyria Foundation. 12 December 2019 (bp) Comprehensive update posted live 14 February 2013 (me) Review posted live 12 June 2012 (kea) Original submission • 12 December 2019 (bp) Comprehensive update posted live • 14 February 2013 (me) Review posted live • 12 June 2012 (kea) Original submission ## Acknowledgments This work is supported by the Porphyrias Consortium funded by the NIH/NIDDK and part of the Rare Diseases Clinical Research Network, and the American Porphyria Foundation. ## Revision History 12 December 2019 (bp) Comprehensive update posted live 14 February 2013 (me) Review posted live 12 June 2012 (kea) Original submission • 12 December 2019 (bp) Comprehensive update posted live • 14 February 2013 (me) Review posted live • 12 June 2012 (kea) Original submission Excretion profile of the hepatic porphyrias Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Pathogenic variants that decrease the function of a particular enzyme change the profile of heme precursors in urine and/or stool (vertical dashed lines) to one that is characteristic of the specific type of porphyria. Enzyme abbreviations: ALAD = delta-aminolevulinic acid (ALA) dehydratase HMBS = hydroxymethylbilane synthase; also known as porphobilinogen (PBG) deaminase UROD = uroporphyrinogen (UROgen) decarboxylase CPOX = coproporphyrinogen(COPROgen) decarboxylase PPOX = protoporphyrinogen(PROTOgen) decarboxylase FECH = ferrochelatase	[ "C Andant, H Puy, C Bogard, J Faivre, JC Soulé, Y Nordmann, JC Deybach. Hepatocellular carcinoma in patients with acute hepatic porphyria: frequency of occurrence and related factors.. J Hepatol. 2000;32:933-9", "KE Anderson, JR Bloomer, HL Bonkovsky, JP Kushner, CA Pierach, NR Pimstone, RJ Desnick. 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Nat Genet. 2016;48:126-33", "E Sardh, P Harper, B Balwani, P Stein, D Rees, DM Bissell, R Desnick, C Parker, J Phillips, HL Bonkovsky, D Vassiliou, C Penz, A Chan-Daniels, Q He, W Querbes, K Fitzgerald, JB Kim. MD, Garg P, Vaishnaw A, Simon AR, Anderson KE, A phase 1 study of RNA interference therapy for acute intermittent porphyria.. NEJM 2019;380:549-58", "X Schneider-Yin, AM van Tuyll van Serooskerken, P Went, W Tyblewski, P Poblete-Gutiérrez, EI Minder, J Frank. Hepatocellular carcinoma in variegate porphyria: a serious complication.. Acta Derm Venereol. 2010;90:512-5", "D Schulenburg-Brand, T Gardiner, S Guppy, DC Rees, P Stein, J Barth, MF Stewart, M Badminton. An audit of the use of gonadorelin analogues to prevent recurrent acute symptoms in patients with acute porphyria in the United Kingdom.. JIMD Reports. 2017;36:99-107", "AM van Tuyll van Serooskerken, FW de Rooij, A Edixhoven, RS Bladergroen, JM Baron, S Joussen, HF Merk, PM Steijlen, P Poblete-Gutiérrez, K te Velde, JH Wilson, RH Koole, M van Geel, J Frank. Digenic inheritance of mutations in the coproporphyrinogen oxidase and protoporphyrinogen oxidase genes in a unique type of porphyria.. J Invest Dermatol. 2011;131:2249-54", "AJS Webb, H Ingale, SR Irani, MTM Hu. Acute variegate porphyria presenting with reversible cerebral vasoconstriction.. Clin Neurol Neurosurg. 2016;146:102-4", "SD Whatley, NG Mason, JR Woolf, RG Newcombe, GH Elder, MN Badminton. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene.. Clin Chem. 2009;55:1406-14", "SD Whatley, H Puy, RR Morgan, AM Robreau, AG Roberts, Y Nordmann, GH Elder, JC Deybach. Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation.. Am J Hum Genet. 1999;65:984-94" ]	14/2/2013	12/12/2019		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pot1-tpd	pot1-tpd	[ "Protection of telomeres protein 1", "POT1", "POT1 Tumor Predisposition" ]		Marie-Louise Accardo, Jenae Osborne, Tobias Else	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Multiple cutaneous melanomas One of the A The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Multiple cutaneous melanomas • One of the • A ## Suggestive Findings Multiple cutaneous melanomas One of the A • Multiple cutaneous melanomas • One of the • A ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics No clinically relevant genotype-phenotype correlations have been confirmed. The The penetrance of The prevalence of A ## Clinical Description ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been confirmed. The ## Penetrance The penetrance of ## Prevalence The prevalence of A ## Genetically Related (Allelic) Disorders Homozygosity for the p.Ser322Leu variant, which is not currently considered a pathogenic variant for A germline heterozygous ## Differential Diagnosis Other genes known to be associated with predisposition to cutaneous melanoma, sarcoma, and/or glioma are listed in Autosomal Dominant Tumor Predisposition Syndromes of Interest in the Differential Diagnosis of ## Management No clinical practice guidelines for To establish the extent of disease in an individual diagnosed with CBC w/differential Comprehensive physical exam incl lymph nodes Review of whole-body MRI for enlarged lymph nodes A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The treatments for There are no published guidelines for surveillance for individuals with At least every 6 mos beginning at age 18 yrs w/excision of any lesions suspicious for melanoma Consider every 3 mos in persons w/multiple atypical nevi, history of melanoma, &/or family history of melanoma. Encourage monthly self-exam. Annually beginning at age 18 yrs Consider earlier depending on personal & family history of non-cutaneous, non-brain malignancies. A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a The initial brain MRI should be done with contrast, and subsequent brain MRIs may be done without contrast if the previous MRI was normal and there are no new neurologic manifestations [ To date, there is no evidence that UV light contributes to the pathogenesis of It is currently unknown whether ionizing radiation poses an increased risk to individuals with It is appropriate to clarify the genetic status of first-degree relatives of an affected individual by molecular genetic testing for the In general, molecular genetic testing for See Search • CBC w/differential • Comprehensive physical exam incl lymph nodes • Review of whole-body MRI for enlarged lymph nodes • At least every 6 mos beginning at age 18 yrs w/excision of any lesions suspicious for melanoma • Consider every 3 mos in persons w/multiple atypical nevi, history of melanoma, &/or family history of melanoma. • Encourage monthly self-exam. • Annually beginning at age 18 yrs • Consider earlier depending on personal & family history of non-cutaneous, non-brain malignancies. ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with CBC w/differential Comprehensive physical exam incl lymph nodes Review of whole-body MRI for enlarged lymph nodes A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • CBC w/differential • Comprehensive physical exam incl lymph nodes • Review of whole-body MRI for enlarged lymph nodes ## Treatment of Manifestations The treatments for ## Surveillance There are no published guidelines for surveillance for individuals with At least every 6 mos beginning at age 18 yrs w/excision of any lesions suspicious for melanoma Consider every 3 mos in persons w/multiple atypical nevi, history of melanoma, &/or family history of melanoma. Encourage monthly self-exam. Annually beginning at age 18 yrs Consider earlier depending on personal & family history of non-cutaneous, non-brain malignancies. A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a The initial brain MRI should be done with contrast, and subsequent brain MRIs may be done without contrast if the previous MRI was normal and there are no new neurologic manifestations [ • At least every 6 mos beginning at age 18 yrs w/excision of any lesions suspicious for melanoma • Consider every 3 mos in persons w/multiple atypical nevi, history of melanoma, &/or family history of melanoma. • Encourage monthly self-exam. • Annually beginning at age 18 yrs • Consider earlier depending on personal & family history of non-cutaneous, non-brain malignancies. ## Agents/Circumstances to Avoid To date, there is no evidence that UV light contributes to the pathogenesis of It is currently unknown whether ionizing radiation poses an increased risk to individuals with ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of first-degree relatives of an affected individual by molecular genetic testing for the In general, molecular genetic testing for See ## Therapies Under Investigation Search ## Genetic Counseling To date, most individuals diagnosed with Some individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband has a germline If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for See Management, Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • To date, most individuals diagnosed with • Some individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband has a germline • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members To date, most individuals diagnosed with Some individuals diagnosed with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband has a germline If the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for • To date, most individuals diagnosed with • Some individuals diagnosed with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband has a germline • If the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ## Related Genetic Counseling Issues See Management, Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics POT1 Tumor Predisposition: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for POT1 Tumor Predisposition ( OB1 and OB2 (oligosaccharide/oligonucleotide) folds, which facilitate initial interaction with telomeric single-stranded DNA; OB3 fold, which is important for POT1-TPP1 interaction; Holliday junction resolvase-like domain, which is important for POT1-TPP1 interaction. Disruption of single-stranded DNA binding and/or TPP1 binding domains have been shown to lead to lengthened telomeres, which are believed to lead to increased tumorigenesis via three putative mechanisms: Longer telomeres could delay replicative senescence, increase the replicative life span of cells, and thus lead to the accumulation of pathogenic variants; Longer telomeres predispose to fragility and genomic instability; Chromosomal aberrations, such as sister telomere fusions, have been reported in cells with abnormal POT1. Pathogenic variants in LFL = Li-Fraumeni-like Variants listed in the table have been provided by the authors. • OB1 and OB2 (oligosaccharide/oligonucleotide) folds, which facilitate initial interaction with telomeric single-stranded DNA; • OB3 fold, which is important for POT1-TPP1 interaction; • Holliday junction resolvase-like domain, which is important for POT1-TPP1 interaction. • Longer telomeres could delay replicative senescence, increase the replicative life span of cells, and thus lead to the accumulation of pathogenic variants; • Longer telomeres predispose to fragility and genomic instability; • Chromosomal aberrations, such as sister telomere fusions, have been reported in cells with abnormal POT1. ## Molecular Pathogenesis OB1 and OB2 (oligosaccharide/oligonucleotide) folds, which facilitate initial interaction with telomeric single-stranded DNA; OB3 fold, which is important for POT1-TPP1 interaction; Holliday junction resolvase-like domain, which is important for POT1-TPP1 interaction. Disruption of single-stranded DNA binding and/or TPP1 binding domains have been shown to lead to lengthened telomeres, which are believed to lead to increased tumorigenesis via three putative mechanisms: Longer telomeres could delay replicative senescence, increase the replicative life span of cells, and thus lead to the accumulation of pathogenic variants; Longer telomeres predispose to fragility and genomic instability; Chromosomal aberrations, such as sister telomere fusions, have been reported in cells with abnormal POT1. Pathogenic variants in LFL = Li-Fraumeni-like Variants listed in the table have been provided by the authors. • OB1 and OB2 (oligosaccharide/oligonucleotide) folds, which facilitate initial interaction with telomeric single-stranded DNA; • OB3 fold, which is important for POT1-TPP1 interaction; • Holliday junction resolvase-like domain, which is important for POT1-TPP1 interaction. • Longer telomeres could delay replicative senescence, increase the replicative life span of cells, and thus lead to the accumulation of pathogenic variants; • Longer telomeres predispose to fragility and genomic instability; • Chromosomal aberrations, such as sister telomere fusions, have been reported in cells with abnormal POT1. ## Chapter Notes 13 February 2025 (sw) Comprehensive update posted live 29 October 2020 (sw) Review posted live 12 May 2020 (te) Original submission • 13 February 2025 (sw) Comprehensive update posted live • 29 October 2020 (sw) Review posted live • 12 May 2020 (te) Original submission ## Revision History 13 February 2025 (sw) Comprehensive update posted live 29 October 2020 (sw) Review posted live 12 May 2020 (te) Original submission • 13 February 2025 (sw) Comprehensive update posted live • 29 October 2020 (sw) Review posted live • 12 May 2020 (te) Original submission ## References ## Literature Cited	[]	29/10/2020	13/2/2025	10/3/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
potocki-lupski	potocki-lupski	[ "Duplication 17p11.2 Syndrome", "PTLS", "Duplication 17p11.2 Syndrome", "PTLS", "Folliculin", "Retinoic acid-induced protein 1", "FLCN", "RAI1", "Potocki-Lupski Syndrome" ]	Potocki-Lupski Syndrome	Lorraine Potocki, Juanita Neira-Fresneda, Bo Yuan	Summary Potocki-Lupski syndrome (PTLS) is characterized by cognitive, behavioral, and medical manifestations. Cognitively, most individuals present with developmental delay, later meeting criteria for moderate intellectual disability. Behaviorally, issues with attention, hyperactivity, withdrawal, and anxiety may be seen. Some individuals meet criteria for autism spectrum disorder. Medically, hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, hypoglycemia associated with growth hormone deficiency, and mildly dysmorphic facial features are observed. Medical manifestations typically lead to identification of PTLS in infancy; however, those with only behavioral and cognitive manifestations may be identified in later childhood. The diagnosis of PTLS is established by detection of a heterozygous duplication at chromosome 17p11.2 that encompasses PTLS is inherited in an autosomal dominant manner. The majority of affected individuals have a	## Diagnosis Potocki-Lupski syndrome (PTLS) Neurodevelopmental findings: Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive Developmental delay; intellectual disability (typically moderate) Communication disorder with verbal apraxia and abnormalities of intonation and prosody Sleep-disordered breathing (most evident on sleep studies) Features of autism spectrum disorder; hyperactivity Congenital heart disease, typically left ventricular outflow track spectrum and/or rhythm disturbances Growth hormone deficiency Mildly to nonspecific dysmorphic facial features [ The diagnosis of PTLS For this ISCN nomenclature for the recurrent duplication is: arr[hg19] 17p11.2(16,757,111-20,219,651)x3. Note: Since this duplication is recurrent and mediated by segmental duplications, the unique genetic sequence that is duplicated is the same in all individuals with the syndrome; however, the reported size of the duplication may: (1) be slightly larger or smaller if adjacent segmental duplications are included in the size; and (2) vary based on the design of the microarray used to detect it (see Although several genes are within the 3.7-Mb recurrent duplication, only Genomic Testing Used in Potocki-Lupski Syndrome See For this Standardized ISCN annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 17p11.2 region. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the 17p11.2 recurrent duplication was not detected by CMA designed to target this region. • Neurodevelopmental findings: • Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive • Developmental delay; intellectual disability (typically moderate) • Communication disorder with verbal apraxia and abnormalities of intonation and prosody • Sleep-disordered breathing (most evident on sleep studies) • Features of autism spectrum disorder; hyperactivity • Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive • Developmental delay; intellectual disability (typically moderate) • Communication disorder with verbal apraxia and abnormalities of intonation and prosody • Sleep-disordered breathing (most evident on sleep studies) • Features of autism spectrum disorder; hyperactivity • Congenital heart disease, typically left ventricular outflow track spectrum and/or rhythm disturbances • Growth hormone deficiency • Mildly to nonspecific dysmorphic facial features [ • Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive • Developmental delay; intellectual disability (typically moderate) • Communication disorder with verbal apraxia and abnormalities of intonation and prosody • Sleep-disordered breathing (most evident on sleep studies) • Features of autism spectrum disorder; hyperactivity ## Suggestive Findings Potocki-Lupski syndrome (PTLS) Neurodevelopmental findings: Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive Developmental delay; intellectual disability (typically moderate) Communication disorder with verbal apraxia and abnormalities of intonation and prosody Sleep-disordered breathing (most evident on sleep studies) Features of autism spectrum disorder; hyperactivity Congenital heart disease, typically left ventricular outflow track spectrum and/or rhythm disturbances Growth hormone deficiency Mildly to nonspecific dysmorphic facial features [ • Neurodevelopmental findings: • Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive • Developmental delay; intellectual disability (typically moderate) • Communication disorder with verbal apraxia and abnormalities of intonation and prosody • Sleep-disordered breathing (most evident on sleep studies) • Features of autism spectrum disorder; hyperactivity • Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive • Developmental delay; intellectual disability (typically moderate) • Communication disorder with verbal apraxia and abnormalities of intonation and prosody • Sleep-disordered breathing (most evident on sleep studies) • Features of autism spectrum disorder; hyperactivity • Congenital heart disease, typically left ventricular outflow track spectrum and/or rhythm disturbances • Growth hormone deficiency • Mildly to nonspecific dysmorphic facial features [ • Mild-to-moderate infantile hypotonia with oropharyngeal dysphagia and failure to thrive • Developmental delay; intellectual disability (typically moderate) • Communication disorder with verbal apraxia and abnormalities of intonation and prosody • Sleep-disordered breathing (most evident on sleep studies) • Features of autism spectrum disorder; hyperactivity ## Establishing the Diagnosis The diagnosis of PTLS For this ISCN nomenclature for the recurrent duplication is: arr[hg19] 17p11.2(16,757,111-20,219,651)x3. Note: Since this duplication is recurrent and mediated by segmental duplications, the unique genetic sequence that is duplicated is the same in all individuals with the syndrome; however, the reported size of the duplication may: (1) be slightly larger or smaller if adjacent segmental duplications are included in the size; and (2) vary based on the design of the microarray used to detect it (see Although several genes are within the 3.7-Mb recurrent duplication, only Genomic Testing Used in Potocki-Lupski Syndrome See For this Standardized ISCN annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 17p11.2 region. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the 17p11.2 recurrent duplication was not detected by CMA designed to target this region. ## Clinical Characteristics Potocki-Lupski syndrome (PTLS) is characterized by developmental delay, intellectual disability, behavioral disturbances, organ system involvement, and mildly dysmorphic facial features [ PTLS can manifest in infancy with hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, and hypoglycemia associated with growth hormone deficiency. In contrast, individuals who are more mildly affected may manifest cognitive and behavioral abnormalities only, and not be diagnosed until later in childhood [ Although gross motor delay is observed in the vast majority, most will achieve independent walking by age two years. Rarely, independent ambulation can be delayed until age four years. Speech delay is universal. Standardized testing has revealed expressive and receptive language impairment which can include articulation difficulties and disordered intonation and prosody [ While there are no formal studies of articulation and language abilities in teens and adults with PTLS, verbal abilities appear to improve both with age and speech therapy. Little data regarding findings in adults are available; however, adults with a confirmed molecular genetic diagnosis who have been clinically evaluated have cognitive challenges. Cardiovascular anomalies are reported in about 40% of individuals with PTLS [ A smaller percentage of individuals with PTLS have rhythm disturbances detected on ECG [ Five of seven individuals in the original description of PTLS had short stature; one of the five had documented growth hormone deficiency [ Hyperopia (common, but not significant enough to require corrective lenses in childhood) Mild high-frequency sensorineural hearing loss Dental malocclusion and dental crowding Penetrance is 100%; expression of phenotypic features is variable. The prevalence of PTLS is approximately one in 25,000 [ • Hyperopia (common, but not significant enough to require corrective lenses in childhood) • Mild high-frequency sensorineural hearing loss • Dental malocclusion and dental crowding ## Clinical Description Potocki-Lupski syndrome (PTLS) is characterized by developmental delay, intellectual disability, behavioral disturbances, organ system involvement, and mildly dysmorphic facial features [ PTLS can manifest in infancy with hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, and hypoglycemia associated with growth hormone deficiency. In contrast, individuals who are more mildly affected may manifest cognitive and behavioral abnormalities only, and not be diagnosed until later in childhood [ Although gross motor delay is observed in the vast majority, most will achieve independent walking by age two years. Rarely, independent ambulation can be delayed until age four years. Speech delay is universal. Standardized testing has revealed expressive and receptive language impairment which can include articulation difficulties and disordered intonation and prosody [ While there are no formal studies of articulation and language abilities in teens and adults with PTLS, verbal abilities appear to improve both with age and speech therapy. Little data regarding findings in adults are available; however, adults with a confirmed molecular genetic diagnosis who have been clinically evaluated have cognitive challenges. Cardiovascular anomalies are reported in about 40% of individuals with PTLS [ A smaller percentage of individuals with PTLS have rhythm disturbances detected on ECG [ Five of seven individuals in the original description of PTLS had short stature; one of the five had documented growth hormone deficiency [ Hyperopia (common, but not significant enough to require corrective lenses in childhood) Mild high-frequency sensorineural hearing loss Dental malocclusion and dental crowding • Hyperopia (common, but not significant enough to require corrective lenses in childhood) • Mild high-frequency sensorineural hearing loss • Dental malocclusion and dental crowding ## Neurodevelopmental Although gross motor delay is observed in the vast majority, most will achieve independent walking by age two years. Rarely, independent ambulation can be delayed until age four years. Speech delay is universal. Standardized testing has revealed expressive and receptive language impairment which can include articulation difficulties and disordered intonation and prosody [ While there are no formal studies of articulation and language abilities in teens and adults with PTLS, verbal abilities appear to improve both with age and speech therapy. Little data regarding findings in adults are available; however, adults with a confirmed molecular genetic diagnosis who have been clinically evaluated have cognitive challenges. ## Congenital Heart Disease Cardiovascular anomalies are reported in about 40% of individuals with PTLS [ A smaller percentage of individuals with PTLS have rhythm disturbances detected on ECG [ ## Growth Hormone Deficiency Five of seven individuals in the original description of PTLS had short stature; one of the five had documented growth hormone deficiency [ ## Other Hyperopia (common, but not significant enough to require corrective lenses in childhood) Mild high-frequency sensorineural hearing loss Dental malocclusion and dental crowding • Hyperopia (common, but not significant enough to require corrective lenses in childhood) • Mild high-frequency sensorineural hearing loss • Dental malocclusion and dental crowding ## Penetrance Penetrance is 100%; expression of phenotypic features is variable. ## Prevalence The prevalence of PTLS is approximately one in 25,000 [ ## Genetically Related Disorders Yuan-Harel-Lupski (YUHAL) syndrome (OMIM ## Differential Diagnosis The differential diagnosis of Potocki-Lupski syndrome (PTLS) is broad due to the wide spectrum of findings and presence of developmental delay, learning problems, and neuropsychiatric disorders – for which the differential diagnosis is extensive. All manifestations of PTLS can also be seen individually or in combination in individuals with other genomic disorders. ## Management To establish the extent of disease and needs in an individual diagnosed with Potocki-Lupski syndrome (PTLS), the evaluations and referrals summarized in Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis (e.g., recommendation for cognitive testing for intellectual disability during infancy). Recommended Evaluations and Referrals Following Initial Diagnosis of Potocki-Lupski Syndrome For failure to thrive or poor weight gain: feeding evaluation w/swallow function study to assess for oropharyngeal dysphagia For short stature: bone age, IGF-1, IGFBP-3, referral to endocrinologist ASD = autism spectrum disorder; DD = developmental delay Depending on the age and presenting problems of the individual with PTLS, a multidisciplinary evaluation involving healthcare providers from the following specialties is often necessary: audiology, cardiology, dental, developmental pediatrics, endocrinology, feeding, gastroenterology, general pediatrics, clinical genetics, ophthalmology, orthopedics, otolaryngology, physical medicine and rehabilitation, psychiatry, sleep medicine, speech pathology, and urology. Treatment of Medical Manifestations in Individuals with PTLS The following information represents typical management recommendations for individuals with developmental delay/intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district generally until age 21. Discussion about transition plans including medical and financial guardianship, financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize strength and mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis). Aquatic therapy and hippotherapy (therapeutic horseback riding) may also be considered. Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). Physical medicine and rehabilitation evaluations may be warranted [ Speech and language therapy to address receptive and expressive language deficits, articulation abnormalities, and verbal apraxia; Evaluation for alternative means of communication (e.g., Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child’s behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary. Recommended Surveillance for Individuals with PTLS For failure to thrive or poor weight gain: feeding evaluation For short stature: consider endocrinology evaluation. A developmental pediatrician can perform a comprehensive evaluation w/attention to underlying medical factors influencing developmental abilities. A child psychologist can assess cognitive & behavioral issues. ADI = Autism Diagnostic Interview; ADOS = Autism Diagnostic Observation Schedule See Search • For failure to thrive or poor weight gain: feeding evaluation w/swallow function study to assess for oropharyngeal dysphagia • For short stature: bone age, IGF-1, IGFBP-3, referral to endocrinologist • In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district generally until age 21. • Discussion about transition plans including medical and financial guardianship, financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize strength and mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis). Aquatic therapy and hippotherapy (therapeutic horseback riding) may also be considered. • Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). • Physical medicine and rehabilitation evaluations may be warranted [ • Speech and language therapy to address receptive and expressive language deficits, articulation abnormalities, and verbal apraxia; • Evaluation for alternative means of communication (e.g., • For failure to thrive or poor weight gain: feeding evaluation • For short stature: consider endocrinology evaluation. • A developmental pediatrician can perform a comprehensive evaluation w/attention to underlying medical factors influencing developmental abilities. • A child psychologist can assess cognitive & behavioral issues. ## Evaluations and Referrals Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Potocki-Lupski syndrome (PTLS), the evaluations and referrals summarized in Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis (e.g., recommendation for cognitive testing for intellectual disability during infancy). Recommended Evaluations and Referrals Following Initial Diagnosis of Potocki-Lupski Syndrome For failure to thrive or poor weight gain: feeding evaluation w/swallow function study to assess for oropharyngeal dysphagia For short stature: bone age, IGF-1, IGFBP-3, referral to endocrinologist ASD = autism spectrum disorder; DD = developmental delay • For failure to thrive or poor weight gain: feeding evaluation w/swallow function study to assess for oropharyngeal dysphagia • For short stature: bone age, IGF-1, IGFBP-3, referral to endocrinologist ## Treatment of Manifestations Depending on the age and presenting problems of the individual with PTLS, a multidisciplinary evaluation involving healthcare providers from the following specialties is often necessary: audiology, cardiology, dental, developmental pediatrics, endocrinology, feeding, gastroenterology, general pediatrics, clinical genetics, ophthalmology, orthopedics, otolaryngology, physical medicine and rehabilitation, psychiatry, sleep medicine, speech pathology, and urology. Treatment of Medical Manifestations in Individuals with PTLS The following information represents typical management recommendations for individuals with developmental delay/intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district generally until age 21. Discussion about transition plans including medical and financial guardianship, financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize strength and mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis). Aquatic therapy and hippotherapy (therapeutic horseback riding) may also be considered. Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). Physical medicine and rehabilitation evaluations may be warranted [ Speech and language therapy to address receptive and expressive language deficits, articulation abnormalities, and verbal apraxia; Evaluation for alternative means of communication (e.g., Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child’s behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary. • In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district generally until age 21. • Discussion about transition plans including medical and financial guardianship, financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize strength and mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis). Aquatic therapy and hippotherapy (therapeutic horseback riding) may also be considered. • Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). • Physical medicine and rehabilitation evaluations may be warranted [ • Speech and language therapy to address receptive and expressive language deficits, articulation abnormalities, and verbal apraxia; • Evaluation for alternative means of communication (e.g., ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay/intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district generally until age 21. Discussion about transition plans including medical and financial guardianship, financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district generally until age 21. • Discussion about transition plans including medical and financial guardianship, financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize strength and mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis). Aquatic therapy and hippotherapy (therapeutic horseback riding) may also be considered. Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). Physical medicine and rehabilitation evaluations may be warranted [ Speech and language therapy to address receptive and expressive language deficits, articulation abnormalities, and verbal apraxia; Evaluation for alternative means of communication (e.g., • Physical therapy is recommended to maximize strength and mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis). Aquatic therapy and hippotherapy (therapeutic horseback riding) may also be considered. • Consider use of durable medical equipment as needed (e.g., orthotics, adaptive strollers). • Physical medicine and rehabilitation evaluations may be warranted [ • Speech and language therapy to address receptive and expressive language deficits, articulation abnormalities, and verbal apraxia; • Evaluation for alternative means of communication (e.g., ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child’s behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary. ## Surveillance Recommended Surveillance for Individuals with PTLS For failure to thrive or poor weight gain: feeding evaluation For short stature: consider endocrinology evaluation. A developmental pediatrician can perform a comprehensive evaluation w/attention to underlying medical factors influencing developmental abilities. A child psychologist can assess cognitive & behavioral issues. ADI = Autism Diagnostic Interview; ADOS = Autism Diagnostic Observation Schedule • For failure to thrive or poor weight gain: feeding evaluation • For short stature: consider endocrinology evaluation. • A developmental pediatrician can perform a comprehensive evaluation w/attention to underlying medical factors influencing developmental abilities. • A child psychologist can assess cognitive & behavioral issues. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Potocki-Lupski syndrome (PTLS) is inherited in an autosomal dominant manner. The majority of affected individuals have a Evaluation of the parents by genomic testing that will detect the 17p11.2 duplication present in the proband is recommended. Although not described to date, there is a theoretic (though unlikely) possibility that a parent could have somatic mosaicism for the 17p11.2 duplication. Note: A parent who manifests only cognitive and behavioral abnormalities may not be diagnosed with PTLS until the birth of an affected child (see If the 17p11.2 duplication identified in the proband is not identified in either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism [ If one of the parents has the 17p11.2 duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype of individuals who inherit the duplication. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk apparently asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 17p11.2 duplication. A parent has the 17p11.2 duplication; Neither parent has the duplication but has had a child with the 17p11.2 duplication. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is approximately 1%. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. Note: Regardless of whether a pregnancy is known or not known to be at increased risk for Potocki-Lupski syndrome, prenatal genetic testing results cannot reliably predict the phenotype. • Evaluation of the parents by genomic testing that will detect the 17p11.2 duplication present in the proband is recommended. • Although not described to date, there is a theoretic (though unlikely) possibility that a parent could have somatic mosaicism for the 17p11.2 duplication. • Note: A parent who manifests only cognitive and behavioral abnormalities may not be diagnosed with PTLS until the birth of an affected child (see • If the 17p11.2 duplication identified in the proband is not identified in either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism [ • If one of the parents has the 17p11.2 duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype of individuals who inherit the duplication. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk apparently asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 17p11.2 duplication. • A parent has the 17p11.2 duplication; • Neither parent has the duplication but has had a child with the 17p11.2 duplication. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is approximately 1%. ## Mode of Inheritance Potocki-Lupski syndrome (PTLS) is inherited in an autosomal dominant manner. The majority of affected individuals have a ## Risk to Family Members Evaluation of the parents by genomic testing that will detect the 17p11.2 duplication present in the proband is recommended. Although not described to date, there is a theoretic (though unlikely) possibility that a parent could have somatic mosaicism for the 17p11.2 duplication. Note: A parent who manifests only cognitive and behavioral abnormalities may not be diagnosed with PTLS until the birth of an affected child (see If the 17p11.2 duplication identified in the proband is not identified in either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism [ If one of the parents has the 17p11.2 duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype of individuals who inherit the duplication. • Evaluation of the parents by genomic testing that will detect the 17p11.2 duplication present in the proband is recommended. • Although not described to date, there is a theoretic (though unlikely) possibility that a parent could have somatic mosaicism for the 17p11.2 duplication. • Note: A parent who manifests only cognitive and behavioral abnormalities may not be diagnosed with PTLS until the birth of an affected child (see • If the 17p11.2 duplication identified in the proband is not identified in either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism [ • If one of the parents has the 17p11.2 duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype of individuals who inherit the duplication. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk apparently asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 17p11.2 duplication. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk apparently asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 17p11.2 duplication. ## Prenatal Testing and Preimplantation Genetic Testing A parent has the 17p11.2 duplication; Neither parent has the duplication but has had a child with the 17p11.2 duplication. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is approximately 1%. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. Note: Regardless of whether a pregnancy is known or not known to be at increased risk for Potocki-Lupski syndrome, prenatal genetic testing results cannot reliably predict the phenotype. • A parent has the 17p11.2 duplication; • Neither parent has the duplication but has had a child with the 17p11.2 duplication. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is approximately 1%. ## Resources • • • • ## Molecular Genetics Potocki-Lupski Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Potocki-Lupski Syndrome ( NAHR-mediated unequal crossover between other LCRs at the 17p11.2 region results in a less commonly observed ~5-Mb recurrent duplication [ Moreover, using a transgenic mouse model, a Dp(11)17 allele (duplication of the region on mouse chromosome 11 that is syntenic to human PTLS region) and a null Comparison between the duplication segments in PTLS with renal phenotype and the syntenic duplication in mouse model suggests • Moreover, using a transgenic mouse model, a Dp(11)17 allele (duplication of the region on mouse chromosome 11 that is syntenic to human PTLS region) and a null • Comparison between the duplication segments in PTLS with renal phenotype and the syntenic duplication in mouse model suggests ## Molecular Pathogenesis NAHR-mediated unequal crossover between other LCRs at the 17p11.2 region results in a less commonly observed ~5-Mb recurrent duplication [ Moreover, using a transgenic mouse model, a Dp(11)17 allele (duplication of the region on mouse chromosome 11 that is syntenic to human PTLS region) and a null Comparison between the duplication segments in PTLS with renal phenotype and the syntenic duplication in mouse model suggests • Moreover, using a transgenic mouse model, a Dp(11)17 allele (duplication of the region on mouse chromosome 11 that is syntenic to human PTLS region) and a null • Comparison between the duplication segments in PTLS with renal phenotype and the syntenic duplication in mouse model suggests ## References ## Literature Cited ## Chapter Notes 24 August 2017 (bp) Review posted live 10 October 2016 (jn) Original submission • 24 August 2017 (bp) Review posted live • 10 October 2016 (jn) Original submission ## Revision History 24 August 2017 (bp) Review posted live 10 October 2016 (jn) Original submission • 24 August 2017 (bp) Review posted live • 10 October 2016 (jn) Original submission Individuals with Potocki-Lupski syndrome. The facial features are not strikingly dysmorphic though common findings include micrognathia (in early childhood) and downslanting palpebral fissures. A. Female age three years ten months B. Male age five years C. Male age three years D. Female age eight years E. Female age 12 years F. Male age 29 years	[ "W. Bi. Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome.. Hum Mol Genet 2005;14:983-95", "C Bravo, F Gámez, R Pérez, A Águarón, J. De León-Luis. Prenatal diagnosis of Potocki-Lupski syndrome in a fetus with hypoplastic left heart and aberrant right subclavian artery.. J Perinatol. 2013;33:394-6", "IM Campbell, CA Shaw, P Stankiewicz, JR Lupski. Somatic mosaicism: implications for disease and transmission genetics.. Trends Genet 2015;31:382-92", "D Dhanaraj, A Chu, JG Pappas, E Moran, WB Lehman. Potocki-Lupski syndrome in conjunction with bilateral clubfoot.. J Pediatr Orthop B 2015;24:373-6", "ES-Y Goh, IC Perez, CP Canales, P Ruiz, R Agatep, G Yoon, D Chitayat, Y Dror, M Shago, S Goobie, M Sgro, K Walz, R Mendoza-Londono. Definition of a critical genetic interval related to kidney abnormalities in the Potocki-Lupski syndrome.. Am J Med Genet A 2012;158A:1579-88", "F Greenberg, V Guzzetta, R Montes de Oca-Luna, RE Magenis, ACM Smith, JR Lupski. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(l7)(pl 1.2).. Am J Hum Genet 1991;49:1207-18", "PJ Hastings, JR Lupski, SM Rosenberg, G Ira. Mechanisms of change in gene copy number.. Nat Rev Genet 2009;10:551-64", "JL Jefferies, RH Pignatelli, HR Martinez, PJ Robbins-Furman, P Liu, W Gu, JR Lupski, L Potocki. Cardiovascular findings in duplication 17p11.2 syndrome.. Genet Med 2012;14:90-4", "P Liu, M Lacaria, F Zhang, M Withers, PJ Hastings, JR Lupski. Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over.. Am J Hum Genet 2011;89:580-8", "PL Magoulas, P Liu, V Gelowani, C Soler-Alfonso, EC Kivuva, JR Lupski, L Potocki. Inherited dup(17)(p11.2p11.2): expanding the phenotype of the Potocki-Lupski syndrome.. Am J Med Genet A 2014;164A:500-4", "J Martin, SJL Knight, AJ Sharp, EE Eichler, J Hurst, U Kini. Potocki-Lupski syndrome mimicking a connective tissue disorder.. Clin Dysmorph 2008;17:211-3", "J Neira-Fresneda, L Potocki. Neurodevelopmental disorders associated with abnormal gene dosage: Smith-Magenis and Potocki-Lupski Syndromes.. J Pediatr Genet 2015;4:159-67", "SS Park, P Stankiewicz, W Bi, C Shaw, J Lehoczky, K Dewar, B Birren, JR Lupski. Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs.. Genome Res 2002;12:729-38", "L Potocki, W Bi, D Treadwell-Deering, CMB Carvalho, A Eifert, EM Friedman, D Glaze, K Krull, JA Lee, RA Lewis, R Mendoza-Londono, P Robbins-Furman, C Shaw, X Shi, G Weissenberger, M Withers, SA Yatsenko, EH Zackai, P Stankiewicz, JR Lupski. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism Phenotype.. Am J Hum Genet 2007;80:633-49", "L Potocki, K-S Chen, S-S Park, DE Osterholm, MA Withers, V Kimonis, AM Summers, WS Meschino, K Anyane-Yeboa, CD Kashork, LG Shaffer, JR Lupski. Molecular mechanism for duplication 17p11.2 - the homologous recombination reciprocal of the Smith-Magenis microdeletion.. Nat Genet 2000;24:84-7", "A Sanchez-Valle, ME Pierpont, L Potocki. The severe end of the spectrum. Hypoplastic left heart in Potocki-Lupski syndrome.. Am J Med Genet A. 2011;155A:363-6", "C Soler-Alfonso, KJ Motil, CL Turk, P Robbins-Furman, EM Friedman, F Zhang, JR Lupski, JK Fraley, L Potocki. Potocki-Lupski syndrome: A microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive.. J Pediatr 2011;158:655-9.e2", "P Stankiewicz, JR Lupski. Structural variation in the human genome and its role in disease.. Ann Rev Med 2010;61:437-55", "DE Treadwell-Deering, MP Powell, L Potocki. Cognitive and behavioral characterization of the Potocki-Lupski syndrome (duplication 17p11.2).. J Dev Behav Pediatr 2010;31:137-43", "K Walz, R Paylor, J Yan, W Bi, JR Lupski. Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2).. J Clin Invest 2006;116:3035-41", "K Walz, C Spencer, K Kaasik, CC Lee, JR Lupski, R Paylor. Behavioral characterization of mouse models for Smith-Magenis syndrome and dup(17)(p11.2p11.2).. Hum Mol Genet 2004;13:367-78", "B Yuan, T Harel, S Gu, P Liu, L Burglen, S Chantot-Bastaraud, V Gelowani, CR Beck, CMB Carvalho, SW Cheung, A Coe, V Malan, A Munnich, PL Magoulas, L Potocki, JR Lupski. Nonrecurrent 17p11.2p12 rearrangement events that result in two concomitant genomic disorders: the PMP22-RAI1 contiguous gene duplication syndrome.. Am J Hum Genet 2015;97:691-707", "R Yusupov, AE Roberts, RV Lacro, M Sandstrom, AH Ligon. Potocki-Lupski syndrome: An inherited dup(17)(p11.2p11.2) with hypoplastic left heart.. Am J Med Genet A. 2011;155A:367-71", "F Zhang, M Khajavi, AM Connolly, CF Towne, SD Batish, JR Lupski. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans.. Nat Genet 2009;41:849-53", "F Zhang, L Potocki, JB Sampson, P Liu, A Sanchez-Valle, P Robbins-Furman, AD Navarro, PG Wheeler, JE Spence, CK Brasington, MA Withers, JR Lupski. Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS.. Am J Hum Genet 2010;86:462-70" ]	24/8/2017			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pp-blastoma	pp-blastoma	[ "DICER1 Pleuropulmonary Blastoma Familial Tumor Predisposition Syndrome", "DICER1 Syndrome", "DICER1 Syndrome", "DICER1 Pleuropulmonary Blastoma Familial Tumor Predisposition Syndrome", "Endoribonuclease Dicer", "DICER1", "DICER1 Tumor Predisposition" ]		Kris Ann P Schultz, Douglas R Stewart, Junne Kamihara, Andrew J Bauer, Melissa A Merideth, Pamela Stratton, Laryssa A Huryn, Anne K Harris, Leslie Doros, Amanda Field, Ann G Carr, Louis P Dehner, Yoav Messinger, D Ashley Hill	Summary The diagnosis of DICER1 is established by identification of a heterozygous germline DICER1 is inherited in an autosomal dominant manner with reduced penetrance. In individuals with PPB with a detectable germline	## Diagnosis Pleuropulmonary blastoma (PPB) Single or multiple pulmonary cysts and/or pneumothorax identified in a newborn or young child Thyroid adenomas, multinodular goiter, and/or well-differentiated thyroid cancer, especially in individuals with a family history of additional features of DICER1. Poorly differentiated thyroid cancer has also been described. Ovarian tumors including sex cord-stromal tumors (e.g., Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcoma, undifferentiated sarcomas) Cystic nephroma with or without progression to anaplastic sarcoma of kidney Ciliary body medulloepithelioma Nasal chondromesenchymal hamartoma Embryonal rhabdomyosarcoma of the cervix or other sites with features of adenosarcoma Pituitary blastoma Pineoblastoma Other CNS embryonal tumors / ETMR-like (embryonal tumor with multilayer rosettes) Presacral malignant teratoid neoplasm of infancy Multicystic hepatic lesions Pleuropulmonary blastoma-like peritoneal sarcoma (peritoneal "PPB") Macrocephaly Note: Somatic mosaicism for a The diagnosis DICER1 Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DICER1 is broad, individuals with the distinctive findings described in When clinical, imaging, laboratory, and/or histopathology findings suggest the diagnosis of DICER1, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by increased tumor susceptibility, If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. More than six families with intragenic or whole-gene A small group of individuals has been identified with mosaicism for • Pleuropulmonary blastoma (PPB) • Single or multiple pulmonary cysts and/or pneumothorax identified in a newborn or young child • Thyroid adenomas, multinodular goiter, and/or well-differentiated thyroid cancer, especially in individuals with a family history of additional features of DICER1. Poorly differentiated thyroid cancer has also been described. • Ovarian tumors including sex cord-stromal tumors (e.g., Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcoma, undifferentiated sarcomas) • Cystic nephroma with or without progression to anaplastic sarcoma of kidney • Ciliary body medulloepithelioma • Nasal chondromesenchymal hamartoma • Embryonal rhabdomyosarcoma of the cervix or other sites with features of adenosarcoma • Pituitary blastoma • Pineoblastoma • Other CNS embryonal tumors / ETMR-like (embryonal tumor with multilayer rosettes) • Presacral malignant teratoid neoplasm of infancy • Multicystic hepatic lesions • Pleuropulmonary blastoma-like peritoneal sarcoma (peritoneal "PPB") • Macrocephaly • For an introduction to multigene panels click ## Suggestive Findings Pleuropulmonary blastoma (PPB) Single or multiple pulmonary cysts and/or pneumothorax identified in a newborn or young child Thyroid adenomas, multinodular goiter, and/or well-differentiated thyroid cancer, especially in individuals with a family history of additional features of DICER1. Poorly differentiated thyroid cancer has also been described. Ovarian tumors including sex cord-stromal tumors (e.g., Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcoma, undifferentiated sarcomas) Cystic nephroma with or without progression to anaplastic sarcoma of kidney Ciliary body medulloepithelioma Nasal chondromesenchymal hamartoma Embryonal rhabdomyosarcoma of the cervix or other sites with features of adenosarcoma Pituitary blastoma Pineoblastoma Other CNS embryonal tumors / ETMR-like (embryonal tumor with multilayer rosettes) Presacral malignant teratoid neoplasm of infancy Multicystic hepatic lesions Pleuropulmonary blastoma-like peritoneal sarcoma (peritoneal "PPB") Macrocephaly Note: Somatic mosaicism for a • Pleuropulmonary blastoma (PPB) • Single or multiple pulmonary cysts and/or pneumothorax identified in a newborn or young child • Thyroid adenomas, multinodular goiter, and/or well-differentiated thyroid cancer, especially in individuals with a family history of additional features of DICER1. Poorly differentiated thyroid cancer has also been described. • Ovarian tumors including sex cord-stromal tumors (e.g., Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcoma, undifferentiated sarcomas) • Cystic nephroma with or without progression to anaplastic sarcoma of kidney • Ciliary body medulloepithelioma • Nasal chondromesenchymal hamartoma • Embryonal rhabdomyosarcoma of the cervix or other sites with features of adenosarcoma • Pituitary blastoma • Pineoblastoma • Other CNS embryonal tumors / ETMR-like (embryonal tumor with multilayer rosettes) • Presacral malignant teratoid neoplasm of infancy • Multicystic hepatic lesions • Pleuropulmonary blastoma-like peritoneal sarcoma (peritoneal "PPB") • Macrocephaly ## Establishing the Diagnosis The diagnosis DICER1 Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DICER1 is broad, individuals with the distinctive findings described in When clinical, imaging, laboratory, and/or histopathology findings suggest the diagnosis of DICER1, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by increased tumor susceptibility, If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. More than six families with intragenic or whole-gene A small group of individuals has been identified with mosaicism for • For an introduction to multigene panels click ## Option 1 When clinical, imaging, laboratory, and/or histopathology findings suggest the diagnosis of DICER1, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by increased tumor susceptibility, If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. More than six families with intragenic or whole-gene A small group of individuals has been identified with mosaicism for ## Clinical Characteristics To date, more than 1,000 individuals have been identified with a germline pathogenic variant in Studies to date have focused on germline Select Features of CNS = central nervous system; ETMR = embryonal tumor with multilayer rosettes; PPB = pleuropulmonary blastoma; SLCT = Sertoli-Leydig cell tumor; type Ir PPB = regressed or nonprogressed PPB Two instances of multicystic hepatic lesions reported [ PPB occurs in four main types: Type I PPB is a purely cystic lesion containing a layer of malignant cells. If left in situ, the malignant component of type I PPB may proliferate further, leading to type II PPB. Typically, type I PPB becomes evident in infants and young children (median age at diagnosis: 8 months) with difficulty breathing due to a large space-occupying cyst in the lung or pneumothorax secondary to a rupture of the air-filled cyst. Occasionally lung cysts are identified in asymptomatic children when radiographic studies are performed for nonrespiratory symptoms or surveillance. Five-year survival for type I PPB is 89% [ Type II PPB is a mixed cystic and solid tumor that presents at a median age of 35 months. A child with type II PPB typically presents with weight loss, fever, shortness of breath, and opacity or pneumothorax on chest radiograph. Five-year survival for type II PPB is 71% [ Type III PPB is a purely solid, aggressive sarcoma which may present with respiratory distress and mediastinal shift. Type III PPB presents at a median age of 41 months. Children with type III PPB typically present with weight loss, fever, shortness of breath, and opacity on chest radiograph. Five-year survival for type III PPB is 53% [ Type Ir (regressed or nonprogressed) PPB presents in individuals of any age and lacks a malignant component. Five-year survival for type Ir PPB is 100% [ The natural history of PPB suggests that many tumors have a precancerous / early cancerous stage in the form of lung cysts. Although not all PPB lung cysts transform into high-grade sarcoma, no radiographic characteristics can yet identify which cysts will progress to sarcoma. Progression from cyst to sarcoma can occur quickly. When progression occurs, the mesenchymal cells of a type I PPB expand and overgrow the cyst septa and replace the cyst with a cystic and solid (type II) or purely solid (type III) sarcoma. Type I PPB has no metastatic potential, but individuals with type II or III PPB can present with or develop metastasis to the brain, bone, local thoracic lymph nodes, and liver. Children with PPB type II or III may have tumor recurrence locally in the thorax and/or distant metastatic disease. The brain, followed by bone, is the most common site of distant metastasis in PPB. The outcome for these individuals is poor, although some have survived long-term [ However, data also suggest a risk for A history of PPB is associated with an increased risk of Poorly differentiated thyroid cancer has rarely been reported [ Ovarian sex cord-stromal tumors are staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Well-differentiated, stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher-stage tumors are associated with a poorer prognosis. Most A small number of children with Although CBMEs are considered malignant neoplasms based on their histology, distant metastasis and mortality are rare. Mortality from CBME usually results from intracranial spread rather than systemic metastases. In a study of 103 individuals with a germline Pleuropulmonary blastoma-like peritoneal sarcoma may present as one or several masses or diffuse pelvic and peritoneal thickening. Histopathology may show diffuse, but discontinuous foci of a cambium layer-like proliferation of a primitive sarcoma with and without rhabdomyosarcomatous features and scattered chondroid nodules. The histopathology is similar to cervical embryonal rhabdomyosarcoma with overlapping features of adenosarcoma [ Thyroid nodules, including benign follicular adenomas and nodules of indeterminate cytology; Differentiated thyroid cancer, often low-invasive, encapsulated, follicular variant of papillary thyroid cancer or minimally invasive follicular thyroid cancer, to solid-variant and poorly differentiated follicular thyroid carcinoma associated with spindle cell sarcoma with rhabdomyosarcoma differentiation [ A higher number of disease foci and overgrowth have been observed in individuals with mosaicism for The penetrance of heterozygous germline Risk for cancers associated with DICER1 varies according to age and sex. In a study of 102 female and male non-proband individuals with a germline Pleuropulmonary blastoma (PPB) has been referred to as "rhabdomyosarcoma arising in congenital cyst." Pulmonary blastomas, biphasic epithelial and mesenchymal malignancies of the lung occurring in a broader age group, are not generally related to pleuropulmonary blastoma. Nodular hyperplasia of the thyroid is commonly called goiter. Ciliary body (or ocular) medulloepithelioma has also been called diktyoma or a teratoneuroma. In an analysis of 53,105 non-cancer exomes from the Exome Aggregation Consortium, the prevalence of a germline loss-of-function and/or previously published • Type I PPB is a purely cystic lesion containing a layer of malignant cells. If left in situ, the malignant component of type I PPB may proliferate further, leading to type II PPB. Typically, type I PPB becomes evident in infants and young children (median age at diagnosis: 8 months) with difficulty breathing due to a large space-occupying cyst in the lung or pneumothorax secondary to a rupture of the air-filled cyst. Occasionally lung cysts are identified in asymptomatic children when radiographic studies are performed for nonrespiratory symptoms or surveillance. Five-year survival for type I PPB is 89% [ • Type II PPB is a mixed cystic and solid tumor that presents at a median age of 35 months. A child with type II PPB typically presents with weight loss, fever, shortness of breath, and opacity or pneumothorax on chest radiograph. Five-year survival for type II PPB is 71% [ • Type III PPB is a purely solid, aggressive sarcoma which may present with respiratory distress and mediastinal shift. Type III PPB presents at a median age of 41 months. Children with type III PPB typically present with weight loss, fever, shortness of breath, and opacity on chest radiograph. Five-year survival for type III PPB is 53% [ • Type Ir (regressed or nonprogressed) PPB presents in individuals of any age and lacks a malignant component. Five-year survival for type Ir PPB is 100% [ • Ovarian sex cord-stromal tumors are staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Well-differentiated, stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher-stage tumors are associated with a poorer prognosis. Most • Thyroid nodules, including benign follicular adenomas and nodules of indeterminate cytology; • Differentiated thyroid cancer, often low-invasive, encapsulated, follicular variant of papillary thyroid cancer or minimally invasive follicular thyroid cancer, to solid-variant and poorly differentiated follicular thyroid carcinoma associated with spindle cell sarcoma with rhabdomyosarcoma differentiation [ ## Clinical Description To date, more than 1,000 individuals have been identified with a germline pathogenic variant in Studies to date have focused on germline Select Features of CNS = central nervous system; ETMR = embryonal tumor with multilayer rosettes; PPB = pleuropulmonary blastoma; SLCT = Sertoli-Leydig cell tumor; type Ir PPB = regressed or nonprogressed PPB Two instances of multicystic hepatic lesions reported [ PPB occurs in four main types: Type I PPB is a purely cystic lesion containing a layer of malignant cells. If left in situ, the malignant component of type I PPB may proliferate further, leading to type II PPB. Typically, type I PPB becomes evident in infants and young children (median age at diagnosis: 8 months) with difficulty breathing due to a large space-occupying cyst in the lung or pneumothorax secondary to a rupture of the air-filled cyst. Occasionally lung cysts are identified in asymptomatic children when radiographic studies are performed for nonrespiratory symptoms or surveillance. Five-year survival for type I PPB is 89% [ Type II PPB is a mixed cystic and solid tumor that presents at a median age of 35 months. A child with type II PPB typically presents with weight loss, fever, shortness of breath, and opacity or pneumothorax on chest radiograph. Five-year survival for type II PPB is 71% [ Type III PPB is a purely solid, aggressive sarcoma which may present with respiratory distress and mediastinal shift. Type III PPB presents at a median age of 41 months. Children with type III PPB typically present with weight loss, fever, shortness of breath, and opacity on chest radiograph. Five-year survival for type III PPB is 53% [ Type Ir (regressed or nonprogressed) PPB presents in individuals of any age and lacks a malignant component. Five-year survival for type Ir PPB is 100% [ The natural history of PPB suggests that many tumors have a precancerous / early cancerous stage in the form of lung cysts. Although not all PPB lung cysts transform into high-grade sarcoma, no radiographic characteristics can yet identify which cysts will progress to sarcoma. Progression from cyst to sarcoma can occur quickly. When progression occurs, the mesenchymal cells of a type I PPB expand and overgrow the cyst septa and replace the cyst with a cystic and solid (type II) or purely solid (type III) sarcoma. Type I PPB has no metastatic potential, but individuals with type II or III PPB can present with or develop metastasis to the brain, bone, local thoracic lymph nodes, and liver. Children with PPB type II or III may have tumor recurrence locally in the thorax and/or distant metastatic disease. The brain, followed by bone, is the most common site of distant metastasis in PPB. The outcome for these individuals is poor, although some have survived long-term [ However, data also suggest a risk for A history of PPB is associated with an increased risk of Poorly differentiated thyroid cancer has rarely been reported [ Ovarian sex cord-stromal tumors are staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Well-differentiated, stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher-stage tumors are associated with a poorer prognosis. Most A small number of children with Although CBMEs are considered malignant neoplasms based on their histology, distant metastasis and mortality are rare. Mortality from CBME usually results from intracranial spread rather than systemic metastases. In a study of 103 individuals with a germline Pleuropulmonary blastoma-like peritoneal sarcoma may present as one or several masses or diffuse pelvic and peritoneal thickening. Histopathology may show diffuse, but discontinuous foci of a cambium layer-like proliferation of a primitive sarcoma with and without rhabdomyosarcomatous features and scattered chondroid nodules. The histopathology is similar to cervical embryonal rhabdomyosarcoma with overlapping features of adenosarcoma [ Thyroid nodules, including benign follicular adenomas and nodules of indeterminate cytology; Differentiated thyroid cancer, often low-invasive, encapsulated, follicular variant of papillary thyroid cancer or minimally invasive follicular thyroid cancer, to solid-variant and poorly differentiated follicular thyroid carcinoma associated with spindle cell sarcoma with rhabdomyosarcoma differentiation [ • Type I PPB is a purely cystic lesion containing a layer of malignant cells. If left in situ, the malignant component of type I PPB may proliferate further, leading to type II PPB. Typically, type I PPB becomes evident in infants and young children (median age at diagnosis: 8 months) with difficulty breathing due to a large space-occupying cyst in the lung or pneumothorax secondary to a rupture of the air-filled cyst. Occasionally lung cysts are identified in asymptomatic children when radiographic studies are performed for nonrespiratory symptoms or surveillance. Five-year survival for type I PPB is 89% [ • Type II PPB is a mixed cystic and solid tumor that presents at a median age of 35 months. A child with type II PPB typically presents with weight loss, fever, shortness of breath, and opacity or pneumothorax on chest radiograph. Five-year survival for type II PPB is 71% [ • Type III PPB is a purely solid, aggressive sarcoma which may present with respiratory distress and mediastinal shift. Type III PPB presents at a median age of 41 months. Children with type III PPB typically present with weight loss, fever, shortness of breath, and opacity on chest radiograph. Five-year survival for type III PPB is 53% [ • Type Ir (regressed or nonprogressed) PPB presents in individuals of any age and lacks a malignant component. Five-year survival for type Ir PPB is 100% [ • Ovarian sex cord-stromal tumors are staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Well-differentiated, stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher-stage tumors are associated with a poorer prognosis. Most • Thyroid nodules, including benign follicular adenomas and nodules of indeterminate cytology; • Differentiated thyroid cancer, often low-invasive, encapsulated, follicular variant of papillary thyroid cancer or minimally invasive follicular thyroid cancer, to solid-variant and poorly differentiated follicular thyroid carcinoma associated with spindle cell sarcoma with rhabdomyosarcoma differentiation [ ## Genotype-Phenotype Correlations A higher number of disease foci and overgrowth have been observed in individuals with mosaicism for ## Penetrance The penetrance of heterozygous germline Risk for cancers associated with DICER1 varies according to age and sex. In a study of 102 female and male non-proband individuals with a germline ## Nomenclature Pleuropulmonary blastoma (PPB) has been referred to as "rhabdomyosarcoma arising in congenital cyst." Pulmonary blastomas, biphasic epithelial and mesenchymal malignancies of the lung occurring in a broader age group, are not generally related to pleuropulmonary blastoma. Nodular hyperplasia of the thyroid is commonly called goiter. Ciliary body (or ocular) medulloepithelioma has also been called diktyoma or a teratoneuroma. ## Prevalence In an analysis of 53,105 non-cancer exomes from the Exome Aggregation Consortium, the prevalence of a germline loss-of-function and/or previously published ## Genetically Related (Allelic) Disorders No phenotypes other than those described in this ## Differential Diagnosis Most non-PPB tumors presenting in the newborn period are solid lung tumors; they include fetal lung interstitial tumor [ Synovial sarcoma is the main differential diagnosis for PPB in adolescents and young adults. Synovial sarcomas can be pleural-based and cystic [ Rhabdomyosarcoma and Ewing sarcoma tend to originate in the chest wall or soft tissue of the diaphragm rather than the lung parenchyma. Rarely, malignant peripheral nerve sheath tumors may have sarcomatous elements which resemble PPB. Pulmonary blastoma is a biphasic tumor with malignant epithelial elements and mesenchyme with a median age range at presentation of 43 years [ Inflammatory myofibroblastic tumor (IMT) originates in the lung (typically in children age >3-4 years) as a well-circumscribed, lobar-based mass. These tumors comprise myofibroblasts that can be demonstrated by immunostain for smooth muscle actin; 40%-50% of IMTs have translocations involving Nonsyndromic MNG is associated with iodine deficiency, female sex, and advancing age. Elevated thyroid stimulating hormone from iodine deficiency, goitrogens, and inborn errors of thyroid hormone biosynthesis are also associated with an increased risk of developing MNG. The method of detection correlates with disease prevalence: a higher percent of disease is found by ultrasound examination or autopsy compared to physical examination. In general, in iodine-sufficient countries the prevalence of MNG is estimated at 4% of the population [ MNG is common in adults, even outside of iodine-deficient regions [ Ovarian germ cell tumors are seen more commonly in young children and adolescent girls whereas epithelial ovarian tumors are seen more often in older women. Ovarian small cell carcinoma of the hypercalcemic type may histologically mimic an ovarian sex cord-stromal tumor. Preoperative measurement of calcium levels may be helpful in distinguishing this unique tumor. Sertoli-Leydig cell tumor and (rarely) juvenile granulosa cell tumor may also secrete alpha-fetoprotein (AFP), thus leading to consideration of immature teratoma or yolk sac tumor. Typically, the elevation in AFP is <500 ng/mL with sex cord-stromal tumors, and pathologic examination generally confirms the correct diagnosis. Cystic renal tumors or lesions include congenital mesoblastic nephroma (solid and cystic), cystic partially differentiated nephroblastoma, cystic Mixed epithelial and stromal tumor (MEST) of the kidney, which includes adult cystic nephroma (CN), occurs in women older than age 50 years. Unlike pediatric CN, MEST is not associated with germline Although also seen in individuals with Multiple renal cysts may also be seen in In children, the clinical differential diagnosis of a mass in the ciliary body includes an anteriorly located retinoblastoma, ciliary body cyst, leiomyoma, and juvenile xanthogranuloma of the ciliary body. Anteriorly located retinoblastoma occurs in older children and is frequently calcified [ In adults, the clinical differential diagnosis of a mass in the ciliary body includes adenoma or adenocarcinoma of the ciliary epithelium (pigmented or nonpigmented), mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, ciliochoroidal melanoma, intraocular toxocariasis, and granuloma [ The cartilaginous nodules surrounded by a compact, hypercellular zone of immature stromal cells of NCMH can be confused with embryonal rhabdomyosarcoma. However, the stromal cells of NCMH lack a myogenic phenotype. Other patterns in NCMH may mimic aneurysmal bone cyst or fibrous dysplasia. Because cervical ERMS is a pedunculated polyp presenting at the cervical os, a benign cervical polyp composed in part of endocervical glands and a squamous mucosa is a common clinical impression. Other non-neoplastic polypoid lesions of the cervix are granulation tissue polyp, decidua, and squamous papilloma. Mesodermal stromal polyp is composed of enlarged stellate and spindle cells in a pale staining myxoid stroma without any glandular structures. These stromal cells lack the features of rhabdomyoblasts. Müllerian papilloma is a purely epithelial lesion with a complex papillary pattern which may cause bleeding in children. Müllerian adenosarcoma is a malignant polypoid lesion of the cervix with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation. There is overlap with cervical embryonal rhabdomyosarcoma. Clinically, a pituitary mass in a young child should prompt consideration of craniopharyngioma, adenoma, pituitary hyperplasia, germinoma, Langerhans cell histiocytosis, and much rarer entities including pituitary carcinoma, hamartoma, or teratoma. Non-neoplastic inflammatory and granulomatous entities may also affect this region. Pineoblastomas must be distinguished from better-differentiated pineal parenchymal tumors like pineocytoma and pineal parenchymal tumor of intermediate differentiation. Pineal cysts may also occur. The pineal gland is also a common location for germ cell tumors. Other embryonal tumors such as medulloblastoma should be considered if the tumor is not localized to the pineal region but rather extends into the infratentorial region. Other Genes of Interest in the Differential Diagnosis of Pneumothoraces typically in adulthood Lung cysts usually bilateral & multifocal Unclear whether MNG reported in assoc w/BHD is truly syndrome related Renal tumors typically bilateral & multifocal; median age of diagnosis 48 yrs Characteristic skin lesions (fibrofolliculomas, trichodiscomas, & acrochordons) appear in 3rd & 4th decades of life. Obstructive lung disease w/bronchiectasis ↑ immunoreactive trypsinogen & sweat chloride GI/nutritional abnormalities Congenital absence of vas deferens Spontaneous &/or recurrent pneumothoraces Vascular rupture/dissection GI perforation or organ rupture Recurrent pneumothorax associated w/lung bullae Connective tissue findings Ectopia lentis Aortic root enlargement Chronic obstructive pulmonary disease (emphysema &/or chronic bronchitis), primarily in adults Incidence of liver disease increases w/age Lymphangioleiomyomatosis Renal angiomyolipoma & cysts Thyroid lesions w/or w/o non-autoimmune hyperthyroidism Café au lait macules, fibrous dysplasia, & other endocrinopathies Cribriform-morular variant papillary thyroid cancer Adenomatous colonic polyps, polyps of gastric fundus & duodenum, osteomas, dental anomalies, congenital hypertrophy Familial MNG, mostly nonfunctioning thyroid follicular adenomas Skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, & schwannomas MNG No growth spurt during teen years; loss/graying of hair, hoarseness, scleroderma-like skin changes, bilateral cataracts, diabetes mellitus, hypogonadism, skin ulcers, & osteoporosis Small cell carcinoma of the ovary, hypercalcemic type (malignant rhabdoid tumor of the ovary) Rhabdoid tumor in kidney Cancer in early childhood (age <5 yrs) Multiple renal cysts Liver cysts & ↑ risk of intracranial aneurysms Multiple renal cysts Biliary ductal ectasia & congenital hepatic fibrosis Multiple renal cysts & clear cell renal carcinoma Hemangioblastomas, pheochromocytoma, pancreatic cysts, neuroendocrine tumors, endolymphatic sac tumors, epididymal & broad ligament cysts AD = autosomal dominant; AR = autosomal recessive; BHD = The most commonly reported germline genetic and epigenetic variants in individuals with • Most non-PPB tumors presenting in the newborn period are solid lung tumors; they include fetal lung interstitial tumor [ • Synovial sarcoma is the main differential diagnosis for PPB in adolescents and young adults. Synovial sarcomas can be pleural-based and cystic [ • Rhabdomyosarcoma and Ewing sarcoma tend to originate in the chest wall or soft tissue of the diaphragm rather than the lung parenchyma. Rarely, malignant peripheral nerve sheath tumors may have sarcomatous elements which resemble PPB. • Pulmonary blastoma is a biphasic tumor with malignant epithelial elements and mesenchyme with a median age range at presentation of 43 years [ • Inflammatory myofibroblastic tumor (IMT) originates in the lung (typically in children age >3-4 years) as a well-circumscribed, lobar-based mass. These tumors comprise myofibroblasts that can be demonstrated by immunostain for smooth muscle actin; 40%-50% of IMTs have translocations involving • Nonsyndromic MNG is associated with iodine deficiency, female sex, and advancing age. Elevated thyroid stimulating hormone from iodine deficiency, goitrogens, and inborn errors of thyroid hormone biosynthesis are also associated with an increased risk of developing MNG. • The method of detection correlates with disease prevalence: a higher percent of disease is found by ultrasound examination or autopsy compared to physical examination. In general, in iodine-sufficient countries the prevalence of MNG is estimated at 4% of the population [ • MNG is common in adults, even outside of iodine-deficient regions [ • Ovarian germ cell tumors are seen more commonly in young children and adolescent girls whereas epithelial ovarian tumors are seen more often in older women. • Ovarian small cell carcinoma of the hypercalcemic type may histologically mimic an ovarian sex cord-stromal tumor. Preoperative measurement of calcium levels may be helpful in distinguishing this unique tumor. • Sertoli-Leydig cell tumor and (rarely) juvenile granulosa cell tumor may also secrete alpha-fetoprotein (AFP), thus leading to consideration of immature teratoma or yolk sac tumor. Typically, the elevation in AFP is <500 ng/mL with sex cord-stromal tumors, and pathologic examination generally confirms the correct diagnosis. • Cystic renal tumors or lesions include congenital mesoblastic nephroma (solid and cystic), cystic partially differentiated nephroblastoma, cystic • Mixed epithelial and stromal tumor (MEST) of the kidney, which includes adult cystic nephroma (CN), occurs in women older than age 50 years. Unlike pediatric CN, MEST is not associated with germline • Although also seen in individuals with • Multiple renal cysts may also be seen in • In children, the clinical differential diagnosis of a mass in the ciliary body includes an anteriorly located retinoblastoma, ciliary body cyst, leiomyoma, and juvenile xanthogranuloma of the ciliary body. Anteriorly located retinoblastoma occurs in older children and is frequently calcified [ • In adults, the clinical differential diagnosis of a mass in the ciliary body includes adenoma or adenocarcinoma of the ciliary epithelium (pigmented or nonpigmented), mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, ciliochoroidal melanoma, intraocular toxocariasis, and granuloma [ • The cartilaginous nodules surrounded by a compact, hypercellular zone of immature stromal cells of NCMH can be confused with embryonal rhabdomyosarcoma. However, the stromal cells of NCMH lack a myogenic phenotype. • Other patterns in NCMH may mimic aneurysmal bone cyst or fibrous dysplasia. • Because cervical ERMS is a pedunculated polyp presenting at the cervical os, a benign cervical polyp composed in part of endocervical glands and a squamous mucosa is a common clinical impression. • Other non-neoplastic polypoid lesions of the cervix are granulation tissue polyp, decidua, and squamous papilloma. • Mesodermal stromal polyp is composed of enlarged stellate and spindle cells in a pale staining myxoid stroma without any glandular structures. These stromal cells lack the features of rhabdomyoblasts. • Müllerian papilloma is a purely epithelial lesion with a complex papillary pattern which may cause bleeding in children. • Müllerian adenosarcoma is a malignant polypoid lesion of the cervix with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation. There is overlap with cervical embryonal rhabdomyosarcoma. • Clinically, a pituitary mass in a young child should prompt consideration of craniopharyngioma, adenoma, pituitary hyperplasia, germinoma, Langerhans cell histiocytosis, and much rarer entities including pituitary carcinoma, hamartoma, or teratoma. • Non-neoplastic inflammatory and granulomatous entities may also affect this region. • Pineoblastomas must be distinguished from better-differentiated pineal parenchymal tumors like pineocytoma and pineal parenchymal tumor of intermediate differentiation. Pineal cysts may also occur. The pineal gland is also a common location for germ cell tumors. • Other embryonal tumors such as medulloblastoma should be considered if the tumor is not localized to the pineal region but rather extends into the infratentorial region. • Pneumothoraces typically in adulthood • Lung cysts usually bilateral & multifocal • Unclear whether MNG reported in assoc w/BHD is truly syndrome related • Renal tumors typically bilateral & multifocal; median age of diagnosis 48 yrs • Characteristic skin lesions (fibrofolliculomas, trichodiscomas, & acrochordons) appear in 3rd & 4th decades of life. • Obstructive lung disease w/bronchiectasis • ↑ immunoreactive trypsinogen & sweat chloride • GI/nutritional abnormalities • Congenital absence of vas deferens • Spontaneous &/or recurrent pneumothoraces • Vascular rupture/dissection • GI perforation or organ rupture • Recurrent pneumothorax associated w/lung bullae • Connective tissue findings • Ectopia lentis • Aortic root enlargement • Chronic obstructive pulmonary disease (emphysema &/or chronic bronchitis), primarily in adults • Incidence of liver disease increases w/age • Lymphangioleiomyomatosis • Renal angiomyolipoma & cysts • Thyroid lesions w/or w/o non-autoimmune hyperthyroidism • Café au lait macules, fibrous dysplasia, & other endocrinopathies • Cribriform-morular variant papillary thyroid cancer • Adenomatous colonic polyps, polyps of gastric fundus & duodenum, osteomas, dental anomalies, congenital hypertrophy • Familial MNG, mostly nonfunctioning thyroid follicular adenomas • Skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, & schwannomas • MNG • No growth spurt during teen years; loss/graying of hair, hoarseness, scleroderma-like skin changes, bilateral cataracts, diabetes mellitus, hypogonadism, skin ulcers, & osteoporosis • Small cell carcinoma of the ovary, hypercalcemic type (malignant rhabdoid tumor of the ovary) • Rhabdoid tumor in kidney • Cancer in early childhood (age <5 yrs) • Multiple renal cysts • Liver cysts & ↑ risk of intracranial aneurysms • Multiple renal cysts • Biliary ductal ectasia & congenital hepatic fibrosis • Multiple renal cysts & clear cell renal carcinoma • Hemangioblastomas, pheochromocytoma, pancreatic cysts, neuroendocrine tumors, endolymphatic sac tumors, epididymal & broad ligament cysts ## Pleuropulmonary Blastoma (PPB) Most non-PPB tumors presenting in the newborn period are solid lung tumors; they include fetal lung interstitial tumor [ Synovial sarcoma is the main differential diagnosis for PPB in adolescents and young adults. Synovial sarcomas can be pleural-based and cystic [ Rhabdomyosarcoma and Ewing sarcoma tend to originate in the chest wall or soft tissue of the diaphragm rather than the lung parenchyma. Rarely, malignant peripheral nerve sheath tumors may have sarcomatous elements which resemble PPB. Pulmonary blastoma is a biphasic tumor with malignant epithelial elements and mesenchyme with a median age range at presentation of 43 years [ Inflammatory myofibroblastic tumor (IMT) originates in the lung (typically in children age >3-4 years) as a well-circumscribed, lobar-based mass. These tumors comprise myofibroblasts that can be demonstrated by immunostain for smooth muscle actin; 40%-50% of IMTs have translocations involving • Most non-PPB tumors presenting in the newborn period are solid lung tumors; they include fetal lung interstitial tumor [ • Synovial sarcoma is the main differential diagnosis for PPB in adolescents and young adults. Synovial sarcomas can be pleural-based and cystic [ • Rhabdomyosarcoma and Ewing sarcoma tend to originate in the chest wall or soft tissue of the diaphragm rather than the lung parenchyma. Rarely, malignant peripheral nerve sheath tumors may have sarcomatous elements which resemble PPB. • Pulmonary blastoma is a biphasic tumor with malignant epithelial elements and mesenchyme with a median age range at presentation of 43 years [ • Inflammatory myofibroblastic tumor (IMT) originates in the lung (typically in children age >3-4 years) as a well-circumscribed, lobar-based mass. These tumors comprise myofibroblasts that can be demonstrated by immunostain for smooth muscle actin; 40%-50% of IMTs have translocations involving ## Other Tumors Nonsyndromic MNG is associated with iodine deficiency, female sex, and advancing age. Elevated thyroid stimulating hormone from iodine deficiency, goitrogens, and inborn errors of thyroid hormone biosynthesis are also associated with an increased risk of developing MNG. The method of detection correlates with disease prevalence: a higher percent of disease is found by ultrasound examination or autopsy compared to physical examination. In general, in iodine-sufficient countries the prevalence of MNG is estimated at 4% of the population [ MNG is common in adults, even outside of iodine-deficient regions [ Ovarian germ cell tumors are seen more commonly in young children and adolescent girls whereas epithelial ovarian tumors are seen more often in older women. Ovarian small cell carcinoma of the hypercalcemic type may histologically mimic an ovarian sex cord-stromal tumor. Preoperative measurement of calcium levels may be helpful in distinguishing this unique tumor. Sertoli-Leydig cell tumor and (rarely) juvenile granulosa cell tumor may also secrete alpha-fetoprotein (AFP), thus leading to consideration of immature teratoma or yolk sac tumor. Typically, the elevation in AFP is <500 ng/mL with sex cord-stromal tumors, and pathologic examination generally confirms the correct diagnosis. Cystic renal tumors or lesions include congenital mesoblastic nephroma (solid and cystic), cystic partially differentiated nephroblastoma, cystic Mixed epithelial and stromal tumor (MEST) of the kidney, which includes adult cystic nephroma (CN), occurs in women older than age 50 years. Unlike pediatric CN, MEST is not associated with germline Although also seen in individuals with Multiple renal cysts may also be seen in In children, the clinical differential diagnosis of a mass in the ciliary body includes an anteriorly located retinoblastoma, ciliary body cyst, leiomyoma, and juvenile xanthogranuloma of the ciliary body. Anteriorly located retinoblastoma occurs in older children and is frequently calcified [ In adults, the clinical differential diagnosis of a mass in the ciliary body includes adenoma or adenocarcinoma of the ciliary epithelium (pigmented or nonpigmented), mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, ciliochoroidal melanoma, intraocular toxocariasis, and granuloma [ The cartilaginous nodules surrounded by a compact, hypercellular zone of immature stromal cells of NCMH can be confused with embryonal rhabdomyosarcoma. However, the stromal cells of NCMH lack a myogenic phenotype. Other patterns in NCMH may mimic aneurysmal bone cyst or fibrous dysplasia. Because cervical ERMS is a pedunculated polyp presenting at the cervical os, a benign cervical polyp composed in part of endocervical glands and a squamous mucosa is a common clinical impression. Other non-neoplastic polypoid lesions of the cervix are granulation tissue polyp, decidua, and squamous papilloma. Mesodermal stromal polyp is composed of enlarged stellate and spindle cells in a pale staining myxoid stroma without any glandular structures. These stromal cells lack the features of rhabdomyoblasts. Müllerian papilloma is a purely epithelial lesion with a complex papillary pattern which may cause bleeding in children. Müllerian adenosarcoma is a malignant polypoid lesion of the cervix with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation. There is overlap with cervical embryonal rhabdomyosarcoma. Clinically, a pituitary mass in a young child should prompt consideration of craniopharyngioma, adenoma, pituitary hyperplasia, germinoma, Langerhans cell histiocytosis, and much rarer entities including pituitary carcinoma, hamartoma, or teratoma. Non-neoplastic inflammatory and granulomatous entities may also affect this region. Pineoblastomas must be distinguished from better-differentiated pineal parenchymal tumors like pineocytoma and pineal parenchymal tumor of intermediate differentiation. Pineal cysts may also occur. The pineal gland is also a common location for germ cell tumors. Other embryonal tumors such as medulloblastoma should be considered if the tumor is not localized to the pineal region but rather extends into the infratentorial region. Other Genes of Interest in the Differential Diagnosis of Pneumothoraces typically in adulthood Lung cysts usually bilateral & multifocal Unclear whether MNG reported in assoc w/BHD is truly syndrome related Renal tumors typically bilateral & multifocal; median age of diagnosis 48 yrs Characteristic skin lesions (fibrofolliculomas, trichodiscomas, & acrochordons) appear in 3rd & 4th decades of life. Obstructive lung disease w/bronchiectasis ↑ immunoreactive trypsinogen & sweat chloride GI/nutritional abnormalities Congenital absence of vas deferens Spontaneous &/or recurrent pneumothoraces Vascular rupture/dissection GI perforation or organ rupture Recurrent pneumothorax associated w/lung bullae Connective tissue findings Ectopia lentis Aortic root enlargement Chronic obstructive pulmonary disease (emphysema &/or chronic bronchitis), primarily in adults Incidence of liver disease increases w/age Lymphangioleiomyomatosis Renal angiomyolipoma & cysts Thyroid lesions w/or w/o non-autoimmune hyperthyroidism Café au lait macules, fibrous dysplasia, & other endocrinopathies Cribriform-morular variant papillary thyroid cancer Adenomatous colonic polyps, polyps of gastric fundus & duodenum, osteomas, dental anomalies, congenital hypertrophy Familial MNG, mostly nonfunctioning thyroid follicular adenomas Skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, & schwannomas MNG No growth spurt during teen years; loss/graying of hair, hoarseness, scleroderma-like skin changes, bilateral cataracts, diabetes mellitus, hypogonadism, skin ulcers, & osteoporosis Small cell carcinoma of the ovary, hypercalcemic type (malignant rhabdoid tumor of the ovary) Rhabdoid tumor in kidney Cancer in early childhood (age <5 yrs) Multiple renal cysts Liver cysts & ↑ risk of intracranial aneurysms Multiple renal cysts Biliary ductal ectasia & congenital hepatic fibrosis Multiple renal cysts & clear cell renal carcinoma Hemangioblastomas, pheochromocytoma, pancreatic cysts, neuroendocrine tumors, endolymphatic sac tumors, epididymal & broad ligament cysts AD = autosomal dominant; AR = autosomal recessive; BHD = The most commonly reported germline genetic and epigenetic variants in individuals with • Nonsyndromic MNG is associated with iodine deficiency, female sex, and advancing age. Elevated thyroid stimulating hormone from iodine deficiency, goitrogens, and inborn errors of thyroid hormone biosynthesis are also associated with an increased risk of developing MNG. • The method of detection correlates with disease prevalence: a higher percent of disease is found by ultrasound examination or autopsy compared to physical examination. In general, in iodine-sufficient countries the prevalence of MNG is estimated at 4% of the population [ • MNG is common in adults, even outside of iodine-deficient regions [ • Ovarian germ cell tumors are seen more commonly in young children and adolescent girls whereas epithelial ovarian tumors are seen more often in older women. • Ovarian small cell carcinoma of the hypercalcemic type may histologically mimic an ovarian sex cord-stromal tumor. Preoperative measurement of calcium levels may be helpful in distinguishing this unique tumor. • Sertoli-Leydig cell tumor and (rarely) juvenile granulosa cell tumor may also secrete alpha-fetoprotein (AFP), thus leading to consideration of immature teratoma or yolk sac tumor. Typically, the elevation in AFP is <500 ng/mL with sex cord-stromal tumors, and pathologic examination generally confirms the correct diagnosis. • Cystic renal tumors or lesions include congenital mesoblastic nephroma (solid and cystic), cystic partially differentiated nephroblastoma, cystic • Mixed epithelial and stromal tumor (MEST) of the kidney, which includes adult cystic nephroma (CN), occurs in women older than age 50 years. Unlike pediatric CN, MEST is not associated with germline • Although also seen in individuals with • Multiple renal cysts may also be seen in • In children, the clinical differential diagnosis of a mass in the ciliary body includes an anteriorly located retinoblastoma, ciliary body cyst, leiomyoma, and juvenile xanthogranuloma of the ciliary body. Anteriorly located retinoblastoma occurs in older children and is frequently calcified [ • In adults, the clinical differential diagnosis of a mass in the ciliary body includes adenoma or adenocarcinoma of the ciliary epithelium (pigmented or nonpigmented), mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, ciliochoroidal melanoma, intraocular toxocariasis, and granuloma [ • The cartilaginous nodules surrounded by a compact, hypercellular zone of immature stromal cells of NCMH can be confused with embryonal rhabdomyosarcoma. However, the stromal cells of NCMH lack a myogenic phenotype. • Other patterns in NCMH may mimic aneurysmal bone cyst or fibrous dysplasia. • Because cervical ERMS is a pedunculated polyp presenting at the cervical os, a benign cervical polyp composed in part of endocervical glands and a squamous mucosa is a common clinical impression. • Other non-neoplastic polypoid lesions of the cervix are granulation tissue polyp, decidua, and squamous papilloma. • Mesodermal stromal polyp is composed of enlarged stellate and spindle cells in a pale staining myxoid stroma without any glandular structures. These stromal cells lack the features of rhabdomyoblasts. • Müllerian papilloma is a purely epithelial lesion with a complex papillary pattern which may cause bleeding in children. • Müllerian adenosarcoma is a malignant polypoid lesion of the cervix with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation. There is overlap with cervical embryonal rhabdomyosarcoma. • Clinically, a pituitary mass in a young child should prompt consideration of craniopharyngioma, adenoma, pituitary hyperplasia, germinoma, Langerhans cell histiocytosis, and much rarer entities including pituitary carcinoma, hamartoma, or teratoma. • Non-neoplastic inflammatory and granulomatous entities may also affect this region. • Pineoblastomas must be distinguished from better-differentiated pineal parenchymal tumors like pineocytoma and pineal parenchymal tumor of intermediate differentiation. Pineal cysts may also occur. The pineal gland is also a common location for germ cell tumors. • Other embryonal tumors such as medulloblastoma should be considered if the tumor is not localized to the pineal region but rather extends into the infratentorial region. • Pneumothoraces typically in adulthood • Lung cysts usually bilateral & multifocal • Unclear whether MNG reported in assoc w/BHD is truly syndrome related • Renal tumors typically bilateral & multifocal; median age of diagnosis 48 yrs • Characteristic skin lesions (fibrofolliculomas, trichodiscomas, & acrochordons) appear in 3rd & 4th decades of life. • Obstructive lung disease w/bronchiectasis • ↑ immunoreactive trypsinogen & sweat chloride • GI/nutritional abnormalities • Congenital absence of vas deferens • Spontaneous &/or recurrent pneumothoraces • Vascular rupture/dissection • GI perforation or organ rupture • Recurrent pneumothorax associated w/lung bullae • Connective tissue findings • Ectopia lentis • Aortic root enlargement • Chronic obstructive pulmonary disease (emphysema &/or chronic bronchitis), primarily in adults • Incidence of liver disease increases w/age • Lymphangioleiomyomatosis • Renal angiomyolipoma & cysts • Thyroid lesions w/or w/o non-autoimmune hyperthyroidism • Café au lait macules, fibrous dysplasia, & other endocrinopathies • Cribriform-morular variant papillary thyroid cancer • Adenomatous colonic polyps, polyps of gastric fundus & duodenum, osteomas, dental anomalies, congenital hypertrophy • Familial MNG, mostly nonfunctioning thyroid follicular adenomas • Skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, & schwannomas • MNG • No growth spurt during teen years; loss/graying of hair, hoarseness, scleroderma-like skin changes, bilateral cataracts, diabetes mellitus, hypogonadism, skin ulcers, & osteoporosis • Small cell carcinoma of the ovary, hypercalcemic type (malignant rhabdoid tumor of the ovary) • Rhabdoid tumor in kidney • Cancer in early childhood (age <5 yrs) • Multiple renal cysts • Liver cysts & ↑ risk of intracranial aneurysms • Multiple renal cysts • Biliary ductal ectasia & congenital hepatic fibrosis • Multiple renal cysts & clear cell renal carcinoma • Hemangioblastomas, pheochromocytoma, pancreatic cysts, neuroendocrine tumors, endolymphatic sac tumors, epididymal & broad ligament cysts ## Management For an individual diagnosed with a The extent of disease spread (staging) for malignant or potentially malignant The presence of other synchronous DICER1 conditions (see CT of the chest to evaluate extent of disease and completeness of resection Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up. Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion Rarely, spine MRI for paraspinal or intraspinal extension In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases Note: Bone marrow involvement is extremely rare. When an ovarian sex cord-stromal tumor is suspected based on clinical features or individual or family history of DICER1, preoperative assessment of testosterone levels, AFP, inhibin A and B, and estradiol may be helpful in establishing one or more of these as a tumor marker. Intraoperative staging should be performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria and should include peritoneal cytology and assessment for preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible. Spread of ovarian sex cord-stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions. Type I PPB is treated with complete surgical removal with or without adjuvant chemotherapy. The five-year overall survival for individuals with ytype I PPB is 89%; the only PPB-related deaths in type I PPB have occurred following progression to type II or III PPB. Individuals with type Ir PPB are treated with resection alone (or observation in certain clinical circumstances including adulthood). PPB-related survival is 100% for individuals with type Ir PPB [ Types II and III PPB are treated with aggressive surgical resection and intensive chemotherapy; five-year overall survival is 71% and 53% for types II and III PPB respectively. Extent of disease may preclude initial surgical resection for some children with type II or III PPB. In these instances, biopsy followed by neoadjuvant chemotherapy followed by resection followed by subsequent chemotherapy has been performed. Resection of PPB should be performed with care so as not to disrupt the tumor or induce tumor spill, similar to the care taken with removal of Wilms tumor. Since solid components of PPB are very friable, piecemeal removal and spill are often inevitable. If it is evident at the time of surgery that the tumor has spread to the chest wall, pericardium, and/or diaphragm, removal of all grossly visible tumor is recommended. Sites of unresectable residual disease may be titanium clipped for radiographic localization and possible radiotherapy. Involvement of the diaphragm may require excision of a portion of the diaphragm and use of a Gore-Tex patch. Delayed resection after chemotherapy is performed for tumors deemed unresectable at the time of diagnosis. Individuals receiving neoadjuvant chemotherapy may have marked tumor reduction; however, this response may be transient and tumor can recur rapidly. Chemotherapy alone is insufficient to eradicate solid PPB. If gross-total resection is not achieved with the first or second surgery, additional surgery may be required for local control. Radiation therapy is used primarily to treat PPB recurrence or metastasis, or in the setting of local control of residual, unresectable tumor [ Treatment for recurrence requires an individualized approach. Additional information regarding treatment and results from a uniformly treated cohort of individuals with PPB is available from the International PPB/ Ovarian sex cord-stromal tumors (including Sertoli-Leydig cell tumor [SLCT] and gynandroblastoma) are rare and few studies have focused on clinical variables, treatment, and prognosis. Treatment regimens are based on those used for ovarian germ cell tumors and data are limited [ If imaging or laboratory studies suggest the presence of an ovarian tumor, consultation with specialists in gynecologic oncology is suggested. Surgical resection with staging procedures is usually the initial treatment. Fertility-sparing surgery is recommended for most girls and young women. Most individuals undergo unilateral salpingo-oophorectomy with sampling of peritoneal fluid and cytologic examination of peritoneal washings. Lymph nodes should be assessed radiographically, carefully examined intraoperatively, and removed if they are clinically concerning. Level of differentiation and stage influence outcome and are critical to determining whether adjuvant therapy is necessary. Effort must be made to avoid rupture of the tumor as this would result in an increased stage for some individuals. If rupture occurs, the timing of rupture (preoperative vs intraoperative rupture) must be carefully documented as it may influence the need for adjuvant therapy in some tumor types. The decision to use adjuvant treatment such as chemotherapy following surgery for SLCT is based on histology and stage: When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing PEB to carboplatin and paclitaxel for individuals with previously untreated sex cord-stromal tumors requiring chemotherapy. Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. Available modalities lack sensitivity for small tumors and peritoneal disease. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used. Surveillance guidelines for individuals with a germline Recommended Surveillance for Individuals with Chest x-ray at birth, every 4-6 mos until age 8 yrs, then annually until age 12 Consider chest CT at age 3-6 mos. If initial CT normal: consider repeat CT at age 2.5-3 yrs. If diagnosed after age 12 yrs, consider baseline chest x-ray or chest CT. At diagnosis (any age) Annually Consider US by age 8 yrs. Earlier for thyroid gland asymmetry &/or nodules Post-chemotherapy: By age 10 yrs or w/in 3-5 yrs of treatment Clinical eval as indicated for any signs/symptoms (e.g., hirsutism, virilization, abdominal distention, pain, mass, vaginal bleeding) Pelvic & abdominal US Clinical eval as indicated for any signs/symptoms (e.g., abdominal or flank mass, pain, hematuria) Abdominal US Abdominal US every 6 mos until age 8 yrs, then annually until age 12 If diagnosed after age 12 yrs, consider baseline abdominal US Visual acuity measurement Dilated ophthalmic exam At diagnosis (any age) Annually from age 3 yrs until at least age 10 Annually Referral to ENT for any signs/symptoms CNS = central nervous system; ENT = ear, nose, and throat physician; US = ultrasound Thyroid carcinoma seen in individuals with DICER1 is generally well differentiated. The importance of early detection of differentiated thyroid carcinoma has not been established, as it has been for tumor predispositions with increased risk for medullary thyroid carcinoma. Some providers and families may favor physical exams in childhood with transition to ultrasound by age 18 yrs. Poorly differentiated thyroid carcinoma has rarely been seen in individuals with a Consideration should be given to starting pelvic ultrasound early, at times of abdominal ultrasound in childhood. Optimal end of surveillance range is not known; however, 95% of SLCTs were diagnosed before age 40. Note: In children and young adolescents, transabdominal pelvic ultrasound is most appropriate. Transition to transvaginal ultrasound should be considered in older adolescents and adults when appropriate for the individual. It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the Testing of at-risk newborns (before age 4 months) for the family-specific pathogenic variant is recommended. Pulmonary screening by CT scan can then be initiated for those with a known If not already performed, molecular genetic testing should be prioritized for children younger than age seven years (because they are at greatest risk for PPB tumors that may need intervention) and young girls/women (because of the risk of ovarian tumors during late childhood/early adolescence and young adult years). Note: If at-risk first-degree relatives are not able to or choose not to undergo molecular genetic testing for a known familial See Based on data from the International PPB/ Because large lung cysts can in rare cases cause respiratory distress in newborns, it is recommended that prenatal identification of lung cysts prompt consultation with specialists in high-risk obstetrics and fetal medicine to monitor the pregnancy and manage delivery. Multiple research efforts are under way to refine surveillance guidelines and improve outcomes for children and adults with Search • The extent of disease spread (staging) for malignant or potentially malignant • The presence of other synchronous DICER1 conditions (see • CT of the chest to evaluate extent of disease and completeness of resection • Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up. • Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging • Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion • Rarely, spine MRI for paraspinal or intraspinal extension • In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination • CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases • Note: Bone marrow involvement is extremely rare. • When an ovarian sex cord-stromal tumor is suspected based on clinical features or individual or family history of DICER1, preoperative assessment of testosterone levels, AFP, inhibin A and B, and estradiol may be helpful in establishing one or more of these as a tumor marker. • Intraoperative staging should be performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria and should include peritoneal cytology and assessment for preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible. • Spread of ovarian sex cord-stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions. • When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing PEB to carboplatin and paclitaxel for individuals with previously untreated sex cord-stromal tumors requiring chemotherapy. • Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. Available modalities lack sensitivity for small tumors and peritoneal disease. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used. • Chest x-ray at birth, every 4-6 mos until age 8 yrs, then annually until age 12 • Consider chest CT at age 3-6 mos. If initial CT normal: consider repeat CT at age 2.5-3 yrs. • If diagnosed after age 12 yrs, consider baseline chest x-ray or chest CT. • At diagnosis (any age) • Annually • Consider US by age 8 yrs. • Earlier for thyroid gland asymmetry &/or nodules • Post-chemotherapy: By age 10 yrs or w/in 3-5 yrs of treatment • Clinical eval as indicated for any signs/symptoms (e.g., hirsutism, virilization, abdominal distention, pain, mass, vaginal bleeding) • Pelvic & abdominal US • Clinical eval as indicated for any signs/symptoms (e.g., abdominal or flank mass, pain, hematuria) • Abdominal US • Abdominal US every 6 mos until age 8 yrs, then annually until age 12 • If diagnosed after age 12 yrs, consider baseline abdominal US • Visual acuity measurement • Dilated ophthalmic exam • At diagnosis (any age) • Annually from age 3 yrs until at least age 10 • Annually • Referral to ENT for any signs/symptoms • Testing of at-risk newborns (before age 4 months) for the family-specific pathogenic variant is recommended. Pulmonary screening by CT scan can then be initiated for those with a known • If not already performed, molecular genetic testing should be prioritized for children younger than age seven years (because they are at greatest risk for PPB tumors that may need intervention) and young girls/women (because of the risk of ovarian tumors during late childhood/early adolescence and young adult years). ## Evaluations Following Initial Diagnosis For an individual diagnosed with a The extent of disease spread (staging) for malignant or potentially malignant The presence of other synchronous DICER1 conditions (see CT of the chest to evaluate extent of disease and completeness of resection Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up. Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion Rarely, spine MRI for paraspinal or intraspinal extension In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases Note: Bone marrow involvement is extremely rare. When an ovarian sex cord-stromal tumor is suspected based on clinical features or individual or family history of DICER1, preoperative assessment of testosterone levels, AFP, inhibin A and B, and estradiol may be helpful in establishing one or more of these as a tumor marker. Intraoperative staging should be performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria and should include peritoneal cytology and assessment for preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible. Spread of ovarian sex cord-stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions. • The extent of disease spread (staging) for malignant or potentially malignant • The presence of other synchronous DICER1 conditions (see • CT of the chest to evaluate extent of disease and completeness of resection • Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up. • Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging • Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion • Rarely, spine MRI for paraspinal or intraspinal extension • In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination • CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases • Note: Bone marrow involvement is extremely rare. • When an ovarian sex cord-stromal tumor is suspected based on clinical features or individual or family history of DICER1, preoperative assessment of testosterone levels, AFP, inhibin A and B, and estradiol may be helpful in establishing one or more of these as a tumor marker. • Intraoperative staging should be performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria and should include peritoneal cytology and assessment for preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible. • Spread of ovarian sex cord-stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions. ## Extent of Disease Spread (Staging) CT of the chest to evaluate extent of disease and completeness of resection Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up. Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion Rarely, spine MRI for paraspinal or intraspinal extension In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases Note: Bone marrow involvement is extremely rare. When an ovarian sex cord-stromal tumor is suspected based on clinical features or individual or family history of DICER1, preoperative assessment of testosterone levels, AFP, inhibin A and B, and estradiol may be helpful in establishing one or more of these as a tumor marker. Intraoperative staging should be performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria and should include peritoneal cytology and assessment for preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible. Spread of ovarian sex cord-stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions. • CT of the chest to evaluate extent of disease and completeness of resection • Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up. • Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging • Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion • Rarely, spine MRI for paraspinal or intraspinal extension • In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination • CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases • Note: Bone marrow involvement is extremely rare. • When an ovarian sex cord-stromal tumor is suspected based on clinical features or individual or family history of DICER1, preoperative assessment of testosterone levels, AFP, inhibin A and B, and estradiol may be helpful in establishing one or more of these as a tumor marker. • Intraoperative staging should be performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria and should include peritoneal cytology and assessment for preoperative or intraoperative rupture. Care should be taken to avoid rupturing the tumor if possible. • Spread of ovarian sex cord-stromal tumors to the chest without extensive abdominopelvic disease is unlikely; however, baseline evaluation with chest CT is reasonable given the concern for synchronous conditions. ## Treatment of Manifestations Type I PPB is treated with complete surgical removal with or without adjuvant chemotherapy. The five-year overall survival for individuals with ytype I PPB is 89%; the only PPB-related deaths in type I PPB have occurred following progression to type II or III PPB. Individuals with type Ir PPB are treated with resection alone (or observation in certain clinical circumstances including adulthood). PPB-related survival is 100% for individuals with type Ir PPB [ Types II and III PPB are treated with aggressive surgical resection and intensive chemotherapy; five-year overall survival is 71% and 53% for types II and III PPB respectively. Extent of disease may preclude initial surgical resection for some children with type II or III PPB. In these instances, biopsy followed by neoadjuvant chemotherapy followed by resection followed by subsequent chemotherapy has been performed. Resection of PPB should be performed with care so as not to disrupt the tumor or induce tumor spill, similar to the care taken with removal of Wilms tumor. Since solid components of PPB are very friable, piecemeal removal and spill are often inevitable. If it is evident at the time of surgery that the tumor has spread to the chest wall, pericardium, and/or diaphragm, removal of all grossly visible tumor is recommended. Sites of unresectable residual disease may be titanium clipped for radiographic localization and possible radiotherapy. Involvement of the diaphragm may require excision of a portion of the diaphragm and use of a Gore-Tex patch. Delayed resection after chemotherapy is performed for tumors deemed unresectable at the time of diagnosis. Individuals receiving neoadjuvant chemotherapy may have marked tumor reduction; however, this response may be transient and tumor can recur rapidly. Chemotherapy alone is insufficient to eradicate solid PPB. If gross-total resection is not achieved with the first or second surgery, additional surgery may be required for local control. Radiation therapy is used primarily to treat PPB recurrence or metastasis, or in the setting of local control of residual, unresectable tumor [ Treatment for recurrence requires an individualized approach. Additional information regarding treatment and results from a uniformly treated cohort of individuals with PPB is available from the International PPB/ Ovarian sex cord-stromal tumors (including Sertoli-Leydig cell tumor [SLCT] and gynandroblastoma) are rare and few studies have focused on clinical variables, treatment, and prognosis. Treatment regimens are based on those used for ovarian germ cell tumors and data are limited [ If imaging or laboratory studies suggest the presence of an ovarian tumor, consultation with specialists in gynecologic oncology is suggested. Surgical resection with staging procedures is usually the initial treatment. Fertility-sparing surgery is recommended for most girls and young women. Most individuals undergo unilateral salpingo-oophorectomy with sampling of peritoneal fluid and cytologic examination of peritoneal washings. Lymph nodes should be assessed radiographically, carefully examined intraoperatively, and removed if they are clinically concerning. Level of differentiation and stage influence outcome and are critical to determining whether adjuvant therapy is necessary. Effort must be made to avoid rupture of the tumor as this would result in an increased stage for some individuals. If rupture occurs, the timing of rupture (preoperative vs intraoperative rupture) must be carefully documented as it may influence the need for adjuvant therapy in some tumor types. The decision to use adjuvant treatment such as chemotherapy following surgery for SLCT is based on histology and stage: When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing PEB to carboplatin and paclitaxel for individuals with previously untreated sex cord-stromal tumors requiring chemotherapy. Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. Available modalities lack sensitivity for small tumors and peritoneal disease. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used. • When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing PEB to carboplatin and paclitaxel for individuals with previously untreated sex cord-stromal tumors requiring chemotherapy. • Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. Available modalities lack sensitivity for small tumors and peritoneal disease. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used. ## Pleuropulmonary Blastoma (PPB) Type I PPB is treated with complete surgical removal with or without adjuvant chemotherapy. The five-year overall survival for individuals with ytype I PPB is 89%; the only PPB-related deaths in type I PPB have occurred following progression to type II or III PPB. Individuals with type Ir PPB are treated with resection alone (or observation in certain clinical circumstances including adulthood). PPB-related survival is 100% for individuals with type Ir PPB [ Types II and III PPB are treated with aggressive surgical resection and intensive chemotherapy; five-year overall survival is 71% and 53% for types II and III PPB respectively. Extent of disease may preclude initial surgical resection for some children with type II or III PPB. In these instances, biopsy followed by neoadjuvant chemotherapy followed by resection followed by subsequent chemotherapy has been performed. Resection of PPB should be performed with care so as not to disrupt the tumor or induce tumor spill, similar to the care taken with removal of Wilms tumor. Since solid components of PPB are very friable, piecemeal removal and spill are often inevitable. If it is evident at the time of surgery that the tumor has spread to the chest wall, pericardium, and/or diaphragm, removal of all grossly visible tumor is recommended. Sites of unresectable residual disease may be titanium clipped for radiographic localization and possible radiotherapy. Involvement of the diaphragm may require excision of a portion of the diaphragm and use of a Gore-Tex patch. Delayed resection after chemotherapy is performed for tumors deemed unresectable at the time of diagnosis. Individuals receiving neoadjuvant chemotherapy may have marked tumor reduction; however, this response may be transient and tumor can recur rapidly. Chemotherapy alone is insufficient to eradicate solid PPB. If gross-total resection is not achieved with the first or second surgery, additional surgery may be required for local control. Radiation therapy is used primarily to treat PPB recurrence or metastasis, or in the setting of local control of residual, unresectable tumor [ Treatment for recurrence requires an individualized approach. Additional information regarding treatment and results from a uniformly treated cohort of individuals with PPB is available from the International PPB/ ## Ovarian Sex Cord–Stromal Tumors Ovarian sex cord-stromal tumors (including Sertoli-Leydig cell tumor [SLCT] and gynandroblastoma) are rare and few studies have focused on clinical variables, treatment, and prognosis. Treatment regimens are based on those used for ovarian germ cell tumors and data are limited [ If imaging or laboratory studies suggest the presence of an ovarian tumor, consultation with specialists in gynecologic oncology is suggested. Surgical resection with staging procedures is usually the initial treatment. Fertility-sparing surgery is recommended for most girls and young women. Most individuals undergo unilateral salpingo-oophorectomy with sampling of peritoneal fluid and cytologic examination of peritoneal washings. Lymph nodes should be assessed radiographically, carefully examined intraoperatively, and removed if they are clinically concerning. Level of differentiation and stage influence outcome and are critical to determining whether adjuvant therapy is necessary. Effort must be made to avoid rupture of the tumor as this would result in an increased stage for some individuals. If rupture occurs, the timing of rupture (preoperative vs intraoperative rupture) must be carefully documented as it may influence the need for adjuvant therapy in some tumor types. The decision to use adjuvant treatment such as chemotherapy following surgery for SLCT is based on histology and stage: When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing PEB to carboplatin and paclitaxel for individuals with previously untreated sex cord-stromal tumors requiring chemotherapy. Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. Available modalities lack sensitivity for small tumors and peritoneal disease. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used. • When chemotherapy is used, a platinum-based regimen such as cisplatin, etoposide, and bleomycin (PEB) or cisplatin, etoposide, and ifosfamide (PEI) is often used. Additional regimens more often used in adults may include taxanes or anthracyclines. A Phase II randomized trial is currently open through Gynecology Oncology Group comparing PEB to carboplatin and paclitaxel for individuals with previously untreated sex cord-stromal tumors requiring chemotherapy. • Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither involves ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. Available modalities lack sensitivity for small tumors and peritoneal disease. If MRI is used, the radiologist should be notified of the clinical concern for ovarian tumor so that appropriate imaging protocols are used. ## Other Tumors ## Surveillance Surveillance guidelines for individuals with a germline Recommended Surveillance for Individuals with Chest x-ray at birth, every 4-6 mos until age 8 yrs, then annually until age 12 Consider chest CT at age 3-6 mos. If initial CT normal: consider repeat CT at age 2.5-3 yrs. If diagnosed after age 12 yrs, consider baseline chest x-ray or chest CT. At diagnosis (any age) Annually Consider US by age 8 yrs. Earlier for thyroid gland asymmetry &/or nodules Post-chemotherapy: By age 10 yrs or w/in 3-5 yrs of treatment Clinical eval as indicated for any signs/symptoms (e.g., hirsutism, virilization, abdominal distention, pain, mass, vaginal bleeding) Pelvic & abdominal US Clinical eval as indicated for any signs/symptoms (e.g., abdominal or flank mass, pain, hematuria) Abdominal US Abdominal US every 6 mos until age 8 yrs, then annually until age 12 If diagnosed after age 12 yrs, consider baseline abdominal US Visual acuity measurement Dilated ophthalmic exam At diagnosis (any age) Annually from age 3 yrs until at least age 10 Annually Referral to ENT for any signs/symptoms CNS = central nervous system; ENT = ear, nose, and throat physician; US = ultrasound Thyroid carcinoma seen in individuals with DICER1 is generally well differentiated. The importance of early detection of differentiated thyroid carcinoma has not been established, as it has been for tumor predispositions with increased risk for medullary thyroid carcinoma. Some providers and families may favor physical exams in childhood with transition to ultrasound by age 18 yrs. Poorly differentiated thyroid carcinoma has rarely been seen in individuals with a Consideration should be given to starting pelvic ultrasound early, at times of abdominal ultrasound in childhood. Optimal end of surveillance range is not known; however, 95% of SLCTs were diagnosed before age 40. Note: In children and young adolescents, transabdominal pelvic ultrasound is most appropriate. Transition to transvaginal ultrasound should be considered in older adolescents and adults when appropriate for the individual. • Chest x-ray at birth, every 4-6 mos until age 8 yrs, then annually until age 12 • Consider chest CT at age 3-6 mos. If initial CT normal: consider repeat CT at age 2.5-3 yrs. • If diagnosed after age 12 yrs, consider baseline chest x-ray or chest CT. • At diagnosis (any age) • Annually • Consider US by age 8 yrs. • Earlier for thyroid gland asymmetry &/or nodules • Post-chemotherapy: By age 10 yrs or w/in 3-5 yrs of treatment • Clinical eval as indicated for any signs/symptoms (e.g., hirsutism, virilization, abdominal distention, pain, mass, vaginal bleeding) • Pelvic & abdominal US • Clinical eval as indicated for any signs/symptoms (e.g., abdominal or flank mass, pain, hematuria) • Abdominal US • Abdominal US every 6 mos until age 8 yrs, then annually until age 12 • If diagnosed after age 12 yrs, consider baseline abdominal US • Visual acuity measurement • Dilated ophthalmic exam • At diagnosis (any age) • Annually from age 3 yrs until at least age 10 • Annually • Referral to ENT for any signs/symptoms ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the Testing of at-risk newborns (before age 4 months) for the family-specific pathogenic variant is recommended. Pulmonary screening by CT scan can then be initiated for those with a known If not already performed, molecular genetic testing should be prioritized for children younger than age seven years (because they are at greatest risk for PPB tumors that may need intervention) and young girls/women (because of the risk of ovarian tumors during late childhood/early adolescence and young adult years). Note: If at-risk first-degree relatives are not able to or choose not to undergo molecular genetic testing for a known familial See • Testing of at-risk newborns (before age 4 months) for the family-specific pathogenic variant is recommended. Pulmonary screening by CT scan can then be initiated for those with a known • If not already performed, molecular genetic testing should be prioritized for children younger than age seven years (because they are at greatest risk for PPB tumors that may need intervention) and young girls/women (because of the risk of ovarian tumors during late childhood/early adolescence and young adult years). ## Pregnancy Management Based on data from the International PPB/ Because large lung cysts can in rare cases cause respiratory distress in newborns, it is recommended that prenatal identification of lung cysts prompt consultation with specialists in high-risk obstetrics and fetal medicine to monitor the pregnancy and manage delivery. ## Therapies Under Investigation Multiple research efforts are under way to refine surveillance guidelines and improve outcomes for children and adults with Search ## Genetic Counseling Approximately 80% of individuals diagnosed with Approximately 20% of individuals with a Molecular genetic testing is recommended for the parents of a proband to clarify the genetic status of the parents and to determine if the proband inherited a pathogenic variant from a heterozygous parent, or if the If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals with a single or multiple If a parent of the proband has a germline If the germline pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once a germline Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Approximately 80% of individuals diagnosed with • Approximately 20% of individuals with a • Molecular genetic testing is recommended for the parents of a proband to clarify the genetic status of the parents and to determine if the proband inherited a pathogenic variant from a heterozygous parent, or if the • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals with a single or multiple • If a parent of the proband has a germline • If the germline pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Approximately 80% of individuals diagnosed with Approximately 20% of individuals with a Molecular genetic testing is recommended for the parents of a proband to clarify the genetic status of the parents and to determine if the proband inherited a pathogenic variant from a heterozygous parent, or if the If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals with a single or multiple If a parent of the proband has a germline If the germline pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ If the parents have not been tested for the • Approximately 80% of individuals diagnosed with • Approximately 20% of individuals with a • Molecular genetic testing is recommended for the parents of a proband to clarify the genetic status of the parents and to determine if the proband inherited a pathogenic variant from a heterozygous parent, or if the • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a • Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals with a single or multiple • If a parent of the proband has a germline • If the germline pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once a germline Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • • • • • • • ## Molecular Genetics DICER1 Tumor Predisposition: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DICER1 Tumor Predisposition ( Somatic Somatic missense pathogenic variants appear to preferentially affect amino acids in the RNase IIIb domain (codons 1705, 1709, 1809, 1810, or 1813) and are characterized as "missense hot spots." These somatic pathogenic variants lead to defective production of mature miRNAs from the 5' (5p) end of the miRNA hairpin but preserve the cleavage of the 3' (3p) end of the hairpin [ Examples of somatic Nearly all Sertoli-Leydig cell tumors and gynandroblastoma (based on tumor testing) [ Three out of 15 (20%) PPBs with tumor-specific loss-of-function and missense pathogenic variants in Eighteen out of 20 (90%) CNs with loss-of-function pathogenic variants in 70% (14/20); however, germline DNA was not examined [ Two out of 52 (4%) ERMS tumors with loss-of-function pathogenic variants; however, germline DNA was not examined [ Two pineoblastomas from children with a germline Ninety-five percent of primary intracranial sarcomas in children [ Multiple cases of nasal chondromesenchymal hamartoma. A systematic review of the literature identified 48 cases of NCMH [ Thyroid nodules with indeterminate cytology and a spectrum of disease that spans the range from benign follicular adenomas to differentiated thyroid cancer and rarely poorly differentiated thyroid cancer [ • Nearly all Sertoli-Leydig cell tumors and gynandroblastoma (based on tumor testing) [ • Three out of 15 (20%) PPBs with tumor-specific loss-of-function and missense pathogenic variants in • Eighteen out of 20 (90%) CNs with loss-of-function pathogenic variants in 70% (14/20); however, germline DNA was not examined [ • Two out of 52 (4%) ERMS tumors with loss-of-function pathogenic variants; however, germline DNA was not examined [ • Two pineoblastomas from children with a germline • Ninety-five percent of primary intracranial sarcomas in children [ • Multiple cases of nasal chondromesenchymal hamartoma. A systematic review of the literature identified 48 cases of NCMH [ • Thyroid nodules with indeterminate cytology and a spectrum of disease that spans the range from benign follicular adenomas to differentiated thyroid cancer and rarely poorly differentiated thyroid cancer [ ## Molecular Pathogenesis ## Cancers and Benign Tumors with Somatic Somatic Somatic missense pathogenic variants appear to preferentially affect amino acids in the RNase IIIb domain (codons 1705, 1709, 1809, 1810, or 1813) and are characterized as "missense hot spots." These somatic pathogenic variants lead to defective production of mature miRNAs from the 5' (5p) end of the miRNA hairpin but preserve the cleavage of the 3' (3p) end of the hairpin [ Examples of somatic Nearly all Sertoli-Leydig cell tumors and gynandroblastoma (based on tumor testing) [ Three out of 15 (20%) PPBs with tumor-specific loss-of-function and missense pathogenic variants in Eighteen out of 20 (90%) CNs with loss-of-function pathogenic variants in 70% (14/20); however, germline DNA was not examined [ Two out of 52 (4%) ERMS tumors with loss-of-function pathogenic variants; however, germline DNA was not examined [ Two pineoblastomas from children with a germline Ninety-five percent of primary intracranial sarcomas in children [ Multiple cases of nasal chondromesenchymal hamartoma. A systematic review of the literature identified 48 cases of NCMH [ Thyroid nodules with indeterminate cytology and a spectrum of disease that spans the range from benign follicular adenomas to differentiated thyroid cancer and rarely poorly differentiated thyroid cancer [ • Nearly all Sertoli-Leydig cell tumors and gynandroblastoma (based on tumor testing) [ • Three out of 15 (20%) PPBs with tumor-specific loss-of-function and missense pathogenic variants in • Eighteen out of 20 (90%) CNs with loss-of-function pathogenic variants in 70% (14/20); however, germline DNA was not examined [ • Two out of 52 (4%) ERMS tumors with loss-of-function pathogenic variants; however, germline DNA was not examined [ • Two pineoblastomas from children with a germline • Ninety-five percent of primary intracranial sarcomas in children [ • Multiple cases of nasal chondromesenchymal hamartoma. A systematic review of the literature identified 48 cases of NCMH [ • Thyroid nodules with indeterminate cytology and a spectrum of disease that spans the range from benign follicular adenomas to differentiated thyroid cancer and rarely poorly differentiated thyroid cancer [ ## Chapter Notes Websites with additional information about Dr Stewart's group at the National Cancer Institute is focused on the determination of The authors thank Dr John R Priest and Gretchen M Williams for their contributions to data collection used in this review. This work was supported in part by National Cancer Institute (NCI), NIH/NCI R01CA143167 (PI Hill), the Intramural Research Program of the NIH, Hyundai Hope on Wheels, Pine Tree Apple Tennis Classic, MF Schutt Foundation and Children's Minnesota Foundation, and St Baldrick's Foundation. Andrew J Bauer, MD (2014-present)Ann G Carr, MS, CGC (2014-present)Louis P Dehner, MD (2014-present)Leslie Doros, MD (2014-present)Amanda Field, MPH (2020-present)Anne K Harris, MPH (2020-present)D Ashley Hill, MD (2014-present)Laryssa A Huryn, MD (2020-present)Junne Kamihara, MD, PhD (2020-present)Melissa A Merideth, MD, MPH (2020-present)Yoav Messinger, MD (2014-present)Christopher T Rossi, MD; Children's National Medical Center (2014-2020)Kris Ann P Schultz, MD (2014-present)Douglas R Stewart, MD (2014-present)Pamela Stratton, MD (2020-present)Gretchen Williams, BS; Children's Hospitals and Clinics of Minnesota (2014-2020)Jiandong Yang, PhD; Children's National Medical Center (2014-2020) 30 April 2020 (sw) Comprehensive update posted live 24 April 2014 (me) Review posted live 23 July 2012 (dh/ym) Original submission • • • • 30 April 2020 (sw) Comprehensive update posted live • 24 April 2014 (me) Review posted live • 23 July 2012 (dh/ym) Original submission ## Author Notes Websites with additional information about Dr Stewart's group at the National Cancer Institute is focused on the determination of • • • ## Acknowledgments The authors thank Dr John R Priest and Gretchen M Williams for their contributions to data collection used in this review. This work was supported in part by National Cancer Institute (NCI), NIH/NCI R01CA143167 (PI Hill), the Intramural Research Program of the NIH, Hyundai Hope on Wheels, Pine Tree Apple Tennis Classic, MF Schutt Foundation and Children's Minnesota Foundation, and St Baldrick's Foundation. ## Author History Andrew J Bauer, MD (2014-present)Ann G Carr, MS, CGC (2014-present)Louis P Dehner, MD (2014-present)Leslie Doros, MD (2014-present)Amanda Field, MPH (2020-present)Anne K Harris, MPH (2020-present)D Ashley Hill, MD (2014-present)Laryssa A Huryn, MD (2020-present)Junne Kamihara, MD, PhD (2020-present)Melissa A Merideth, MD, MPH (2020-present)Yoav Messinger, MD (2014-present)Christopher T Rossi, MD; Children's National Medical Center (2014-2020)Kris Ann P Schultz, MD (2014-present)Douglas R Stewart, MD (2014-present)Pamela Stratton, MD (2020-present)Gretchen Williams, BS; Children's Hospitals and Clinics of Minnesota (2014-2020)Jiandong Yang, PhD; Children's National Medical Center (2014-2020) ## Revision History 30 April 2020 (sw) Comprehensive update posted live 24 April 2014 (me) Review posted live 23 July 2012 (dh/ym) Original submission • 30 April 2020 (sw) Comprehensive update posted live • 24 April 2014 (me) Review posted live • 23 July 2012 (dh/ym) Original submission ## References American Thyroid Association. Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules – 2016 Update. Endocr Pract. 2016;22:622-39. Available • American Thyroid Association. Thyroid Nodules and Differentiated Thyroid Cancer Guidelines • Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules – 2016 Update. Endocr Pract. 2016;22:622-39. Available ## Published Guidelines / Consensus Statements American Thyroid Association. Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules – 2016 Update. Endocr Pract. 2016;22:622-39. Available • American Thyroid Association. Thyroid Nodules and Differentiated Thyroid Cancer Guidelines • Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules – 2016 Update. Endocr Pract. 2016;22:622-39. Available ## Literature Cited	[]	24/4/2014	30/4/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
pph	pph	[ "Activin receptor type-1-like", "Bone morphogenetic protein receptor type-1B", "Bone morphogenetic protein receptor type-2", "Caveolin-1", "Endoglin", "Methylcytosine dioxygenase TET2", "Mothers against decapentaplegic homolog 9", "Potassium channel subfamily K member 3", "T-box transcription factor TBX4", "Vascular endothelial growth factor receptor 2", "ACVRL1", "BMPR1B", "BMPR2", "CAV1", "ENG", "KCNK3", "KDR", "SMAD9", "TBX4", "TET2", "Heritable Pulmonary Arterial Hypertension", "Overview" ]	Heritable Pulmonary Arterial Hypertension Overview	Eric D Austin, John A Phillips, James E Loyd	Summary The purpose of this overview is to: Describe the Review the Provide an Review a high-level view of Inform	## Clinical Characteristics of Heritable Pulmonary Arterial Hypertension Note: Pulmonary hypertension (PH) is a general designation for increased blood pressure in the lungs from any cause and is classified into five groups by the World Symposium of PH (WSPH) [ Confirmation of the presence of PAH (i.e., mean pulmonary artery pressure >20 mm Hg at rest during cardiac catheterization [ Exclusion of other known causes of PAH; see Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes known to be associated with HPAH ( Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making. Reference to "pathogenic variants" in this Clinical symptoms of HPAH include dyspnea, fatigue, chest pain, palpitation, syncope, or edema. HPAH affects all ages, including the very young and the elderly; the mean age at diagnosis is 34.9±14.9 years [ Females are twice as likely to be affected as males; survival is worse in males than in females [ The clinical course varies considerably, but untreated individuals gradually deteriorate, with a mean survival of 2.8 years after diagnosis. The variability in survival across individuals is broad, ranging from sudden death to decades (rare). The physiologic stress of pregnancy in an individual with HPAH is significant and maternal mortality is believed to be substantial, with risk variable according to pulmonary arterial pressure and right ventricular dysfunction [ Because the symptoms of HPAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. Some individuals report no symptoms, and diagnosis is suspected on an incidental basis because of signs (abnormal findings on physical examination) including: Accentuation of the pulmonic component of the second heart sound; Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation; Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course). The approach to the individual with suspected PAH has been carefully described by several international guidelines [ Once symptoms or signs concerning for PAH are identified on clinical exam, the following evaluations are recommended: Electrocardiogram Transthoracic echocardiogram Laboratory work to include complete blood count, comprehensive metabolic panel, brain natriuretic peptide, antinuclear antibody, Rh factor, HIV testing, and coagulation studies Computed tomography of the chest and likely a ventilation/perfusion scan and pulmonary function studies Ultimately, the diagnosis of PAH is formally made at the time of cardiac catheterization at rest, which is recommended for all individuals with suspected PAH. Specifically, cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities. Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy. Other cardiopulmonary causes of PH are far more common than PAH. Importantly, causes of PH associated with related conditions need to be excluded before the diagnosis of PAH can be established. Other causes of PH include connective tissue diseases, cirrhosis, HIV infection, treatment with appetite suppressants, and the following acquired and hereditary disorders [ • Confirmation of the presence of PAH (i.e., mean pulmonary artery pressure >20 mm Hg at rest during cardiac catheterization [ • Exclusion of other known causes of PAH; see • Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes known to be associated with HPAH ( • Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making. Reference to "pathogenic variants" in this • Accentuation of the pulmonic component of the second heart sound; • Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation; • Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course). • Electrocardiogram • Transthoracic echocardiogram • Laboratory work to include complete blood count, comprehensive metabolic panel, brain natriuretic peptide, antinuclear antibody, Rh factor, HIV testing, and coagulation studies • Computed tomography of the chest and likely a ventilation/perfusion scan and pulmonary function studies • Specifically, cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities. • Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy. ## Clinical Symptoms Clinical symptoms of HPAH include dyspnea, fatigue, chest pain, palpitation, syncope, or edema. HPAH affects all ages, including the very young and the elderly; the mean age at diagnosis is 34.9±14.9 years [ Females are twice as likely to be affected as males; survival is worse in males than in females [ The clinical course varies considerably, but untreated individuals gradually deteriorate, with a mean survival of 2.8 years after diagnosis. The variability in survival across individuals is broad, ranging from sudden death to decades (rare). The physiologic stress of pregnancy in an individual with HPAH is significant and maternal mortality is believed to be substantial, with risk variable according to pulmonary arterial pressure and right ventricular dysfunction [ ## Clinical Examination Because the symptoms of HPAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or being overweight. Some individuals report no symptoms, and diagnosis is suspected on an incidental basis because of signs (abnormal findings on physical examination) including: Accentuation of the pulmonic component of the second heart sound; Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation; Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course). • Accentuation of the pulmonic component of the second heart sound; • Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation; • Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course). ## Clinical Testing to Confirm PAH The approach to the individual with suspected PAH has been carefully described by several international guidelines [ Once symptoms or signs concerning for PAH are identified on clinical exam, the following evaluations are recommended: Electrocardiogram Transthoracic echocardiogram Laboratory work to include complete blood count, comprehensive metabolic panel, brain natriuretic peptide, antinuclear antibody, Rh factor, HIV testing, and coagulation studies Computed tomography of the chest and likely a ventilation/perfusion scan and pulmonary function studies Ultimately, the diagnosis of PAH is formally made at the time of cardiac catheterization at rest, which is recommended for all individuals with suspected PAH. Specifically, cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities. Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy. • Electrocardiogram • Transthoracic echocardiogram • Laboratory work to include complete blood count, comprehensive metabolic panel, brain natriuretic peptide, antinuclear antibody, Rh factor, HIV testing, and coagulation studies • Computed tomography of the chest and likely a ventilation/perfusion scan and pulmonary function studies • Specifically, cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities. • Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy. ## Differential Diagnosis of HPAH Other cardiopulmonary causes of PH are far more common than PAH. Importantly, causes of PH associated with related conditions need to be excluded before the diagnosis of PAH can be established. Other causes of PH include connective tissue diseases, cirrhosis, HIV infection, treatment with appetite suppressants, and the following acquired and hereditary disorders [ ## Genetic Causes of Heritable Pulmonary Arterial Hypertension To date, ten genes are convincingly known to be associated with heritable pulmonary arterial hypertension (HPAH), although more discoveries will likely emerge over the next few years. Of note: Heritable Pulmonary Arterial Hypertension (HPAH): Genes and Distinguishing Clinical Features Acromesomelic chrondrodysplasia w/genital anomalies (OMIM Brachydactyly (OMIM Congenital heart disease Fenfluramine-assoc pulmonary arterial hypertension (fen-PAH) Pulmonary venoocclusive disease (OMIM Congenital generalized lipodystrophy (OMIM Type 3 partial lipodystrophy, congenital cataracts, & neurodegeneration syndrome (OMIM Based on data from the Note: HPAH caused by pathogenic variants in the genes listed in Genes are listed alphabetically. Out of 2572 individuals with World Symposium of Pulmonary Hypertension (WSPH) Group 1 PAH Since the discovery of In a retrospective study, the records of all persons with a diagnosis of fen-PAH evaluated from 1986 to 2004 were studied. The median duration of fenfluramine exposure was six months, with a median of 4.5 years between exposure & onset of symptoms. Nine (22.5%) of the 40 persons evaluated had a • Acromesomelic chrondrodysplasia w/genital anomalies (OMIM • Brachydactyly (OMIM • Congenital heart disease • Fenfluramine-assoc pulmonary arterial hypertension (fen-PAH) • Pulmonary venoocclusive disease (OMIM • Congenital generalized lipodystrophy (OMIM • Type 3 partial lipodystrophy, congenital cataracts, & neurodegeneration syndrome (OMIM ## Evaluation Strategies to Identify the Genetic Cause of Heritable Pulmonary Arterial Hypertension in a Proband Establishing a specific genetic cause of heritable pulmonary arterial hypertension (HPAH): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, family history, and molecular genetic testing. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, family history, and molecular genetic testing. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management of Heritable Pulmonary Arterial Hypertension See Referral centers specializing in diagnosis and therapy of pulmonary arterial hypertension (PAH) are available across the US (see Pulmonary Hypertension Association Unprecedented approval of medications for PAH by the FDA in the last two decades has led to availability of a dozen therapies which all demonstrate some efficacy. However, substantial limitations remain: none of them cures the disease, nor is effective in all patients, nor stops or reverses the underlying pathogenesis (obstruction of the pulmonary arteries). The most effective among them, continuous IV prostacyclin or prostanoids, delivered by continuous IV or subcutaneous delivery, are the most complicated to administer as they require patient management of a pump for continuous infusion, with a myriad of possible problems, including sepsis related to chronic central venous catheters. Patient preference often dictates the route of medication administration (continuous IV or subcutaneous, aerosol, oral) or side effects determine which agents are personally acceptable. There are no different therapeutic approaches for pregnant women with PAH; standard PAH-directed care remains a crucial component of care in addition to high-risk obstetric approaches. Continuous patient monitoring for progression of disease and medication adjustment requires a dedicated multidisciplinary team that communicates seamlessly with multiple specialty pharmacies and insurers. ## Genetic Risk Assessment and Surveillance of At-Risk Relatives Clarification of the genetic status of first-degree family members of an individual with heritable pulmonary arterial hypertension (HPAH) can allow early detection of HPAH and prompt initiation of treatment and improve long-term outcome. A basic view of HPAH genetic risk assessment and surveillance for at-risk relatives is presented in this section; issues that may be specific to a given family or genetic cause of HPAH are not comprehensively addressed. Note: Given the complexity of the genetics and surveillance recommendations for HPAH, health care providers should consider referring at-risk asymptomatic relatives to a Pulmonary Hypertension Specialty Referral Center, or to a Cardiovascular Genetics Center or genetic counselor specializing in cardiac or cardiopulmonary genetics (see HPAH is inherited in an autosomal dominant manner. Some individuals diagnosed with HPAH have an affected parent. Some individuals diagnosed with HPAH have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case) and has a known HPAH-causing pathogenic variant, molecular genetic testing is recommended for the parents of the proband. If the proband has a known HPAH-associated pathogenic variant that is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. The family history of some individuals diagnosed with HPAH may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected and/or is known to have the HPAH-associated pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of the significant possibility of reduced penetrance of PAH in an individual who is heterozygous for a PAH-associated pathogenic variant (and the possibility that an individual's sex may influence penetrance), a sib who inherits the pathogenic variant identified in the proband may or may not develop clinically expressed PAH. For example, approximately 14% of males and 42% of females with a known If the proband has a known HPAH-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be approximately 1.3% or less because of the theoretic possibility of parental germline mosaicism [ If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a proband with a known PAH-associated pathogenic variant has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see Those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing HPAH should be screened each year with a clinical evaluation and echocardiogram [ Those without the familial HPAH-associated pathogenic variant are no longer considered to be at increased risk and thus may be discharged from cardiac surveillance. • Some individuals diagnosed with HPAH have an affected parent. • Some individuals diagnosed with HPAH have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case) and has a known HPAH-causing pathogenic variant, molecular genetic testing is recommended for the parents of the proband. • If the proband has a known HPAH-associated pathogenic variant that is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The family history of some individuals diagnosed with HPAH may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If a parent of the proband is affected and/or is known to have the HPAH-associated pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Because of the significant possibility of reduced penetrance of PAH in an individual who is heterozygous for a PAH-associated pathogenic variant (and the possibility that an individual's sex may influence penetrance), a sib who inherits the pathogenic variant identified in the proband may or may not develop clinically expressed PAH. For example, approximately 14% of males and 42% of females with a known • If the proband has a known HPAH-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be approximately 1.3% or less because of the theoretic possibility of parental germline mosaicism [ • If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a proband with a known PAH-associated pathogenic variant has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see • Those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing HPAH should be screened each year with a clinical evaluation and echocardiogram [ • Those without the familial HPAH-associated pathogenic variant are no longer considered to be at increased risk and thus may be discharged from cardiac surveillance. ## Mode of Inheritance HPAH is inherited in an autosomal dominant manner. ## Risk to Family Members Some individuals diagnosed with HPAH have an affected parent. Some individuals diagnosed with HPAH have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case) and has a known HPAH-causing pathogenic variant, molecular genetic testing is recommended for the parents of the proband. If the proband has a known HPAH-associated pathogenic variant that is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. The family history of some individuals diagnosed with HPAH may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). If a parent of the proband is affected and/or is known to have the HPAH-associated pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of the significant possibility of reduced penetrance of PAH in an individual who is heterozygous for a PAH-associated pathogenic variant (and the possibility that an individual's sex may influence penetrance), a sib who inherits the pathogenic variant identified in the proband may or may not develop clinically expressed PAH. For example, approximately 14% of males and 42% of females with a known If the proband has a known HPAH-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be approximately 1.3% or less because of the theoretic possibility of parental germline mosaicism [ If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a proband with a known PAH-associated pathogenic variant has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see • Some individuals diagnosed with HPAH have an affected parent. • Some individuals diagnosed with HPAH have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case) and has a known HPAH-causing pathogenic variant, molecular genetic testing is recommended for the parents of the proband. • If the proband has a known HPAH-associated pathogenic variant that is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The family history of some individuals diagnosed with HPAH may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband). • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If a parent of the proband is affected and/or is known to have the HPAH-associated pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Because of the significant possibility of reduced penetrance of PAH in an individual who is heterozygous for a PAH-associated pathogenic variant (and the possibility that an individual's sex may influence penetrance), a sib who inherits the pathogenic variant identified in the proband may or may not develop clinically expressed PAH. For example, approximately 14% of males and 42% of females with a known • If the proband has a known HPAH-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be approximately 1.3% or less because of the theoretic possibility of parental germline mosaicism [ • If the parents are clinically unaffected but their genetic status is unknown, the risk that a sib of a proband with a known PAH-associated pathogenic variant has inherited the pathogenic variant is assumed to be 50% for clinical screening purposes (see ## Clinical Surveillance for Relatives at Risk Those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing HPAH should be screened each year with a clinical evaluation and echocardiogram [ Those without the familial HPAH-associated pathogenic variant are no longer considered to be at increased risk and thus may be discharged from cardiac surveillance. • Those identified as heterozygous for the pathogenic variant present in the affected family member and thus at high risk for developing HPAH should be screened each year with a clinical evaluation and echocardiogram [ • Those without the familial HPAH-associated pathogenic variant are no longer considered to be at increased risk and thus may be discharged from cardiac surveillance. ## Resources • • • • • • • • • • ## Chapter Notes Genetic and genomic discovery efforts in PAH are rapidly progressing. Some sites of interest include the following: The authors – and the entire field – are indebted to the commitment and efforts of so many patients, families, and researchers who have propelled the genetics of PAH forward. While it is risky to list names for fear of omission, at a minimum we thank the following: The countless patients, families, and related individuals who graciously participate in genetic studies of PAH across the world Lisa Wheeler, former Coordinator of Familial PAH efforts at Vanderbilt The countless collaborative research teams who work tirelessly to study PAH across the world Sources of funding, including the National Institutes of Health, which has funded work at Vanderbilt for many years on this topic 23 December 2020 (ha) Comprehensive update posted live; scope changed to overview 11 June 2015 (me) Comprehensive update posted live 29 March 2011 (me) Comprehensive update posted live 18 July 2007 (me) Comprehensive update posted live 2 November 2004 (me) Comprehensive update posted live 18 July 2002 (me) Review posted live 14 January 2002 (jl) Original submission • • • • • The countless patients, families, and related individuals who graciously participate in genetic studies of PAH across the world • Lisa Wheeler, former Coordinator of Familial PAH efforts at Vanderbilt • The countless collaborative research teams who work tirelessly to study PAH across the world • Sources of funding, including the National Institutes of Health, which has funded work at Vanderbilt for many years on this topic • 23 December 2020 (ha) Comprehensive update posted live; scope changed to overview • 11 June 2015 (me) Comprehensive update posted live • 29 March 2011 (me) Comprehensive update posted live • 18 July 2007 (me) Comprehensive update posted live • 2 November 2004 (me) Comprehensive update posted live • 18 July 2002 (me) Review posted live • 14 January 2002 (jl) Original submission ## Author Notes Genetic and genomic discovery efforts in PAH are rapidly progressing. Some sites of interest include the following: • • • • ## Acknowledgments The authors – and the entire field – are indebted to the commitment and efforts of so many patients, families, and researchers who have propelled the genetics of PAH forward. While it is risky to list names for fear of omission, at a minimum we thank the following: The countless patients, families, and related individuals who graciously participate in genetic studies of PAH across the world Lisa Wheeler, former Coordinator of Familial PAH efforts at Vanderbilt The countless collaborative research teams who work tirelessly to study PAH across the world Sources of funding, including the National Institutes of Health, which has funded work at Vanderbilt for many years on this topic • The countless patients, families, and related individuals who graciously participate in genetic studies of PAH across the world • Lisa Wheeler, former Coordinator of Familial PAH efforts at Vanderbilt • The countless collaborative research teams who work tirelessly to study PAH across the world • Sources of funding, including the National Institutes of Health, which has funded work at Vanderbilt for many years on this topic ## Revision History 23 December 2020 (ha) Comprehensive update posted live; scope changed to overview 11 June 2015 (me) Comprehensive update posted live 29 March 2011 (me) Comprehensive update posted live 18 July 2007 (me) Comprehensive update posted live 2 November 2004 (me) Comprehensive update posted live 18 July 2002 (me) Review posted live 14 January 2002 (jl) Original submission • 23 December 2020 (ha) Comprehensive update posted live; scope changed to overview • 11 June 2015 (me) Comprehensive update posted live • 29 March 2011 (me) Comprehensive update posted live • 18 July 2007 (me) Comprehensive update posted live • 2 November 2004 (me) Comprehensive update posted live • 18 July 2002 (me) Review posted live • 14 January 2002 (jl) Original submission ## References ## Literature Cited	[]	18/7/2002	23/12/2020	20/12/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ppp1r12a-ubm	ppp1r12a-ubm	[ "Protein phosphatase 1 regulatory subunit 12A", "PPP1R12A", "PPP1R12A-Related Urogenital and/or Brain Malformation Syndrome" ]		Ebba Alkhunaizi, David Chitayat	Summary Individuals with The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Atypical external genitalia in individuals with a 46,XY chromosome complement, including: Normal female external genitalia Urogenital sinus abnormalities Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. Microcephaly or macrocephaly with variable degrees of developmental delay, intellectual disability, and/or autistic features Brain malformations (See Eye abnormalities such as strabismus, microphthalmia/anophthalmia Skeletal anomalies (e.g., unilateral or bilateral fifth-finger clinodactyly, syndactyly of the toes, kyphoscoliosis) Brain MRI imaging demonstrating: Alobar, semilobar, or middle interhemispheric variant holoprosencephaly Abnormalities of the corpus callosum Anencephaly Cortical dysplasia (polymicrogyria, heterotopia) Abdominal/pelvic ultrasound/MRI demonstrating: Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) Structural renal abnormalities including duplicated renal collecting system The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and imaging findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by brain malformations and/or undervirilization in a 46,XY individual, comprehensive genomic testing may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Fourteen additional individuals with contiguous gene deletions (not included in these calculations) have been reported in the literature [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Atypical external genitalia in individuals with a 46,XY chromosome complement, including: • Normal female external genitalia • Urogenital sinus abnormalities • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. • Normal female external genitalia • Urogenital sinus abnormalities • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. • Microcephaly or macrocephaly with variable degrees of developmental delay, intellectual disability, and/or autistic features • Brain malformations (See • Eye abnormalities such as strabismus, microphthalmia/anophthalmia • Skeletal anomalies (e.g., unilateral or bilateral fifth-finger clinodactyly, syndactyly of the toes, kyphoscoliosis) • Normal female external genitalia • Urogenital sinus abnormalities • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. • Brain MRI imaging demonstrating: • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly • Abnormalities of the corpus callosum • Anencephaly • Cortical dysplasia (polymicrogyria, heterotopia) • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly • Abnormalities of the corpus callosum • Anencephaly • Cortical dysplasia (polymicrogyria, heterotopia) • Abdominal/pelvic ultrasound/MRI demonstrating: • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) • Structural renal abnormalities including duplicated renal collecting system • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) • Structural renal abnormalities including duplicated renal collecting system • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly • Abnormalities of the corpus callosum • Anencephaly • Cortical dysplasia (polymicrogyria, heterotopia) • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) • Structural renal abnormalities including duplicated renal collecting system • For an introduction to multigene panels click ## Suggestive Findings Atypical external genitalia in individuals with a 46,XY chromosome complement, including: Normal female external genitalia Urogenital sinus abnormalities Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. Microcephaly or macrocephaly with variable degrees of developmental delay, intellectual disability, and/or autistic features Brain malformations (See Eye abnormalities such as strabismus, microphthalmia/anophthalmia Skeletal anomalies (e.g., unilateral or bilateral fifth-finger clinodactyly, syndactyly of the toes, kyphoscoliosis) Brain MRI imaging demonstrating: Alobar, semilobar, or middle interhemispheric variant holoprosencephaly Abnormalities of the corpus callosum Anencephaly Cortical dysplasia (polymicrogyria, heterotopia) Abdominal/pelvic ultrasound/MRI demonstrating: Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) Structural renal abnormalities including duplicated renal collecting system • Atypical external genitalia in individuals with a 46,XY chromosome complement, including: • Normal female external genitalia • Urogenital sinus abnormalities • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. • Normal female external genitalia • Urogenital sinus abnormalities • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. • Microcephaly or macrocephaly with variable degrees of developmental delay, intellectual disability, and/or autistic features • Brain malformations (See • Eye abnormalities such as strabismus, microphthalmia/anophthalmia • Skeletal anomalies (e.g., unilateral or bilateral fifth-finger clinodactyly, syndactyly of the toes, kyphoscoliosis) • Normal female external genitalia • Urogenital sinus abnormalities • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus. • Brain MRI imaging demonstrating: • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly • Abnormalities of the corpus callosum • Anencephaly • Cortical dysplasia (polymicrogyria, heterotopia) • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly • Abnormalities of the corpus callosum • Anencephaly • Cortical dysplasia (polymicrogyria, heterotopia) • Abdominal/pelvic ultrasound/MRI demonstrating: • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) • Structural renal abnormalities including duplicated renal collecting system • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) • Structural renal abnormalities including duplicated renal collecting system • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly • Abnormalities of the corpus callosum • Anencephaly • Cortical dysplasia (polymicrogyria, heterotopia) • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina) • Structural renal abnormalities including duplicated renal collecting system ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and imaging findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by brain malformations and/or undervirilization in a 46,XY individual, comprehensive genomic testing may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Fourteen additional individuals with contiguous gene deletions (not included in these calculations) have been reported in the literature [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click ## Option 1 When the phenotypic and imaging findings suggest the diagnosis of For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by brain malformations and/or undervirilization in a 46,XY individual, comprehensive genomic testing may be considered. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Fourteen additional individuals with contiguous gene deletions (not included in these calculations) have been reported in the literature [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Individuals with DSD = disorders/differences of sex development Atypical external genitalia in individuals with a 46,XY karyotype range from mild to severe undervirilization and can include: Micropenis Chordee Variable degrees of hypospadias Bifid and high insertion of the scrotum Urogenital sinus abnormalities Normal appearing female external genitalia Gonadal abnormalities can range from cryptorchidism to complete gonadal dysgenesis. Gonads may be dysgenetic. In the most severe cases, streak gonads have been found. Müllerian structures, including fallopian tubes, uterus, and upper part of the vagina, may be present. Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management, Feeding may worsen with intercurrent illnesses and with advancing age and size. In this scenario, gastrostomy tube placement may be considered. Individuals with low central tone frequently develop constipation. Growth abnormalities: microcephaly, macrocephaly, intrauterine growth restriction (IUGR), postnatal growth restriction/failure to thrive (FTT) and decreased subcutaneous fat Dysmorphic features including long face, facial asymmetry, arched eyebrows, widely-spaced eyes, hypotelorism/closely-spaced eyes, ptosis, long or short palpebral fissures, long eyelashes, epicanthal folds, short and upturned nose, micrognathia, large low-set and protruding ears, preauricular pit, earlobe creases, long philtrum Gastrointestinal: omphalocele; jejunal and ileal atresia with aberrant mesenteric blood supply Pyelectasis Patent ductus arteriosus No genotype-phenotype correlations have been identified. • Atypical external genitalia in individuals with a 46,XY karyotype range from mild to severe undervirilization and can include: • Micropenis • Chordee • Variable degrees of hypospadias • Bifid and high insertion of the scrotum • Urogenital sinus abnormalities • Normal appearing female external genitalia • Micropenis • Chordee • Variable degrees of hypospadias • Bifid and high insertion of the scrotum • Urogenital sinus abnormalities • Normal appearing female external genitalia • Gonadal abnormalities can range from cryptorchidism to complete gonadal dysgenesis. • Gonads may be dysgenetic. • In the most severe cases, streak gonads have been found. • Gonads may be dysgenetic. • In the most severe cases, streak gonads have been found. • Müllerian structures, including fallopian tubes, uterus, and upper part of the vagina, may be present. • Micropenis • Chordee • Variable degrees of hypospadias • Bifid and high insertion of the scrotum • Urogenital sinus abnormalities • Normal appearing female external genitalia • Gonads may be dysgenetic. • In the most severe cases, streak gonads have been found. • Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management, • Feeding may worsen with intercurrent illnesses and with advancing age and size. In this scenario, gastrostomy tube placement may be considered. • Individuals with low central tone frequently develop constipation. • Growth abnormalities: microcephaly, macrocephaly, intrauterine growth restriction (IUGR), postnatal growth restriction/failure to thrive (FTT) and decreased subcutaneous fat • Dysmorphic features including long face, facial asymmetry, arched eyebrows, widely-spaced eyes, hypotelorism/closely-spaced eyes, ptosis, long or short palpebral fissures, long eyelashes, epicanthal folds, short and upturned nose, micrognathia, large low-set and protruding ears, preauricular pit, earlobe creases, long philtrum • Gastrointestinal: omphalocele; jejunal and ileal atresia with aberrant mesenteric blood supply • Pyelectasis • Patent ductus arteriosus ## Clinical Description Individuals with DSD = disorders/differences of sex development Atypical external genitalia in individuals with a 46,XY karyotype range from mild to severe undervirilization and can include: Micropenis Chordee Variable degrees of hypospadias Bifid and high insertion of the scrotum Urogenital sinus abnormalities Normal appearing female external genitalia Gonadal abnormalities can range from cryptorchidism to complete gonadal dysgenesis. Gonads may be dysgenetic. In the most severe cases, streak gonads have been found. Müllerian structures, including fallopian tubes, uterus, and upper part of the vagina, may be present. Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management, Feeding may worsen with intercurrent illnesses and with advancing age and size. In this scenario, gastrostomy tube placement may be considered. Individuals with low central tone frequently develop constipation. Growth abnormalities: microcephaly, macrocephaly, intrauterine growth restriction (IUGR), postnatal growth restriction/failure to thrive (FTT) and decreased subcutaneous fat Dysmorphic features including long face, facial asymmetry, arched eyebrows, widely-spaced eyes, hypotelorism/closely-spaced eyes, ptosis, long or short palpebral fissures, long eyelashes, epicanthal folds, short and upturned nose, micrognathia, large low-set and protruding ears, preauricular pit, earlobe creases, long philtrum Gastrointestinal: omphalocele; jejunal and ileal atresia with aberrant mesenteric blood supply Pyelectasis Patent ductus arteriosus • Atypical external genitalia in individuals with a 46,XY karyotype range from mild to severe undervirilization and can include: • Micropenis • Chordee • Variable degrees of hypospadias • Bifid and high insertion of the scrotum • Urogenital sinus abnormalities • Normal appearing female external genitalia • Micropenis • Chordee • Variable degrees of hypospadias • Bifid and high insertion of the scrotum • Urogenital sinus abnormalities • Normal appearing female external genitalia • Gonadal abnormalities can range from cryptorchidism to complete gonadal dysgenesis. • Gonads may be dysgenetic. • In the most severe cases, streak gonads have been found. • Gonads may be dysgenetic. • In the most severe cases, streak gonads have been found. • Müllerian structures, including fallopian tubes, uterus, and upper part of the vagina, may be present. • Micropenis • Chordee • Variable degrees of hypospadias • Bifid and high insertion of the scrotum • Urogenital sinus abnormalities • Normal appearing female external genitalia • Gonads may be dysgenetic. • In the most severe cases, streak gonads have been found. • Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management, • Feeding may worsen with intercurrent illnesses and with advancing age and size. In this scenario, gastrostomy tube placement may be considered. • Individuals with low central tone frequently develop constipation. • Growth abnormalities: microcephaly, macrocephaly, intrauterine growth restriction (IUGR), postnatal growth restriction/failure to thrive (FTT) and decreased subcutaneous fat • Dysmorphic features including long face, facial asymmetry, arched eyebrows, widely-spaced eyes, hypotelorism/closely-spaced eyes, ptosis, long or short palpebral fissures, long eyelashes, epicanthal folds, short and upturned nose, micrognathia, large low-set and protruding ears, preauricular pit, earlobe creases, long philtrum • Gastrointestinal: omphalocele; jejunal and ileal atresia with aberrant mesenteric blood supply • Pyelectasis • Patent ductus arteriosus ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; GU = genitourinary; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked Other disorders to consider in the differential diagnosis of Trisomy 13 (holoprosencephaly, GU malformation) Pseudotrisomy 13 syndrome (OMIM • Trisomy 13 (holoprosencephaly, GU malformation) • Pseudotrisomy 13 syndrome (OMIM ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Attempt to palpate gonads in the scrotum/labioscrotal folds Inspection of scrotum / labioscrotal folds, phallic structure for length, breadth, chordee, foreskin, & location of urethral opening, labio/scrotal-anal distance Presence of vaginal dimple/introitus Assessment of labioscrotal folds for fusion, rugation, & pigmentation To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl eval of nutritional status & aspiration risk Consider eval for nasogastric or gastrostomy tube placement in those w/severe feeding issues, dysphagia, &/or aspiration risk. Consider eval for structural GI issues, if signs/symptoms are consistent w/obstruction. Community or Social work involvement for parental support; Home nursing referral. DSD = differences of sex development; FISH = fluorescence in situ hybridization; FTT = failure to thrive; GI = gastrointestinal; MOI = mode of inheritance Including but not limited to total testosterone, dihydrotestosterone, inhibin B, anti-müllerian hormone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) to assess for gonadal function Although hearing loss is not a primary feature of Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Consider gonadectomay in those w/dysgenetic gonads. In 46,XY undervirilized persons, referral to urologist or gynecologist for standard treatment of atypical genitalia/hypospadias, cryptorchidism, &/or urogenital sinus anomalies Standard treatment of hormonal issues at & after puberty, incl sex HRT Consider referral to endocrinologist for hormonal issues. Consider referral to psychologist or a multidisciplinary DSD clinic, if available. For further details on 46,XY DSD mgmt see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues or FTT. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications & supplies. Ensure psychological support for those w/gender identity concerns. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or DSD = differences of sex development; ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; GERD = gastroesophageal reflux disease; HRT = hormone replacement therapy; ID = intellectual disability; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor timing & progression of puberty & need for puberty induction & hormone replacement therapy. Assess for gender identity concerns. DSD = disorder/differences of sex development Routine follow up by an interdisciplinary DSD team (if available) including endocrinology, genetics, obstetrics/gynecology, psychology, and urology. See Search • Attempt to palpate gonads in the scrotum/labioscrotal folds • Inspection of scrotum / labioscrotal folds, phallic structure for length, breadth, chordee, foreskin, & location of urethral opening, labio/scrotal-anal distance • Presence of vaginal dimple/introitus • Assessment of labioscrotal folds for fusion, rugation, & pigmentation • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl eval of nutritional status & aspiration risk • Consider eval for nasogastric or gastrostomy tube placement in those w/severe feeding issues, dysphagia, &/or aspiration risk. • Consider eval for structural GI issues, if signs/symptoms are consistent w/obstruction. • Community or • Social work involvement for parental support; • Home nursing referral. • Consider gonadectomay in those w/dysgenetic gonads. • In 46,XY undervirilized persons, referral to urologist or gynecologist for standard treatment of atypical genitalia/hypospadias, cryptorchidism, &/or urogenital sinus anomalies • Standard treatment of hormonal issues at & after puberty, incl sex HRT • Consider referral to endocrinologist for hormonal issues. • Consider referral to psychologist or a multidisciplinary DSD clinic, if available. • For further details on 46,XY DSD mgmt see • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues or FTT. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications & supplies. • Ensure psychological support for those w/gender identity concerns. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor timing & progression of puberty & need for puberty induction & hormone replacement therapy. • Assess for gender identity concerns. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Attempt to palpate gonads in the scrotum/labioscrotal folds Inspection of scrotum / labioscrotal folds, phallic structure for length, breadth, chordee, foreskin, & location of urethral opening, labio/scrotal-anal distance Presence of vaginal dimple/introitus Assessment of labioscrotal folds for fusion, rugation, & pigmentation To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl eval of nutritional status & aspiration risk Consider eval for nasogastric or gastrostomy tube placement in those w/severe feeding issues, dysphagia, &/or aspiration risk. Consider eval for structural GI issues, if signs/symptoms are consistent w/obstruction. Community or Social work involvement for parental support; Home nursing referral. DSD = differences of sex development; FISH = fluorescence in situ hybridization; FTT = failure to thrive; GI = gastrointestinal; MOI = mode of inheritance Including but not limited to total testosterone, dihydrotestosterone, inhibin B, anti-müllerian hormone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) to assess for gonadal function Although hearing loss is not a primary feature of Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Attempt to palpate gonads in the scrotum/labioscrotal folds • Inspection of scrotum / labioscrotal folds, phallic structure for length, breadth, chordee, foreskin, & location of urethral opening, labio/scrotal-anal distance • Presence of vaginal dimple/introitus • Assessment of labioscrotal folds for fusion, rugation, & pigmentation • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl eval of nutritional status & aspiration risk • Consider eval for nasogastric or gastrostomy tube placement in those w/severe feeding issues, dysphagia, &/or aspiration risk. • Consider eval for structural GI issues, if signs/symptoms are consistent w/obstruction. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Consider gonadectomay in those w/dysgenetic gonads. In 46,XY undervirilized persons, referral to urologist or gynecologist for standard treatment of atypical genitalia/hypospadias, cryptorchidism, &/or urogenital sinus anomalies Standard treatment of hormonal issues at & after puberty, incl sex HRT Consider referral to endocrinologist for hormonal issues. Consider referral to psychologist or a multidisciplinary DSD clinic, if available. For further details on 46,XY DSD mgmt see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues or FTT. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications & supplies. Ensure psychological support for those w/gender identity concerns. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or DSD = differences of sex development; ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; GERD = gastroesophageal reflux disease; HRT = hormone replacement therapy; ID = intellectual disability; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Consider gonadectomay in those w/dysgenetic gonads. • In 46,XY undervirilized persons, referral to urologist or gynecologist for standard treatment of atypical genitalia/hypospadias, cryptorchidism, &/or urogenital sinus anomalies • Standard treatment of hormonal issues at & after puberty, incl sex HRT • Consider referral to endocrinologist for hormonal issues. • Consider referral to psychologist or a multidisciplinary DSD clinic, if available. • For further details on 46,XY DSD mgmt see • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues or FTT. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications & supplies. • Ensure psychological support for those w/gender identity concerns. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor timing & progression of puberty & need for puberty induction & hormone replacement therapy. Assess for gender identity concerns. DSD = disorder/differences of sex development Routine follow up by an interdisciplinary DSD team (if available) including endocrinology, genetics, obstetrics/gynecology, psychology, and urology. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor timing & progression of puberty & need for puberty induction & hormone replacement therapy. • Assess for gender identity concerns. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable counseling regarding recurrence risk and prenatal diagnosis options. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs for inheriting the pathogenic variant is 50%. If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable counseling regarding recurrence risk and prenatal diagnosis options. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs for inheriting the pathogenic variant is 50%. • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable counseling regarding recurrence risk and prenatal diagnosis options. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs for inheriting the pathogenic variant is 50%. If the • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable counseling regarding recurrence risk and prenatal diagnosis options. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs for inheriting the pathogenic variant is 50%. • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 1219 North Wittfield Street Indianapolis IN 46229 InterNational Council on Infertility Information Dissemination PO Box 5801 Bethesda MD 20824 • • • • • • 1219 North Wittfield Street • Indianapolis IN 46229 • • • • • InterNational Council on Infertility Information Dissemination • • • PO Box 5801 • Bethesda MD 20824 • • • ## Molecular Genetics PPP1R12A-Related Urogenital and/or Brain Malformation Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PPP1R12A-Related Urogenital and/or Brain Malformation Syndrome ( The number of copies of ## Molecular Pathogenesis ## Cancer and Benign Tumors The number of copies of ## Chapter Notes 7 March 2024 (ea) Revision: removed information regarding individuals with a 46,XX chromosome complement 9 September 2021 (ma) Review posted live 8 January 2021 (ea) Original submission • 7 March 2024 (ea) Revision: removed information regarding individuals with a 46,XX chromosome complement • 9 September 2021 (ma) Review posted live • 8 January 2021 (ea) Original submission ## Revision History 7 March 2024 (ea) Revision: removed information regarding individuals with a 46,XX chromosome complement 9 September 2021 (ma) Review posted live 8 January 2021 (ea) Original submission • 7 March 2024 (ea) Revision: removed information regarding individuals with a 46,XX chromosome complement • 9 September 2021 (ma) Review posted live • 8 January 2021 (ea) Original submission ## References ## Literature Cited	[]	9/9/2021		7/3/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ppp2r1a-ndd	ppp2r1a-ndd	[ "Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform", "PPP2R1A", "PPP2R1A-Related Neurodevelopmental Disorder" ]		Sofia Douzgou, Veerle Janssens, Gunnar Houge	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Mild-to-profound developmental delay and/or intellectual disability Delayed walking Language delay Generalized hypotonia, postnatal/infantile onset AND any of the following features presenting in infancy or childhood: Feeding problems Abnormal head circumference (macrocephaly/microcephaly) Epilepsy Behavioral problems: attention-deficit/hyperactivity disorder, autism spectrum disorder, self-injurious behavior, anxiety, destructive behaviors Joint hypermobility Partial or complete agenesis of the corpus callosum (common) Ventriculomegaly (frequent) Periventricular leukomalacia Delayed myelination Hypoplasia of the cerebellum and/or brain stem The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Fewer than 50 affected individuals with pathogenic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Only pathogenic missense variants with likely dominant-negative effects have so far been reported to cause • Mild-to-profound developmental delay and/or intellectual disability • Delayed walking • Language delay • Delayed walking • Language delay • Generalized hypotonia, postnatal/infantile onset • Delayed walking • Language delay • Feeding problems • Abnormal head circumference (macrocephaly/microcephaly) • Epilepsy • Behavioral problems: attention-deficit/hyperactivity disorder, autism spectrum disorder, self-injurious behavior, anxiety, destructive behaviors • Joint hypermobility • Partial or complete agenesis of the corpus callosum (common) • Ventriculomegaly (frequent) • Periventricular leukomalacia • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Mild-to-profound developmental delay and/or intellectual disability Delayed walking Language delay Generalized hypotonia, postnatal/infantile onset AND any of the following features presenting in infancy or childhood: Feeding problems Abnormal head circumference (macrocephaly/microcephaly) Epilepsy Behavioral problems: attention-deficit/hyperactivity disorder, autism spectrum disorder, self-injurious behavior, anxiety, destructive behaviors Joint hypermobility Partial or complete agenesis of the corpus callosum (common) Ventriculomegaly (frequent) Periventricular leukomalacia Delayed myelination Hypoplasia of the cerebellum and/or brain stem • Mild-to-profound developmental delay and/or intellectual disability • Delayed walking • Language delay • Delayed walking • Language delay • Generalized hypotonia, postnatal/infantile onset • Delayed walking • Language delay • Feeding problems • Abnormal head circumference (macrocephaly/microcephaly) • Epilepsy • Behavioral problems: attention-deficit/hyperactivity disorder, autism spectrum disorder, self-injurious behavior, anxiety, destructive behaviors • Joint hypermobility • Partial or complete agenesis of the corpus callosum (common) • Ventriculomegaly (frequent) • Periventricular leukomalacia • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Fewer than 50 affected individuals with pathogenic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Only pathogenic missense variants with likely dominant-negative effects have so far been reported to cause • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, fewer than 50 individuals have been identified with a pathogenic variant in Select Features of The most severely affected individuals are typically nonambulatory, and those who learned to walk did so between ages one and five years (average age ~2 years). Delayed/absent ambulation could be related to chronic hypotonia seen in most affected individuals. One individual did not have ID but had a full-scale IQ of 86 and a clinical diagnosis of autism spectrum disorder [ Language delays are similarly variable, ranging from individuals with no speech and language development to those with relatively normal verbal language skills, but on average language development is moderately to severely delayed. Individuals with microcephaly appear to be at an increased risk for developing epilepsy. Most individuals with epilepsy develop seizures within the first year of life. Seizure types and frequency are variable. In a few individuals, seizures are multifocal and refractory to treatment. The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. Some affected individuals have gastroesophageal reflux disease that requires treatment (see High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. The severity is variable, but some individuals need gastrostomy tube placement. Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see A range of In a number of individuals, ventriculomegaly was identified and may be associated with a specific pathogenic variant (see In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. Less frequent findings include: Delayed myelination Hypoplasia of the cerebellum and/or brain stem Periventricular leukomalacia Individuals with a heterozygous pathogenic variant that does not affect PPP2R1A binding to PPP2R2A (B55α) – for example, c.421T>A ( Macrocephaly, defined as head circumference >2 SD for age and sex Less severe intellectual disability No seizures Frontal bossing / long face Individuals with pathogenic missense variants that are more likely to cause severe epilepsy – for example, c.536C>T ( Microcephaly is most often associated with the following pathogenic missense variants: c.536C>T ( Most individuals with the pathogenic variants c.544C>T ( The prevalence of • The most severely affected individuals are typically nonambulatory, and those who learned to walk did so between ages one and five years (average age ~2 years). • Delayed/absent ambulation could be related to chronic hypotonia seen in most affected individuals. • One individual did not have ID but had a full-scale IQ of 86 and a clinical diagnosis of autism spectrum disorder [ • Individuals with microcephaly appear to be at an increased risk for developing epilepsy. • Most individuals with epilepsy develop seizures within the first year of life. • Seizure types and frequency are variable. • In a few individuals, seizures are multifocal and refractory to treatment. • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving • In a few individuals, seizures are multifocal and refractory to treatment. • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving • In a few individuals, seizures are multifocal and refractory to treatment. • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. • Some affected individuals have gastroesophageal reflux disease that requires treatment (see • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. • The severity is variable, but some individuals need gastrostomy tube placement. • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. • Some affected individuals have gastroesophageal reflux disease that requires treatment (see • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. • The severity is variable, but some individuals need gastrostomy tube placement. • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. • Some affected individuals have gastroesophageal reflux disease that requires treatment (see • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. • The severity is variable, but some individuals need gastrostomy tube placement. • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see • A range of • In a number of individuals, ventriculomegaly was identified and may be associated with a specific pathogenic variant (see • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. • Less frequent findings include: • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • Periventricular leukomalacia • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • Periventricular leukomalacia • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • Periventricular leukomalacia • Macrocephaly, defined as head circumference >2 SD for age and sex • Less severe intellectual disability • No seizures • Frontal bossing / long face ## Clinical Description To date, fewer than 50 individuals have been identified with a pathogenic variant in Select Features of The most severely affected individuals are typically nonambulatory, and those who learned to walk did so between ages one and five years (average age ~2 years). Delayed/absent ambulation could be related to chronic hypotonia seen in most affected individuals. One individual did not have ID but had a full-scale IQ of 86 and a clinical diagnosis of autism spectrum disorder [ Language delays are similarly variable, ranging from individuals with no speech and language development to those with relatively normal verbal language skills, but on average language development is moderately to severely delayed. Individuals with microcephaly appear to be at an increased risk for developing epilepsy. Most individuals with epilepsy develop seizures within the first year of life. Seizure types and frequency are variable. In a few individuals, seizures are multifocal and refractory to treatment. The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. Some affected individuals have gastroesophageal reflux disease that requires treatment (see High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. The severity is variable, but some individuals need gastrostomy tube placement. Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see A range of In a number of individuals, ventriculomegaly was identified and may be associated with a specific pathogenic variant (see In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. Less frequent findings include: Delayed myelination Hypoplasia of the cerebellum and/or brain stem Periventricular leukomalacia • The most severely affected individuals are typically nonambulatory, and those who learned to walk did so between ages one and five years (average age ~2 years). • Delayed/absent ambulation could be related to chronic hypotonia seen in most affected individuals. • One individual did not have ID but had a full-scale IQ of 86 and a clinical diagnosis of autism spectrum disorder [ • Individuals with microcephaly appear to be at an increased risk for developing epilepsy. • Most individuals with epilepsy develop seizures within the first year of life. • Seizure types and frequency are variable. • In a few individuals, seizures are multifocal and refractory to treatment. • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving • In a few individuals, seizures are multifocal and refractory to treatment. • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving • In a few individuals, seizures are multifocal and refractory to treatment. • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. • Some affected individuals have gastroesophageal reflux disease that requires treatment (see • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. • The severity is variable, but some individuals need gastrostomy tube placement. • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. • Some affected individuals have gastroesophageal reflux disease that requires treatment (see • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. • The severity is variable, but some individuals need gastrostomy tube placement. • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods. • Some affected individuals have gastroesophageal reflux disease that requires treatment (see • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties. • The severity is variable, but some individuals need gastrostomy tube placement. • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus. • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex. • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see • A range of • In a number of individuals, ventriculomegaly was identified and may be associated with a specific pathogenic variant (see • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. • Less frequent findings include: • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • Periventricular leukomalacia • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • Periventricular leukomalacia • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting. • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus. • Delayed myelination • Hypoplasia of the cerebellum and/or brain stem • Periventricular leukomalacia ## Genotype-Phenotype Correlations Individuals with a heterozygous pathogenic variant that does not affect PPP2R1A binding to PPP2R2A (B55α) – for example, c.421T>A ( Macrocephaly, defined as head circumference >2 SD for age and sex Less severe intellectual disability No seizures Frontal bossing / long face Individuals with pathogenic missense variants that are more likely to cause severe epilepsy – for example, c.536C>T ( Microcephaly is most often associated with the following pathogenic missense variants: c.536C>T ( Most individuals with the pathogenic variants c.544C>T ( • Macrocephaly, defined as head circumference >2 SD for age and sex • Less severe intellectual disability • No seizures • Frontal bossing / long face ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis See Selected Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MCAP = megalencephaly-capillary malformation; MOI = mode of inheritance; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus; NDD = neurodevelopmental disorder MCAP syndrome is not known to be inherited, as most identified pathogenic variants are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date. ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech/language evals Eval for early intervention / special education To incl eval of nutritional status & gastroesophageal reflux Consider eval for gastric tube placement in persons w/dysphagia &/or severe feeding issues. Gross motor & fine motor skills Scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; EEG = electroencephalogram; ENT = ears, nose, throat; MOI = mode of inheritance; MRI = magnetic resonance imaging; OT = occupational therapy; PDA = patent ductus arteriosus; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Some affected persons have epilepsy that is refractory to ASM therapy or may require multiple ASMs. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports. ASM = anti-seizure medication Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Monitor seizures as clinically indicated. Assess for new manifestations such as seizures & changes in muscle tone. Measure growth parameters. Evaluate nutritional status & safety of oral intake. Consider whether GERD may be a contributing issue. GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy See Search • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech/language evals • Eval for early intervention / special education • To incl eval of nutritional status & gastroesophageal reflux • Consider eval for gastric tube placement in persons w/dysphagia &/or severe feeding issues. • Gross motor & fine motor skills • Scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Some affected persons have epilepsy that is refractory to ASM therapy or may require multiple ASMs. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Monitor seizures as clinically indicated. • Assess for new manifestations such as seizures & changes in muscle tone. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Consider whether GERD may be a contributing issue. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech/language evals Eval for early intervention / special education To incl eval of nutritional status & gastroesophageal reflux Consider eval for gastric tube placement in persons w/dysphagia &/or severe feeding issues. Gross motor & fine motor skills Scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; EEG = electroencephalogram; ENT = ears, nose, throat; MOI = mode of inheritance; MRI = magnetic resonance imaging; OT = occupational therapy; PDA = patent ductus arteriosus; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech/language evals • Eval for early intervention / special education • To incl eval of nutritional status & gastroesophageal reflux • Consider eval for gastric tube placement in persons w/dysphagia &/or severe feeding issues. • Gross motor & fine motor skills • Scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Some affected persons have epilepsy that is refractory to ASM therapy or may require multiple ASMs. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports. ASM = anti-seizure medication Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Some affected persons have epilepsy that is refractory to ASM therapy or may require multiple ASMs. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Monitor seizures as clinically indicated. Assess for new manifestations such as seizures & changes in muscle tone. Measure growth parameters. Evaluate nutritional status & safety of oral intake. Consider whether GERD may be a contributing issue. GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy • Monitor seizures as clinically indicated. • Assess for new manifestations such as seizures & changes in muscle tone. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Consider whether GERD may be a contributing issue. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the If a parent of the proband is known to have the Each child of an individual with Individuals with The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If the • If a parent of the proband is known to have the • Each child of an individual with • Individuals with • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the If a parent of the proband is known to have the Each child of an individual with Individuals with • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If the • If a parent of the proband is known to have the • Each child of an individual with • Individuals with ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Speaking out for People with Intellectual and Developmental Disabilities • • • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics PPP2R1A-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PPP2R1A-Related Neurodevelopmental Disorder ( All known pathogenic variants causing The most important B-subunit for brain function appears to be the PP2A B56-delta subunit PPP2R5D, and pathogenic missense variants in this gene are the cause of a phenotypically overlapping condition, It should be noted that Notable ASD = autism spectrum diagnosis; ID = intellectual disability Variants listed in the table have been provided by the authors. Even though many of the ## Molecular Pathogenesis All known pathogenic variants causing The most important B-subunit for brain function appears to be the PP2A B56-delta subunit PPP2R5D, and pathogenic missense variants in this gene are the cause of a phenotypically overlapping condition, It should be noted that Notable ASD = autism spectrum diagnosis; ID = intellectual disability Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors Even though many of the ## Chapter Notes The first author is an international expert in clinical dysmorphology with a specific interest in overgrowth syndromes. The second author is a biochemist and the foremost authority on PP2A dysfunction in both intellectual disability and cancer. The last author is a professor of medical genetics with extensive knowledge of clinical dysmorphology, genetic variant interpretation, and basic biochemistry. The latter two authors first described 12 May 2022 (ma) Review posted live 3 January 2022 (gh) Original submission • 12 May 2022 (ma) Review posted live • 3 January 2022 (gh) Original submission ## Author Notes The first author is an international expert in clinical dysmorphology with a specific interest in overgrowth syndromes. The second author is a biochemist and the foremost authority on PP2A dysfunction in both intellectual disability and cancer. The last author is a professor of medical genetics with extensive knowledge of clinical dysmorphology, genetic variant interpretation, and basic biochemistry. The latter two authors first described ## Revision History 12 May 2022 (ma) Review posted live 3 January 2022 (gh) Original submission • 12 May 2022 (ma) Review posted live • 3 January 2022 (gh) Original submission ## References ## Literature Cited	[ "S Barbosa, S Greville-Heygate, M Bonnet, A Godwin, C Fagotto-Kaufmann, AV Kajava, D Laouteouet, R Mawby, HA Wai, AJM Dingemans, J Hehir-Kwa, M Willems, Y Capri, SG Mehta, H Cox, D Goudie, F Vansenne, P Turnpenny, M Vincent, B Cogné, G Lesca, J Hertecant, D Rodriguez, B Keren, L Burglen, M Gérard, A Putoux. C4RCD Research Group, Cantagrel V, Siquier-Pernet K, Rio M, Banka S, Sarkar A, Steeves M, Parker M, Clement E, Moutton S, Tran Mau-Them F, Piton A, de Vries BBA, Guille M, Debant A, Schmidt S, Baralle D. Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.. Am J Hum Genet. 2020;106:338-55", "DD Burkardt, K Tatton-Brown, W Dobyns, JM Graham. Approach to overgrowth syndromes in the genome era.. Am J Med Genet C Semin Med Genet. 2019;181:483-90", "G Houge, D Haesen, LE Vissers, S Mehta, MJ Parker, M Wright, J Vogt, S McKee, JL Tolmie, N Cordeiro, T Kleefstra, MH Willemsen, MR Reijnders, S Berland, E Hayman, E Lahat, EH Brilstra, KL van Gassen, E Zonneveld-Huijssoon, CI de Bie, A Hoischen, EE Eichler, R Holdhus, VM Steen, SO Døskeland, ME Hurles, DR FitzPatrick, V Janssens. B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.. J Clin Invest. 2015;125:3051-62", "L Lenaerts, S Reynhout, I Verbinnen, F Laumonnier, A Toutain, F Bonnet-Brilhault, Y Hoorne, S Joss, AK Chassevent, C Smith-Hicks, B Loeys, P Joset, K Steindl, A Rauch, SG Mehta, WK Chung, K Devriendt, SE Holder, T Jewett, LM Baldwin, WG Wilson, S Towner, S Srivastava, HF Johnson, C Daumer-Haas, M Baethmann, A Ruiz, E Gabau, V Jain, V Varghese, A Al-Beshri, S Fulton, O Wechsberg, N Orenstein, K Prescott, AM Childs, L Faivre, S Moutton, JA Sullivan, V Shashi, SM Koudijs, M Heijligers, E Kivuva, A McTague, A Male, Y van Ierland, B Plecko, I Maystadt, R Hamid, VL Hannig, G Houge, V Janssens. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.. Genet Med. 2021;23:352-62", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "MRF Reijnders, NM Ansor, M Kousi, WW Yue, PL Tan, K Clarkson, J Clayton-Smith, K Corning, JR Jones, WWK Lam, GMS Mancini, C Marcelis, S Mohammed, R Pfundt, M Roifman, R Cohn, D Chitayat, TH Millard, N Katsanis, HG Brunner, S Banka. RAC1 missense mutations in developmental disorders with diverse phenotypes.. Am J Hum Genet. 2017;101:466-77", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "K Tatton-Brown, C Loveday, S Yost, M Clarke, E Ramsay, A Zachariou, A Elliott, H Wylie, A Ardissone, O Rittinger, F Stewart, IK Temple, T Cole. Mahamdallie S, Seal S, Ruark E, Rahman N. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability.. Am J Hum Genet. 2017;100:725-36", "I Verbinnen, P Vaneynde, S Reynhout, L Lenaerts, R Derua, G Houge, V. Janssens. Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease.. Biochem Soc Trans. 2021;49:1567-88", "A Wallace, P Caruso, A. Karaa. A newborn with severe ventriculomegaly: expanding the. J Pediatr Genet. 2019;8:240-3", "Y Zhang, H Li, H Wang, Z Jia, H Xi, X. Mao. A de novo variant identified in the PPP2R1A gene in an infant induces neurodevelopmental abnormalities.. Neurosci Bull. 2020;36:179-82" ]	12/5/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ppp2r5d-dis	ppp2r5d-dis	[ "Jordan's Syndrome", "PPP2 Syndrome Type R5D", "PPP2 Syndrome Type R5D", "Jordan's Syndrome", "Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform", "PPP2R5D", "PPP2R5D-Related Neurodevelopmental Disorder" ]		Ghayda Mirzaa, Kimberly Foss, Khemika Sudnawa, Wendy K Chung	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Generalized hypotonia of infancy Mild-to-profound developmental delays and/or intellectual disability Autism spectrum disorder Macrocephaly Epilepsy (reported seizure types: generalized tonic-clonic, myoclonic, multifocal, complex partial, and generalized epileptic spasms) Early-onset parkinsonism Macrocephaly or megalencephaly Nonspecific findings including focal cortical abnormalities (n=2), cavum septum pellucidum et vergae (n=3), mesial temporal sclerosis (n=1), plagiocephaly (n=1), white matter abnormalities (n=3) and mild ventriculomegaly (n=5), hydrocephalus (n=2), small or dysplastic corpus callosum (n=2), and cavum septum pellucidum (n=1) The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of A For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Generalized hypotonia of infancy • Mild-to-profound developmental delays and/or intellectual disability • Autism spectrum disorder • Macrocephaly • Epilepsy (reported seizure types: generalized tonic-clonic, myoclonic, multifocal, complex partial, and generalized epileptic spasms) • Early-onset parkinsonism • Macrocephaly or megalencephaly • Nonspecific findings including focal cortical abnormalities (n=2), cavum septum pellucidum et vergae (n=3), mesial temporal sclerosis (n=1), plagiocephaly (n=1), white matter abnormalities (n=3) and mild ventriculomegaly (n=5), hydrocephalus (n=2), small or dysplastic corpus callosum (n=2), and cavum septum pellucidum (n=1) ## Suggestive Findings Generalized hypotonia of infancy Mild-to-profound developmental delays and/or intellectual disability Autism spectrum disorder Macrocephaly Epilepsy (reported seizure types: generalized tonic-clonic, myoclonic, multifocal, complex partial, and generalized epileptic spasms) Early-onset parkinsonism Macrocephaly or megalencephaly Nonspecific findings including focal cortical abnormalities (n=2), cavum septum pellucidum et vergae (n=3), mesial temporal sclerosis (n=1), plagiocephaly (n=1), white matter abnormalities (n=3) and mild ventriculomegaly (n=5), hydrocephalus (n=2), small or dysplastic corpus callosum (n=2), and cavum septum pellucidum (n=1) • Generalized hypotonia of infancy • Mild-to-profound developmental delays and/or intellectual disability • Autism spectrum disorder • Macrocephaly • Epilepsy (reported seizure types: generalized tonic-clonic, myoclonic, multifocal, complex partial, and generalized epileptic spasms) • Early-onset parkinsonism • Macrocephaly or megalencephaly • Nonspecific findings including focal cortical abnormalities (n=2), cavum septum pellucidum et vergae (n=3), mesial temporal sclerosis (n=1), plagiocephaly (n=1), white matter abnormalities (n=3) and mild ventriculomegaly (n=5), hydrocephalus (n=2), small or dysplastic corpus callosum (n=2), and cavum septum pellucidum (n=1) ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of A For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 A For an introduction to multigene panels click ## Option 2 When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics The age at which individuals walk independently varies widely, from age 18 months to nine years, with some individuals still unable to walk at age ten years. Most, but not all, individuals are able to achieve independent walking. Six individuals were reported to walk with an ataxic gait [ Almost all reported individuals had speech impairment, with a wide range of abilities. Seven individuals, ranging in age from two to 53 years, remained nonverbal. Eleven individuals were able to use words, although this ranged from two words with poor articulation at age ten years to 100-200 words and the ability to form short sentences at age 15 years. All individuals with Greater cognitive impairment has been seen in individuals with the Individuals with p.Glu200Lys have higher adaptive function compared to p.Glu198Lys and p.Glu420Lys [ Individuals with the Increased aggression was reported more often in individuals with p.Glu198Lys and p.Glu200Lys compared with individuals with pathogenic variants of amino acid residue 251 [ Individuals with p.Glu200Lys demonstrated increased oppositional behavior with age [ Seizures were commonly seen in those with pathogenic variant p.Glu198Lys (60.6%) [ All groups, except those with amino acid changes involving residue 251, had increased attention difficulties and hyperactivity [ The majority of the reported pathogenic variants are confirmed There is one report of reduced penetrance. A proband with developmental delay (speech and social) and normal head circumference had a maternally transmitted The prevalence of ## Clinical Description The age at which individuals walk independently varies widely, from age 18 months to nine years, with some individuals still unable to walk at age ten years. Most, but not all, individuals are able to achieve independent walking. Six individuals were reported to walk with an ataxic gait [ Almost all reported individuals had speech impairment, with a wide range of abilities. Seven individuals, ranging in age from two to 53 years, remained nonverbal. Eleven individuals were able to use words, although this ranged from two words with poor articulation at age ten years to 100-200 words and the ability to form short sentences at age 15 years. All individuals with ## Genotype-Phenotype Correlations Greater cognitive impairment has been seen in individuals with the Individuals with p.Glu200Lys have higher adaptive function compared to p.Glu198Lys and p.Glu420Lys [ Individuals with the Increased aggression was reported more often in individuals with p.Glu198Lys and p.Glu200Lys compared with individuals with pathogenic variants of amino acid residue 251 [ Individuals with p.Glu200Lys demonstrated increased oppositional behavior with age [ Seizures were commonly seen in those with pathogenic variant p.Glu198Lys (60.6%) [ All groups, except those with amino acid changes involving residue 251, had increased attention difficulties and hyperactivity [ ## Penetrance The majority of the reported pathogenic variants are confirmed There is one report of reduced penetrance. A proband with developmental delay (speech and social) and normal head circumference had a maternally transmitted ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Contiguous gene deletions and duplications of 6p21.1 that include Duplications including Deletions including • Duplications including • Deletions including ## Differential Diagnosis Genes of interest in the differential diagnosis of Disorders to Consider in the Differential Diagnosis of ID; speech & language disorders Autism spectrum disorder Seizures Obesity in adolescence & later in life Congenital anomalies such as low-set ears & syndactyly of toes DD/ID; expressive language or speech delay Epilepsy Hypotonia Megalencephaly Cortical brain malformations (particularly polymicrogyria) Polydactyly ID Macrocephaly Hypotonia Seizures Kyphoscoliosis Dysmorphic features such as thick, low-set eyebrows, narrow palpebral fissures, & prominent upper central incisors ↑ risk of AML Autistic-like features Hypotonia ID; severe expressive speech delay w/little speech development Seizures Distinctive facial features such as synophrys, arched eyebrows, protruding tongue, exaggerated Cupid's bow of vermilion of upper lip Microcephaly & brachycephaly Obesity Autism spectrum disorder Hypotonia ID Megalencephaly Cortical brain malformations (polymicrogyria, focal cortical dysplasia) Pigmentary abnormalities of skin DD/ID Overgrowth (head circumference ≥2 SD above mean) Additional congenital anomalies (e.g., cardiac, skeletal) Distinctive facial features incl high forehead, long, narrow face, & long chin ID Autistic features Seizures Hypotonia Megalencephaly Vascular malformations Somatic overgrowth (that can be focal) Lymphatic abnormalities Digital abnormalities (syndactyly, polydactyly) Cortical brain malformations (incl polymicrogyria) Macrocephaly Autism spectrum disorder DD Hamartomatous overgrowths of multiple tissues ↑ cancer predisposition AD = autosomal dominant; AML = acute myelogenous leukemia; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; Kleefstra syndrome is associated with either a heterozygous deletion at chromosome 9q34.3 that includes at least part of • ID; speech & language disorders • Autism spectrum disorder • Seizures • Obesity in adolescence & later in life • Congenital anomalies such as low-set ears & syndactyly of toes • DD/ID; expressive language or speech delay • Epilepsy • Hypotonia • Megalencephaly • Cortical brain malformations (particularly polymicrogyria) • Polydactyly • ID • Macrocephaly • Hypotonia • Seizures • Kyphoscoliosis • Dysmorphic features such as thick, low-set eyebrows, narrow palpebral fissures, & prominent upper central incisors • ↑ risk of AML • Autistic-like features • Hypotonia • ID; severe expressive speech delay w/little speech development • Seizures • Distinctive facial features such as synophrys, arched eyebrows, protruding tongue, exaggerated Cupid's bow of vermilion of upper lip • Microcephaly & brachycephaly • Obesity • Autism spectrum disorder • Hypotonia • ID • Megalencephaly • Cortical brain malformations (polymicrogyria, focal cortical dysplasia) • Pigmentary abnormalities of skin • DD/ID • Overgrowth (head circumference ≥2 SD above mean) • Additional congenital anomalies (e.g., cardiac, skeletal) • Distinctive facial features incl high forehead, long, narrow face, & long chin • ID • Autistic features • Seizures • Hypotonia • Megalencephaly • Vascular malformations • Somatic overgrowth (that can be focal) • Lymphatic abnormalities • Digital abnormalities (syndactyly, polydactyly) • Cortical brain malformations (incl polymicrogyria) • Macrocephaly • Autism spectrum disorder • DD • Hamartomatous overgrowths of multiple tissues • ↑ cancer predisposition ## Management Clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. In some children, seizures are well controlled using a single ASM or ketogenic diet. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; GERD = gastroesophageal reflux disease Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. • In some children, seizures are well controlled using a single ASM or ketogenic diet. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. In some children, seizures are well controlled using a single ASM or ketogenic diet. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; GERD = gastroesophageal reflux disease Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. • In some children, seizures are well controlled using a single ASM or ketogenic diet. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling To date, most individuals diagnosed with Rarely, an individual diagnosed with In one family, the proband had the disorder as the result of a In another family, transmission of a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced penetrance (reduced penetrance is rare and to date has only been described in a family segregating the c.1321C>T [p.Arg441Ter] pathogenic variant). Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * Theoretically, if the parent is the individual in whom the If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Parent-to-child transmission of a If the If the parents have not been tested for the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • To date, most individuals diagnosed with • Rarely, an individual diagnosed with • In one family, the proband had the disorder as the result of a • In another family, transmission of a • In one family, the proband had the disorder as the result of a • In another family, transmission of a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced penetrance (reduced penetrance is rare and to date has only been described in a family segregating the c.1321C>T [p.Arg441Ter] pathogenic variant). Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * Theoretically, if the parent is the individual in whom the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * Theoretically, if the parent is the individual in whom the • In one family, the proband had the disorder as the result of a • In another family, transmission of a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * Theoretically, if the parent is the individual in whom the • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Parent-to-child transmission of a • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members To date, most individuals diagnosed with Rarely, an individual diagnosed with In one family, the proband had the disorder as the result of a In another family, transmission of a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced penetrance (reduced penetrance is rare and to date has only been described in a family segregating the c.1321C>T [p.Arg441Ter] pathogenic variant). Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * Theoretically, if the parent is the individual in whom the If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Parent-to-child transmission of a If the If the parents have not been tested for the • To date, most individuals diagnosed with • Rarely, an individual diagnosed with • In one family, the proband had the disorder as the result of a • In another family, transmission of a • In one family, the proband had the disorder as the result of a • In another family, transmission of a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced penetrance (reduced penetrance is rare and to date has only been described in a family segregating the c.1321C>T [p.Arg441Ter] pathogenic variant). Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * Theoretically, if the parent is the individual in whom the • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * Theoretically, if the parent is the individual in whom the • In one family, the proband had the disorder as the result of a • In another family, transmission of a • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * Theoretically, if the parent is the individual in whom the • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Parent-to-child transmission of a • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics PPP2R5D-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PPP2R5D-Related Neurodevelopmental Disorder ( All known pathogenic variants to date are missense variants. Four variants ( Variants listed in the table have been provided by the author. ## Molecular Pathogenesis All known pathogenic variants to date are missense variants. Four variants ( Variants listed in the table have been provided by the author. ## Chapter Notes Dr Ghayda Mirzaa is a geneticist and researcher at the University of Washington and Seattle Children's Hospital. Her research program studies the underlying causes, natural history, and medical management of developmental brain disorders including brain growth disorders (macrocephaly and megalencephaly) and malformations of cortical development. Dr Wendy Chung is a medical and molecular geneticist at Boston Children's Hospital / Harvard Medical School and studies the genetic basis of autism neurodevelopmental disorders, congenital anomalies, and other conditions. Kimberly Foss, LGC, is a genetic counselor and associate professor at the University of North Carolina at Chapel Hill. She works on many research projects centered around population screening and neurogenetics. She also spends time in clinic with adult patients. Dr Khemika Sudnawa is a developmental-behavioral pediatrician at Phramongkutklao Hospital and Phramongkutklao College of Medicine. She previously served as a research fellow at Boston Children's Hospital / Harvard Medical School. Dr Sudnawa focuses on the developmental and behavioral aspects of various childhood neurodevelopmental disorders. We thank Wendy K Chung, MD, PhD (2019-present)Kimberly Foss, MS, CGC (2019-present)Ghayda Mirzaa, MD (2019-present)Mary Nattakom, BA; Columbia University (2019-2024)Khemika Sudnawa, MD (2025-present) 9 January 2025 (sw) Comprehensive update posted live 24 January 2019 (sw) Review posted live 7 September 2018 (kf) Original submission • 9 January 2025 (sw) Comprehensive update posted live • 24 January 2019 (sw) Review posted live • 7 September 2018 (kf) Original submission ## Author Notes Dr Ghayda Mirzaa is a geneticist and researcher at the University of Washington and Seattle Children's Hospital. Her research program studies the underlying causes, natural history, and medical management of developmental brain disorders including brain growth disorders (macrocephaly and megalencephaly) and malformations of cortical development. Dr Wendy Chung is a medical and molecular geneticist at Boston Children's Hospital / Harvard Medical School and studies the genetic basis of autism neurodevelopmental disorders, congenital anomalies, and other conditions. Kimberly Foss, LGC, is a genetic counselor and associate professor at the University of North Carolina at Chapel Hill. She works on many research projects centered around population screening and neurogenetics. She also spends time in clinic with adult patients. Dr Khemika Sudnawa is a developmental-behavioral pediatrician at Phramongkutklao Hospital and Phramongkutklao College of Medicine. She previously served as a research fellow at Boston Children's Hospital / Harvard Medical School. Dr Sudnawa focuses on the developmental and behavioral aspects of various childhood neurodevelopmental disorders. ## Acknowledgments We thank ## Author History Wendy K Chung, MD, PhD (2019-present)Kimberly Foss, MS, CGC (2019-present)Ghayda Mirzaa, MD (2019-present)Mary Nattakom, BA; Columbia University (2019-2024)Khemika Sudnawa, MD (2025-present) ## Revision History 9 January 2025 (sw) Comprehensive update posted live 24 January 2019 (sw) Review posted live 7 September 2018 (kf) Original submission • 9 January 2025 (sw) Comprehensive update posted live • 24 January 2019 (sw) Review posted live • 7 September 2018 (kf) Original submission ## References ## Literature Cited	[]	24/1/2019	9/1/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ppr-dysp	ppr-dysp	[ "Progressive Pseudorheumatoid Arthropathy of Childhood", "Spondyloepiphyseal Dysplasia Tarda with Progressive Arthropathy", "Progressive Pseudorheumatoid Arthropathy of Childhood", "Spondyloepiphyseal Dysplasia Tarda with Progressive Arthropathy", "Cellular communication network factor 6", "CCN6", "Progressive Pseudorheumatoid Dysplasia" ]	Progressive Pseudorheumatoid Dysplasia	Gandham SriLakshmi Bhavani, Hitesh Shah, Anju Shukla, Ashwin Dalal, Katta Mohan Girisha	Summary Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement in the absence of inflammation. Onset – typically between ages three and six years – begins with the involvement of the interphalangeal joints. Over time, involvement of large joints and the spine causes significant joint contractures, gait disturbance, and scoliosis and/or kyphosis, resulting in abnormal posture and significant morbidity. Despite the considerable arthropathy, pain is not a major presenting feature of this condition. Initially height is normal; however, short stature (<3rd centile) becomes evident in adolescence as the skeletal changes progress. The diagnosis of PPD is established in a proband with characteristic radiographic features and/or identification of biallelic pathogenic variants in PPD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus clinical diagnostic criteria for progressive pseudorheumatoid dysplasia (PPD) have been published. PPD Healthy at birth Onset of arthropathy early in childhood, usually between ages three and six years Enlargement of interphalangeal joints of hands ( Progressive restricted mobility of all joints Gait abnormalities Genu valgum / genu varum Progressive hip disease (commonly coxa vara at the late stage) Articular pain Motor weakness and fatigability Spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk Adult height below the third centile Absence of signs of inflammation The diagnosis of PPD Note: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in If only one or no pathogenic variant is found, sequence analysis of cDNA from peripheral blood or cultured skin fibroblasts may be performed to detect splicing aberrations resulting from intronic pathogenic variants [ Targeted analysis for pathogenic variants can include the following: For an introduction to multigene panels click When the diagnosis of PPD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Progressive Pseudorheumatoid Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Among the pathogenic variants were three intronic variant alleles identified by fibroblast cDNA sequence analysis; two of the three are deep intronic pathogenic variants [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A 9-kb deletion encompassing the 5′ untranslated region and exon 1 was reported in one family [ • Healthy at birth • Onset of arthropathy early in childhood, usually between ages three and six years • Enlargement of interphalangeal joints of hands ( • Progressive restricted mobility of all joints • Gait abnormalities • Genu valgum / genu varum • Progressive hip disease (commonly coxa vara at the late stage) • Articular pain • Motor weakness and fatigability • Spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk • Adult height below the third centile • Absence of signs of inflammation ## Suggestive Findings PPD Healthy at birth Onset of arthropathy early in childhood, usually between ages three and six years Enlargement of interphalangeal joints of hands ( Progressive restricted mobility of all joints Gait abnormalities Genu valgum / genu varum Progressive hip disease (commonly coxa vara at the late stage) Articular pain Motor weakness and fatigability Spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk Adult height below the third centile Absence of signs of inflammation • Healthy at birth • Onset of arthropathy early in childhood, usually between ages three and six years • Enlargement of interphalangeal joints of hands ( • Progressive restricted mobility of all joints • Gait abnormalities • Genu valgum / genu varum • Progressive hip disease (commonly coxa vara at the late stage) • Articular pain • Motor weakness and fatigability • Spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk • Adult height below the third centile • Absence of signs of inflammation ## Establishing the Diagnosis The diagnosis of PPD Note: Identification of biallelic Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in If only one or no pathogenic variant is found, sequence analysis of cDNA from peripheral blood or cultured skin fibroblasts may be performed to detect splicing aberrations resulting from intronic pathogenic variants [ Targeted analysis for pathogenic variants can include the following: For an introduction to multigene panels click When the diagnosis of PPD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Progressive Pseudorheumatoid Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Among the pathogenic variants were three intronic variant alleles identified by fibroblast cDNA sequence analysis; two of the three are deep intronic pathogenic variants [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A 9-kb deletion encompassing the 5′ untranslated region and exon 1 was reported in one family [ ## Option 1 If only one or no pathogenic variant is found, sequence analysis of cDNA from peripheral blood or cultured skin fibroblasts may be performed to detect splicing aberrations resulting from intronic pathogenic variants [ Targeted analysis for pathogenic variants can include the following: For an introduction to multigene panels click ## Option 2 When the diagnosis of PPD has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Progressive Pseudorheumatoid Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Among the pathogenic variants were three intronic variant alleles identified by fibroblast cDNA sequence analysis; two of the three are deep intronic pathogenic variants [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A 9-kb deletion encompassing the 5′ untranslated region and exon 1 was reported in one family [ ## Clinical Characteristics Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement, and the absence of signs of inflammation [ PPD does not have any extraskeletal manifestations, such as craniofacial features or cognitive involvement. To date, approximately 215 families with members affected with PPD have been identified with biallelic pathogenic variants in Progressive Pseudorheumatoid Dysplasia: Frequency of Select Features Initial presenting features in the majority are interphalangeal joint swelling, pain, and gait abnormalities. Joint deformities become manifest over time. Joint pain is rarely the presenting symptom and is disproportionately mild compared to the severity of arthropathy. The joint enlargement, stiffness, and restricted range of movement gradually involve all large joints (e.g., knees, hips, wrists, and elbows) [ No genotype-phenotype correlations have been observed. Mild variation in age of onset, severity, and progression noted in different families is not explained by the type of pathogenic variants or their locations. Intrafamilial variation has been observed [ The name "progressive PPD was previously referred to as "spondyloepiphyseal dysplasia with progressive arthropathy" or "progressive pseudorheumatoid chondrodysplasia." The prevalence of PPD has been estimated at one per million in the United Kingdom (prevalence category of <1-9:1,000,000) [ PPD is more frequent in communities with a high rate of consanguinity [ PPD has also been observed among populations with a high rate of consanguinity in Kuwait, Lebanon, Iran, Jordan, Saudi Arabia, Syria, Palestine, and Morocco. ## Clinical Description Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement, and the absence of signs of inflammation [ PPD does not have any extraskeletal manifestations, such as craniofacial features or cognitive involvement. To date, approximately 215 families with members affected with PPD have been identified with biallelic pathogenic variants in Progressive Pseudorheumatoid Dysplasia: Frequency of Select Features Initial presenting features in the majority are interphalangeal joint swelling, pain, and gait abnormalities. Joint deformities become manifest over time. Joint pain is rarely the presenting symptom and is disproportionately mild compared to the severity of arthropathy. The joint enlargement, stiffness, and restricted range of movement gradually involve all large joints (e.g., knees, hips, wrists, and elbows) [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been observed. Mild variation in age of onset, severity, and progression noted in different families is not explained by the type of pathogenic variants or their locations. Intrafamilial variation has been observed [ ## Nomenclature The name "progressive PPD was previously referred to as "spondyloepiphyseal dysplasia with progressive arthropathy" or "progressive pseudorheumatoid chondrodysplasia." ## Prevalence The prevalence of PPD has been estimated at one per million in the United Kingdom (prevalence category of <1-9:1,000,000) [ PPD is more frequent in communities with a high rate of consanguinity [ PPD has also been observed among populations with a high rate of consanguinity in Kuwait, Lebanon, Iran, Jordan, Saudi Arabia, Syria, Palestine, and Morocco. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Juvenile idiopathic arthritis and all skeletal dysplasias with epiphyseal and spondylar involvement are to be considered in the differential diagnosis of progressive pseudorheumatoid dysplasia (PPD). Joint inflammation (tenderness and warmth) in JIA Elevation of erythrocyte sedimentation rate and C-reactive protein levels in JIA and not in PPD. However, in some instances elevation of these acute reactants in JIA can be minimal. In JIA, joint destruction is seen on radiographs. In PPD, radiographs show dysplasia along with epiphyseal enlargement and platyspondyly. Genes of Interest in the Differential Diagnosis of Progressive Pseudorheumatoid Dysplasia AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; MPSs = mucopolysaccharidoses; PPD = progressive pseudorheumatoid dysplasia; XL = X-linked Czech dysplasia is typically associated with the See • Joint inflammation (tenderness and warmth) in JIA • Elevation of erythrocyte sedimentation rate and C-reactive protein levels in JIA and not in PPD. However, in some instances elevation of these acute reactants in JIA can be minimal. • In JIA, joint destruction is seen on radiographs. In PPD, radiographs show dysplasia along with epiphyseal enlargement and platyspondyly. ## Management To establish the extent of disease and needs in an individual diagnosed with progressive pseudorheumatoid dysplasia (PPD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Progressive Pseudorheumatoid Dysplasia Complete skeletal survey Referral to pediatric orthopedic surgeon or specialist in treating bone dysplasias MOI = mode of inheritance; PPD = progressive pseudorheumatoid dysplasia Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment is supportive. No specific therapy for PPD is available. Treatment of Manifestations in Individuals with Progressive Pseudorheumatoid Dysplasia Large-joint stiffness is managed by PT, activity modification, & walking aids. Small joint arthropathy is managed by OT, who may advise adaptive devices, modification of activity, &/or vocational training. NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapist; PT = physical therapist No specific guidelines for surveillance have been published. Recommended Surveillance for Individuals with Progressive Pseudorheumatoid Dysplasia Avoid immobilization (e.g., casting). See Deformities of pelvis may necessitate delivery by cæsarean section in pregnant women who have PPD. Search • Complete skeletal survey • Referral to pediatric orthopedic surgeon or specialist in treating bone dysplasias • Large-joint stiffness is managed by PT, activity modification, & walking aids. • Small joint arthropathy is managed by OT, who may advise adaptive devices, modification of activity, &/or vocational training. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with progressive pseudorheumatoid dysplasia (PPD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Progressive Pseudorheumatoid Dysplasia Complete skeletal survey Referral to pediatric orthopedic surgeon or specialist in treating bone dysplasias MOI = mode of inheritance; PPD = progressive pseudorheumatoid dysplasia Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Complete skeletal survey • Referral to pediatric orthopedic surgeon or specialist in treating bone dysplasias ## Treatment of Manifestations Treatment is supportive. No specific therapy for PPD is available. Treatment of Manifestations in Individuals with Progressive Pseudorheumatoid Dysplasia Large-joint stiffness is managed by PT, activity modification, & walking aids. Small joint arthropathy is managed by OT, who may advise adaptive devices, modification of activity, &/or vocational training. NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapist; PT = physical therapist • Large-joint stiffness is managed by PT, activity modification, & walking aids. • Small joint arthropathy is managed by OT, who may advise adaptive devices, modification of activity, &/or vocational training. ## Surveillance No specific guidelines for surveillance have been published. Recommended Surveillance for Individuals with Progressive Pseudorheumatoid Dysplasia ## Agents/Circumstances to Avoid Avoid immobilization (e.g., casting). ## Evaluation of Relatives at Risk See ## Pregnancy Management Deformities of pelvis may necessitate delivery by cæsarean section in pregnant women who have PPD. ## Therapies Under Investigation Search ## Genetic Counseling Progressive pseudorheumatoid dysplasia (PPD) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Mild-to-moderate intrafamilial clinical variability may be observed in sibs who inherit biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a • Mild-to-moderate intrafamilial clinical variability may be observed in sibs who inherit biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Progressive pseudorheumatoid dysplasia (PPD) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Mild-to-moderate intrafamilial clinical variability may be observed in sibs who inherit biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a • Mild-to-moderate intrafamilial clinical variability may be observed in sibs who inherit biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 1330 W. Peachtree Street Suite 100 Atlanta GA 30309 • • 1330 W. Peachtree Street • Suite 100 • Atlanta GA 30309 • • • • • ## Molecular Genetics Progressive Pseudorheumatoid Dysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Progressive Pseudorheumatoid Dysplasia ( Notable Variants listed in the table have been provided by the authors. Loss or downregulation of WISP-3 is associated with breast cancers, colorectal cancers, and hepatocellular carcinoma as reduction of WISP-3 stimulates tumorigenesis. The ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors Loss or downregulation of WISP-3 is associated with breast cancers, colorectal cancers, and hepatocellular carcinoma as reduction of WISP-3 stimulates tumorigenesis. The ## Chapter Notes Indian Council of Medical Research – Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects (BMS 54/2/2013) Department of Science and Technology – Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development (SB/SO/HS/005/2014) 23 December 2020 (sw) Comprehensive update posted live 25 November 2015 (me) Review posted live 30 June 2015 (kmg) Original submission • 23 December 2020 (sw) Comprehensive update posted live • 25 November 2015 (me) Review posted live • 30 June 2015 (kmg) Original submission ## Acknowledgments Indian Council of Medical Research – Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects (BMS 54/2/2013) Department of Science and Technology – Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development (SB/SO/HS/005/2014) ## Revision History 23 December 2020 (sw) Comprehensive update posted live 25 November 2015 (me) Review posted live 30 June 2015 (kmg) Original submission • 23 December 2020 (sw) Comprehensive update posted live • 25 November 2015 (me) Review posted live • 30 June 2015 (kmg) Original submission ## References ## Literature Cited Hands of individuals showing progressive swelling and limited range of movement of the interphalangeal joints A. Age 5 years B. Age 7 years C. Age 11 years D. Age 12 years E. Age 13 years F. Age 15 years G. Age 16 years H. Age 17 years I. Age 23 years Radiographs of hands showing large epiphyses and widened metaphyses of metacarpals and phalanges. Joint space is also reduced. A. Age 5 years B. Age 6 years C. Age 7 years D. Age 8 years E. Age 9 years F. Age 10 years G. Age 11 years H. Age 12 years I. Age 13 years J. Age 15 years K. Age 16 years L. Age 17 years M. Age 30 years N. Age 50 years Pelvic radiographs demonstrating reduced hip joint spaces, large capital femoral epiphyses, short and broad femoral necks, and irregular acetabular roofs. Iliac crests are also irregular in adolescence. A. Age 5 years B. Age 7 years C. Age 8 years D. Age 9 years E. Age 11 years F. Age 12 years G. Age 13 years H. Age 15 years I. Age 16 years J. Age 19 years K. Age 30 years L. Age 50 years Progressive platyspondyly due to erosion of the superior and inferior articular cartilages A. Age 5 years B. Age 7 years C. 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A homozygous deletion of exon 1 in WISP3 causes progressive pseudorheumatoid dysplasia in two siblings.. Hum Genome Var. 2015;2:15049", "D Pennica, TA Swanson, JW Welsh, MA Roy, DA Lawrence, J Lee, J Brush, LA Taneyhill, B Deuel, M Lew, C Watanabe, RL Cohen, MF Melhem, GG Finley, P Quirke, AD Goddard, KJ Hillan, AL Gurney, D Botstein, AJ Levine. WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.. Proc Natl Acad Sci U S A. 1998;95:14717-22", "M Sen, YH Cheng, MB Goldring, MK Lotz, DA Carson. WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes.. Arthritis Rheum. 2004;50:488-97", "PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. 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primrose	primrose	[ "Zinc finger and BTB domain-containing protein 20", "ZBTB20", "Primrose Syndrome" ]	Primrose Syndrome	Veronica Arora, Carlos R Ferreira, Ratna Dua Puri, Ishwar Chandar Verma	Summary Primrose syndrome is characterized by macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, a recognizable facial phenotype, radiographic features, and altered glucose metabolism. Additional features seen in adults: sparse body hair, distal muscle wasting, and contractures. Characteristic craniofacial features include brachycephaly, high anterior hairline, deeply set eyes, ptosis, downslanted palpebral fissures, high palate with torus palatinus, broad jaw, and large ears with small or absent lobes. Radiographic features include calcification of the external ear cartilage, multiple wormian bones, platybasia, bathrocephaly, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Additional features include hearing impairment, ocular anomalies, cryptorchidism, and nonspecific findings on brain MRI. The diagnosis of Primrose syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in Primrose syndrome is an autosomal dominant disorder. All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a	## Diagnosis No consensus clinical diagnostic criteria for Primrose syndrome have been published. Primrose syndrome Developmental delay with speech delay Intellectual disability Behavioral issues (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder) Typically postnatal-onset macrocephaly (macrocephaly at birth in <50%) Characteristic craniofacial features (brachycephaly, high anterior hairline, sparse eyebrows, deeply set eyes, downslanted palpebral fissures, ptosis, high palate, torus palatinus, broad jaw, and large ears with small or absent lobes; see Hearing loss Ocular anomalies (e.g., cataracts, strabismus, glaucoma) Cryptorchidism Distal muscle atrophy and contractures Sparse body hair Abnormal plasma acylcarnitine profile (increased levels of C2, C4OH, C5OH, C6OH, C14, and C14:2). Abnormal urine organic acids (mildly elevated dicarboxylic acids (adipic, sebacic, and/or suberic acid); elevated ethylmalonic acid and glutaric acid) Abnormal glucose metabolic profile (e.g., elevated fasting glucose, hemoglobin A1c, and glucose levels on oral glucose tolerance testing) Increased serum alphafeto protein levels Calcification of the external ear cartilage on head CT; cerebral calcification (mainly of the basal ganglia) may also occur. Radiographs show unique skeletal manifestations: multiple wormian bones, platybasia, bathrocephaly, bitemporal bossing, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Brain MRI may show agenesis/dysgenesis of the corpus callosum, mild cerebral atrophy, and delayed myelination. The diagnosis of Primrose syndrome Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic, laboratory, and imaging findings suggest the diagnosis of Primrose syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay and macrocephaly, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primrose Syndrome See See Additional individuals [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by No data on detection rate of gene-targeted deletion/duplication analysis are available. • Developmental delay with speech delay • Intellectual disability • Behavioral issues (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder) • Typically postnatal-onset macrocephaly (macrocephaly at birth in <50%) • Characteristic craniofacial features (brachycephaly, high anterior hairline, sparse eyebrows, deeply set eyes, downslanted palpebral fissures, ptosis, high palate, torus palatinus, broad jaw, and large ears with small or absent lobes; see • Hearing loss • Ocular anomalies (e.g., cataracts, strabismus, glaucoma) • Cryptorchidism • Distal muscle atrophy and contractures • Sparse body hair • Abnormal plasma acylcarnitine profile (increased levels of C2, C4OH, C5OH, C6OH, C14, and C14:2). • Abnormal urine organic acids (mildly elevated dicarboxylic acids (adipic, sebacic, and/or suberic acid); elevated ethylmalonic acid and glutaric acid) • Abnormal glucose metabolic profile (e.g., elevated fasting glucose, hemoglobin A1c, and glucose levels on oral glucose tolerance testing) • Increased serum alphafeto protein levels • Calcification of the external ear cartilage on head CT; cerebral calcification (mainly of the basal ganglia) may also occur. • Radiographs show unique skeletal manifestations: multiple wormian bones, platybasia, bathrocephaly, bitemporal bossing, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. • Brain MRI may show agenesis/dysgenesis of the corpus callosum, mild cerebral atrophy, and delayed myelination. • For an introduction to multigene panels click ## Suggestive Findings Primrose syndrome Developmental delay with speech delay Intellectual disability Behavioral issues (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder) Typically postnatal-onset macrocephaly (macrocephaly at birth in <50%) Characteristic craniofacial features (brachycephaly, high anterior hairline, sparse eyebrows, deeply set eyes, downslanted palpebral fissures, ptosis, high palate, torus palatinus, broad jaw, and large ears with small or absent lobes; see Hearing loss Ocular anomalies (e.g., cataracts, strabismus, glaucoma) Cryptorchidism Distal muscle atrophy and contractures Sparse body hair Abnormal plasma acylcarnitine profile (increased levels of C2, C4OH, C5OH, C6OH, C14, and C14:2). Abnormal urine organic acids (mildly elevated dicarboxylic acids (adipic, sebacic, and/or suberic acid); elevated ethylmalonic acid and glutaric acid) Abnormal glucose metabolic profile (e.g., elevated fasting glucose, hemoglobin A1c, and glucose levels on oral glucose tolerance testing) Increased serum alphafeto protein levels Calcification of the external ear cartilage on head CT; cerebral calcification (mainly of the basal ganglia) may also occur. Radiographs show unique skeletal manifestations: multiple wormian bones, platybasia, bathrocephaly, bitemporal bossing, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Brain MRI may show agenesis/dysgenesis of the corpus callosum, mild cerebral atrophy, and delayed myelination. • Developmental delay with speech delay • Intellectual disability • Behavioral issues (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder) • Typically postnatal-onset macrocephaly (macrocephaly at birth in <50%) • Characteristic craniofacial features (brachycephaly, high anterior hairline, sparse eyebrows, deeply set eyes, downslanted palpebral fissures, ptosis, high palate, torus palatinus, broad jaw, and large ears with small or absent lobes; see • Hearing loss • Ocular anomalies (e.g., cataracts, strabismus, glaucoma) • Cryptorchidism • Distal muscle atrophy and contractures • Sparse body hair • Abnormal plasma acylcarnitine profile (increased levels of C2, C4OH, C5OH, C6OH, C14, and C14:2). • Abnormal urine organic acids (mildly elevated dicarboxylic acids (adipic, sebacic, and/or suberic acid); elevated ethylmalonic acid and glutaric acid) • Abnormal glucose metabolic profile (e.g., elevated fasting glucose, hemoglobin A1c, and glucose levels on oral glucose tolerance testing) • Increased serum alphafeto protein levels • Calcification of the external ear cartilage on head CT; cerebral calcification (mainly of the basal ganglia) may also occur. • Radiographs show unique skeletal manifestations: multiple wormian bones, platybasia, bathrocephaly, bitemporal bossing, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. • Brain MRI may show agenesis/dysgenesis of the corpus callosum, mild cerebral atrophy, and delayed myelination. ## Establishing the Diagnosis The diagnosis of Primrose syndrome Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic, laboratory, and imaging findings suggest the diagnosis of Primrose syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay and macrocephaly, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primrose Syndrome See See Additional individuals [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click ## Option 1 When the phenotypic, laboratory, and imaging findings suggest the diagnosis of Primrose syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay and macrocephaly, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Primrose Syndrome See See Additional individuals [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Primrose syndrome is a rare disorder characterized by macrocephaly with developmental delay, intellectual disability, behavioral issues, a recognizable facial phenotype, altered glucose metabolism, hearing loss, ocular anomalies, cryptorchidism, and unique imaging findings including calcification of the ear cartilage [ To date, 52 individuals have been identified with a pathogenic variant in Primrose Syndrome: Frequency of Select Features The majority of affected individuals have macrocephaly. Head circumference >+2SD at birth was seen in 9/22 newborns, 21/26 children (81%), and 8/12 adults (67%). Individuals with Primrose syndrome have disrupted glucose metabolism and may develop diabetes mellitus requiring oral hypoglycemics and/or insulin therapy in adulthood. Rarely, congenital hypothyroidism has been reported [ Growth hormone deficiency (2 individuals) Delayed puberty (average onset of puberty: age 16 years) Sparse body hair is present in both males and females Pulmonary artery stenosis was described in an adult [ IgG2 deficiency with recurrent otitis media and testicular cancer was diagnosed at age 27 years in one individual [ No genotype-phenotype correlations have been identified. The penetrance is 100%. The authors of this To date, approximately 52 individuals with Primrose syndrome have been identified. • Individuals with Primrose syndrome have disrupted glucose metabolism and may develop diabetes mellitus requiring oral hypoglycemics and/or insulin therapy in adulthood. • Rarely, congenital hypothyroidism has been reported [ • Growth hormone deficiency (2 individuals) • Delayed puberty (average onset of puberty: age 16 years) • Sparse body hair is present in both males and females • Pulmonary artery stenosis was described in an adult [ • IgG2 deficiency with recurrent otitis media and testicular cancer was diagnosed at age 27 years in one individual [ ## Clinical Description Primrose syndrome is a rare disorder characterized by macrocephaly with developmental delay, intellectual disability, behavioral issues, a recognizable facial phenotype, altered glucose metabolism, hearing loss, ocular anomalies, cryptorchidism, and unique imaging findings including calcification of the ear cartilage [ To date, 52 individuals have been identified with a pathogenic variant in Primrose Syndrome: Frequency of Select Features The majority of affected individuals have macrocephaly. Head circumference >+2SD at birth was seen in 9/22 newborns, 21/26 children (81%), and 8/12 adults (67%). Individuals with Primrose syndrome have disrupted glucose metabolism and may develop diabetes mellitus requiring oral hypoglycemics and/or insulin therapy in adulthood. Rarely, congenital hypothyroidism has been reported [ Growth hormone deficiency (2 individuals) Delayed puberty (average onset of puberty: age 16 years) Sparse body hair is present in both males and females Pulmonary artery stenosis was described in an adult [ IgG2 deficiency with recurrent otitis media and testicular cancer was diagnosed at age 27 years in one individual [ • Individuals with Primrose syndrome have disrupted glucose metabolism and may develop diabetes mellitus requiring oral hypoglycemics and/or insulin therapy in adulthood. • Rarely, congenital hypothyroidism has been reported [ • Growth hormone deficiency (2 individuals) • Delayed puberty (average onset of puberty: age 16 years) • Sparse body hair is present in both males and females • Pulmonary artery stenosis was described in an adult [ • IgG2 deficiency with recurrent otitis media and testicular cancer was diagnosed at age 27 years in one individual [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance The penetrance is 100%. ## Nomenclature The authors of this ## Prevalence To date, approximately 52 individuals with Primrose syndrome have been identified. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this 3q13.31 contiguous deletions that include ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Primrose Syndrome AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; PDA = patent ductus arteriosus; XL = X-linked Contiguous gene deletion involving Phelan-McDermid syndrome, caused by a deletion of 22q13.3 that includes at least a part of ## Management No clinical practice guidelines for Primrose syndrome have been published. To establish the extent of disease and needs in an individual diagnosed with Primrose syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Primrose Syndrome To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl brain MRI Consider EEG if seizures are a concern. Blood glucose level incl fasting & post-prandial Hemoglobin A1c Oral glucose tolerance test Serum TSH & free T4 Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with Primrose Syndrome Developmental preschool w/IEP Speech therapy, PT, &/or OT for speech & motor delays Consultation w/a developmental pediatrician to ensure involvement of appropriate community, state, & educational agencies & to support parents in maximizing quality of life Developmental pediatricians can provide assistance w/transition to adulthood. Continue IEP & therapies w/modifications as needed. Discussion of transition plans incl financial, vocation/employment, & medical arrangements should begin at age 12 yrs. Supportive therapies as needed Aggressive, hyperactive & destructive behaviors should be managed by child developmental team & child psychiatrist. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; IEP = individualized education program; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Surveillance for Individuals with Primrose Syndrome Developmental assessment Monitor educational needs. Fasting & postprandial blood glucose Hemoglobin A1c Assess for signs/symptoms of thyroid dysfunction. OT = occupational therapy; PT = physical therapy See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl brain MRI • Consider EEG if seizures are a concern. • Blood glucose level incl fasting & post-prandial • Hemoglobin A1c • Oral glucose tolerance test • Serum TSH & free T4 • Community or • Social work involvement for parental support; • Home nursing referral. • Developmental preschool w/IEP • Speech therapy, PT, &/or OT for speech & motor delays • Consultation w/a developmental pediatrician to ensure involvement of appropriate community, state, & educational agencies & to support parents in maximizing quality of life • Developmental pediatricians can provide assistance w/transition to adulthood. • Continue IEP & therapies w/modifications as needed. • Discussion of transition plans incl financial, vocation/employment, & medical arrangements should begin at age 12 yrs. • Supportive therapies as needed • Aggressive, hyperactive & destructive behaviors should be managed by child developmental team & child psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Developmental assessment • Monitor educational needs. • Fasting & postprandial blood glucose • Hemoglobin A1c • Assess for signs/symptoms of thyroid dysfunction. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Primrose syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Primrose Syndrome To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl brain MRI Consider EEG if seizures are a concern. Blood glucose level incl fasting & post-prandial Hemoglobin A1c Oral glucose tolerance test Serum TSH & free T4 Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl brain MRI • Consider EEG if seizures are a concern. • Blood glucose level incl fasting & post-prandial • Hemoglobin A1c • Oral glucose tolerance test • Serum TSH & free T4 • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Primrose Syndrome Developmental preschool w/IEP Speech therapy, PT, &/or OT for speech & motor delays Consultation w/a developmental pediatrician to ensure involvement of appropriate community, state, & educational agencies & to support parents in maximizing quality of life Developmental pediatricians can provide assistance w/transition to adulthood. Continue IEP & therapies w/modifications as needed. Discussion of transition plans incl financial, vocation/employment, & medical arrangements should begin at age 12 yrs. Supportive therapies as needed Aggressive, hyperactive & destructive behaviors should be managed by child developmental team & child psychiatrist. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; IEP = individualized education program; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • Developmental preschool w/IEP • Speech therapy, PT, &/or OT for speech & motor delays • Consultation w/a developmental pediatrician to ensure involvement of appropriate community, state, & educational agencies & to support parents in maximizing quality of life • Developmental pediatricians can provide assistance w/transition to adulthood. • Continue IEP & therapies w/modifications as needed. • Discussion of transition plans incl financial, vocation/employment, & medical arrangements should begin at age 12 yrs. • Supportive therapies as needed • Aggressive, hyperactive & destructive behaviors should be managed by child developmental team & child psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers ## Surveillance Recommended Surveillance for Individuals with Primrose Syndrome Developmental assessment Monitor educational needs. Fasting & postprandial blood glucose Hemoglobin A1c Assess for signs/symptoms of thyroid dysfunction. OT = occupational therapy; PT = physical therapy • Developmental assessment • Monitor educational needs. • Fasting & postprandial blood glucose • Hemoglobin A1c • Assess for signs/symptoms of thyroid dysfunction. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Primrose syndrome is an autosomal dominant disorder. All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If a parent of the proband is known to have the If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance Primrose syndrome is an autosomal dominant disorder. ## Risk to Family Members All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If a parent of the proband is known to have the If the • All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Primrose Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Primrose Syndrome ( Primrose syndrome is caused by functional dysregulation of ## Molecular Pathogenesis Primrose syndrome is caused by functional dysregulation of ## Chapter Notes Dr Veronica Arora, Associate consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India Dr Carlos R Ferreira, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Dr Ratna Dua Puri, Chairperson and Senior consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India Dr Ishwar Chander Verma, Advisor, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India 17 June 2021 (ma) Revision: modifications to 6 May 2021 (sw) Review posted live 1 February 2021 (crf) Original submission • 17 June 2021 (ma) Revision: modifications to • 6 May 2021 (sw) Review posted live • 1 February 2021 (crf) Original submission ## Author Notes Dr Veronica Arora, Associate consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India Dr Carlos R Ferreira, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Dr Ratna Dua Puri, Chairperson and Senior consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India Dr Ishwar Chander Verma, Advisor, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India ## Revision History 17 June 2021 (ma) Revision: modifications to 6 May 2021 (sw) Review posted live 1 February 2021 (crf) Original submission • 17 June 2021 (ma) Revision: modifications to • 6 May 2021 (sw) Review posted live • 1 February 2021 (crf) Original submission ## Literature Cited ## References Male age two years with Primrose syndrome Note macrocephaly, high anterior hairline, sparse eyebrows, deeply set eyes, large prominent ears, and genu valgum. Modified from	[ "V Arora, E Leon, J Diaz, HB Hove, DR Carvalho, K Kurosawa, N Nishimura, G Nishimura, R Saxena, C Ferreira, RD Puri, IC Verma. Unique skeletal manifestations in patients with Primrose syndrome.. Eur J Med Genet. 2020;63", "C Battisti, MT Dotti, A Cerase, A Rufa, F Sicurelli, C Scarpini, A Federico. The Primrose syndrome with progressive neurological involvement and cerebral calcification.. J Neurol. 2002;249:1466-8", "DR Carvalho, CE Speck-Martins. Additional features of unique Primrose syndrome phenotype.. Am J Med Genet. 2011;155A:1379-83", "R Cleaver, J Berg, E Craft, A Foster, RJ Gibbons, E Hobson, K Lachlan, S Naik, JR Sampson, S Sharif, S Smithson, MJ Parker, K Tatton-Brown. Refining the Primrose syndrome phenotype: a study of five patients with ZBTB20 de novo variants and a review of the literature.. Am J Med Genet A. 2019;179:344-9", "P Dalal, ND Leslie, NM Lindor, DL Giulbert, AJ Espay. Motor tics, stereotypies, and self-flagellation in Primrose syndrome.. 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Am J Med Genet A. 2016;170:1626-9", "D Melis, D Carvalho, T Barbaro-Dieber, AJ Espay, MJ Gambello, B Gener, E Gerkes, MM Hitzert, HB Hove, S Jansen, PE Jira, K Lachlan, LA Menke, V Narayanan, D Ortiz, E Overwater, R Posmyk, K Ramsey, A Rossi, RL Sandoval, C Stumpel, KE Stuurman, V Cordeddu, P Turnpenny, P Strisciuglio, M Tartaglia, S Unger, T Waters, C Turnbull, RC Hennekam. Primrose syndrome: characterization of the phenotype in 42 patients.. Clin Genet. 2020;97:890-901", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates, and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "MB Rasmussen, JV Nielsen, CM Lourenço, JB Melo, C Halgren, CV Geraldi, W Marques, GR Rodrigues, M Thomassen, M Bak, C Hansen, SI Ferreira, M Venâncio, KF Henriksen, A Lind-Thomsen, IM Carreira, NA Jensen, N Tommerup. Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes.. J Med Genet. 2014;51:605-13", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "A Shuvarikov, IM Campbell, P Dittwald, NJ Neill, MG Bialer, C Moore, PG Wheeler, SE Wallace, MC Hannibal, MF Murray, MA Giovanni, D Terespolsky, S Sodhi, M Cassina, D Viskochil, B Moghaddam, K Herman, CW Brown, CR Beck, A Gambin, SW Cheung, A Patel, AN Lamb, LG Shaffer, JW Ellison, JB Ravnan, P Stankiewicz, JA Rosenfeld. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays.. 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Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders.. Eur J Hum Genet. 2013;21:620-5", "K Yamamoto-Shimojima, T Imaizumi, H Akagawa, H Kanno, T Yamamoto. Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation.. Am J Med Genet A. 2020;182:521-6", "H Zhang, D Cao, L Zhou, Y Zhang, X Guo, H Li, Y Chen, BT Spear, JW Wu, Z Xie, WJ Zhang. ZBTB20 is a sequence-specific transcriptional repressor of alpha-fetoprotein gene.. Sci Rep. 2015;5:11979" ]	6/5/2021		17/6/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]

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